Publications by authors named "Ji-Hun Jang"

63 Publications

Simultaneous determination of fourteen components of Gumiganghwal-tang tablet in human plasma by UPLC-ESI-MS/MS and its application to pharmacokinetic study.

J Pharm Anal 2021 Aug 15;11(4):444-457. Epub 2020 Aug 15.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea.

Gumiganghwal-tang is a traditional herbal medicine widely used for its anti-inflammatory, analgesic, and antipyretic effects. However, the safety and efficacy of its active ingredients based on an in vivo pharmacokinetic (PK) study have yet been investigated. We have established a sensitive and accurate UPLC-ESI-MS/MS method and conducted a PK study on 14 constituents of Gumiganghwal-tang through human plasma analysis. Analytical conditions were optimized according to the physicochemical properties of the 14 compounds to facilitate efficient separation and eliminate overlap or interference between peaks. KINETEX-C and Inertsil-C columns were used as UPLC stationary phases, and acetonitrile and aqueous formic acid were used as mobile phases. All the analytes were quantified with a triple quadrupole mass spectrometer using electrospray ionization in multiple reaction monitoring mode. The chromatograms of 14 bioactive compounds showed excellent elution and sensitivity, and each peak was selectively separated and quantified without interference with each other or impurities. The established analytical method was based on international guidelines and was successfully used to perform PK studies of 14 herbal ingredients in humans after oral administration with Gumiganghwal-tang tablets. The oral absorption of most active components of Gumiganghwal-tang was relatively rapid and remained considerably long in the body to be quantified in plasma up to 48 h after administration.
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http://dx.doi.org/10.1016/j.jpha.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424372PMC
August 2021

Toxicokinetics of di-isodecyl phthalate and its major metabolites in rats through the application of a developed and validated UHPLC-ESI-MS/MS method.

Arch Toxicol 2021 Nov 6;95(11):3515-3537. Epub 2021 Sep 6.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea.

Di-isodecyl phthalate (DiDP) is a high-molecular-weight phthalate that is mainly used as a plasticizer for plastics. Therefore, exposure to DiDP in the environment has become common with the increasing use of plastics around the world. Environmental regulations and scientific risk management for DiDP, which can be associated with endocrine disruption and various metabolic diseases, are urgently needed. The purpose of this study was to provide useful reference material for future human DiDP risk assessments by conducting toxicokinetic studies on DiDP. Rats were given 100 mg/kg of DiDP orally or intravenously, and plasma, urine, feces, and various tissues were sampled at preset times. DiDP and its major metabolites mono-isodecyl-phthalate (MiDP), mono-hydroxy-isodecyl-phthalate (MHiDP), mono-carboxy-isononyl-phthalate (MCiNP), and mono-oxo-isodecyl-phthalate (MOiDP) were simultaneously quantified from collected biological samples through the application of a newly developed and verified ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometer (UHPLC-ESI-MS/MS) method. Based on the quantitative results for each analyte, toxicokinetic analyses were performed. DiDP was rapidly and extensively metabolized to MiDP, MHiDP, MCiNP, and MOiDP. The major metabolite excreted in the urine was MCiNP, suggesting that it could be a useful biomarker. The conjugated forms of DiDP and its metabolites have been significantly quantified in the plasma, urine, and feces. DiDP and its major metabolites were also distributed in various tissues in significant quantities. The toxicokinetic properties of DiDP, which have not been clearly reported previously, were identified through this study. This report will serve as a useful reference for future DiDP environmental regulation and scientific human risk assessment studies.
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http://dx.doi.org/10.1007/s00204-021-03153-6DOI Listing
November 2021

Pharmacokinetic Comparison between Methotrexate-Loaded Nanoparticles and Nanoemulsions as Hard- and Soft-Type Nanoformulations: A Population Pharmacokinetic Modeling Approach.

Pharmaceutics 2021 Jul 9;13(7). Epub 2021 Jul 9.

College of Pharmacy, Chonnam National University, Gwangju 61186, Korea.

The purpose of this study was to identify and explore the differences in pharmacokinetics between different nanoformulations. This was done by comparing the pharmacokinetics of methotrexate-loaded nanoparticles [poly(lactic-co-glycolic acid); size of 163.70 ± 10.25 nm] and nanoemulsions (olive oil and Labrasol; size of 173.77 ± 5.76 nm), which represent hard- and soft-type nanoformulations, respectively. In addition, the population pharmacokinetic modeling approach as a useful tool for the comparison of pharmacokinetics between nanoformulations was newly proposed through this study. Significant pharmacokinetic differences were identified between nanoformulations through the new population pharmacokinetic modeling approach. As a result, the formulation type was explored as a significant covariate. The clearance and bioavailability of methotrexate-loaded nanoemulsions tended to decrease by 99% and increase by 19%, respectively, compared to those of the nanoparticles. The exploration of significant pharmacokinetic differences between drug formulations and their correlations presented in this study provide new perspectives on the development of nanoformulations.
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http://dx.doi.org/10.3390/pharmaceutics13071050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309067PMC
July 2021

Toxicokinetic studies of di-isobutyl phthalate focusing on the exploration of gender differences in rats.

Chemosphere 2022 Jan 28;286(Pt 1):131706. Epub 2021 Jul 28.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea. Electronic address:

Due to the use of di-isobutyl-phthalate (DiBP) in the production of soft-polyvinyl chloride articles, it is currently a hazardous substance prevalent in human daily life. However, reports on DiBP's toxicokinetics are still very scarce. And no studies have been reported on gender differences in DiBP toxicokinetics. Therefore, this study was conducted in accordance with these research needs. DiBP of 100 mg/kg has been exposed to male and female rats single or multiple times. DiBP and its major metabolite, mono-isobutyl-phthalate (MiBP), were quantified from various biological samples obtained from rats administered with DiBP. Based on these results, several toxicokinetic parameters were estimated. Toxicokinetic results between genders were compared, and from this, existence and extent of gender differences in DiBP's toxicokinetics were explored. Investigation of presence and extent of subacute toxicity in male and female rats following multiple exposures to DiBP were also conducted. This study provided comprehensive information on DiBP toxicity and gender differences that have not been reported in detail. Results of these studies imply that subacute toxicity in liver, kidney, lung, and testis of rats at 100 mg/kg of DiBP is modest and that there is little difference in toxicokinetics between genders. And in both male and female rats, the metabolism of DiBP (to MiBP) was significant, and excretion of MiBP into urine was a major indicator of DiBP exposure.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131706DOI Listing
January 2022

Pharmacokinetic comparison with different assays for simultaneous determination of cefprozil diastereomers in human plasma.

J Pharm Anal 2021 Jun 5;11(3):351-363. Epub 2020 Jul 5.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea.

The purpose of this study was to compare pharmacokinetic (PK) parameters obtained using two newly developed assays, HPLC-UV and UPLC-ESI-MS/MS. Selection of assay and results obtained therefrom are very important in PK studies and can have a major impact on the PK-based clinical dose and usage settings. For this study, we developed two new methods that are most commonly used in biosample analysis and focused on PK parameters obtained from them. By HPLC-UV equipped with a Luna-C column using UV detector, cefprozil diastereomers were separated using water containing 2% () acetic acid and acetonitrile as a mobile phase. By UPLC-ESI-MS/MS equipped with a HALO-Ccolumn, cefprozil diastereomers were separated using 0.5% ( aqueous formic acid containing 5 mM ammonium-formate buffer and methanol as a mobile phase. Chromatograms showed high resolution, sensitivity, and selectivity without interference by plasma constituents. Both intra- and inter-day precisions (CV, %) were within 8.88% for HPLC-UV and UPLC-ESI-MS/MS. Accuracy of both methods was 95.67%-107.50%. These two analytical methods satisfied the criteria of international guidance and could be successfully applied to PK study. Comparison of PK parameters between two assays confirmed that there is a difference in the predicted minimum plasma concentrations at steady state, which may affect clinical dose and usage settings. Furthermore, we confirmed possible correlation between PK parameters and various biochemical parameters after oral administration of 1000 mg cefprozil to humans.
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http://dx.doi.org/10.1016/j.jpha.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264462PMC
June 2021

Population Pharmacokinetic Analysis of Cefaclor in Healthy Korean Subjects.

Pharmaceutics 2021 May 19;13(5). Epub 2021 May 19.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Korea.

The aims of this study were: (1) to perform population pharmacokinetic analysis of cefaclor in healthy Korean subjects, and (2) to investigate possible effects of various covariates on pharmacokinetic parameters of cefaclor. Although cefaclor belongs to the cephalosporin family antibiotic that has been used in various indications, there have been very few population studies on factors affecting its pharmacokinetics. Therefore, this study is very important in that effective therapy could be possible through a population pharmacokinetic study that explores effective covariates related to cefaclor pharmacokinetic diversity between individuals. Pharmacokinetic results of 48 subjects with physical and biochemical parameters were used for the population pharmacokinetic analysis of cefaclor. A one-compartment with lag-time and first-order absorption/elimination was constructed as a base model and extended to include covariates that could influence between-subject variability. Creatinine clearance and body weight significantly influenced systemic clearance and distribution volume of cefaclor. Cefaclor's final population pharmacokinetic model was validated and some of the population's pharmacokinetic diversity could be explained. Herein, we first describe the establishment of a population pharmacokinetic model of cefaclor for healthy Koreans that might be useful for customizing cefaclor or exploring additional covariates in patients.
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http://dx.doi.org/10.3390/pharmaceutics13050754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160640PMC
May 2021

Oral delivery of topotecan in polymeric nanoparticles: Lymphatic distribution and pharmacokinetics.

J Control Release 2021 07 17;335:86-102. Epub 2021 May 17.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea. Electronic address:

There have been many attempts to formulate a variety of drugs in nano-size formulations. However, biodistribution characteristics of these formulated drugs remain unclear. Information about the pharmacokinetics and distributions of these formulations is essential for future practical use and advanced formulation development. Topotecan is a useful agent for treating a variety of cancers. It exhibits anti-cancer activity by inhibiting topoisomerase. However, oral bioavailability of topotecan was not satisfactory in previous studies. Reversible hydrolysis of its active site according to pH environment was a major limitation in terms of treatment. To improve the bioavailability and retention of topotecan in target organs (such as lung and brain) and increase its delivery to the lymphatic system as a major pathway for cancer metastasis, this study was conducted on topotecan-loaded nanoparticles using poly(lactic-co-glycolic acid) (PLGA). These nanoparticles were prepared by double emulsion solvent evaporation. Formulated topotecan-loaded PLGA nanoparticles were subjected to several in vitro tests to determine various physicochemical properties such as size, zeta potential, encapsulation efficiency, morphology, and release profile. These nanoparticles were also subjected to in vivo studies using rats. Based on in vivo results, pharmacokinetic properties, distribution in the body, and delivery efficiency of these formulated nanoparticles were confirmed. Topotecan-loaded PLGA nanoparticles showed a delayed release pattern in vitro. Their pharmacokinetic profiles and distributions in the body were clearly different from those of free topotecan hydrochloride. Results confirmed that topotecan encapsulated in the PLGA polymer was stable from hydrolysis and present in an active form for a longer time in the body. Biometric imaging revealed in vivo properties of topotecan-loaded PLGA nanoparticles for qualitative confirmation. And oral delivery of topotecan in polymeric nanoparticles to lymph and various body tissues has been identified. Findings of this study indicate that topotecan formulated into nanoparticles (using PLGA) has a better pharmacokinetic profile and a better delivery to lymphoid tissues, lung, and brain than free topotecan hydrochloride, suggesting that these topotecan-loaded PLGA nanoparticles might provide better therapeutic results.
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http://dx.doi.org/10.1016/j.jconrel.2021.05.017DOI Listing
July 2021

Pharmacokinetic Changes According to Single or Multiple Oral Administrations of Socheongryong-Tang to Rats: Presented as a Typical Example of Changes in the Pharmacokinetics Following Multiple Exposures to Herbal Medicines.

Pharmaceutics 2021 Apr 1;13(4). Epub 2021 Apr 1.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Korea.

The purpose of this study was to investigate the pharmacokinetic properties of ephedrine, paeoniflorin, and cinnamic acid after single or multiple doses of Socheongryong-tang (SCRT) were administered to rats, and to present an example of the pharmacokinetic changes following multiple doses of an herbal medicine. SCRT is a traditional herbal medicine that has been used clinically for a long time, and its main ingredients include ephedrine, paeoniflorin, and cinnamic acid. However, studies on the pharmacokinetic properties of SCRT are insufficient, and particularly, no pharmacokinetic information has been reported for multiple doses. In this study, SCRT was administered orally to rats once or multiple times, and plasma sampled at different times was quantitatively analyzed for ephedrine, paeoniflorin, and cinnamic acid using ultra-high-performance liquid chromatography-tandem mass spectrometry. There was a difference between the pharmacokinetic parameter values of each component (especially in paeoniflorin and cinnamic acid) obtained after single or multiple doses of SCRT. The actual observed values of each component obtained after multiple doses of SCRT were clearly different from the predicted results of multiple-dose simulations based on the pharmacokinetic profiles obtained after a single dose. The results confirmed that the plasma concentrations and, thus, exposures to paeoniflorin and cinnamic acid were significantly increased when SCRT was administered multiple times, whereas that of ephedrine was not. The results of this study are expected to provide useful pharmacokinetic data for the safety and efficacy evaluation of SCRT in the future and demonstrate the necessity of pharmacokinetic comparison studies according to single or multiple oral administrations of herbal medicines.
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http://dx.doi.org/10.3390/pharmaceutics13040478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103508PMC
April 2021

Human risk assessment of di-isobutyl phthalate through the application of a developed physiologically based pharmacokinetic model of di-isobutyl phthalate and its major metabolite mono-isobutyl phthalate.

Arch Toxicol 2021 07 27;95(7):2385-2402. Epub 2021 Apr 27.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea.

Di-isobutyl phthalate (DiBP) is a substance used in the production of objects frequently used in human life. Mono-isobutyl phthalate (MiBP), a major in vivo metabolite of DiBP, is a biomarker for DiBP exposure assessment. Therefore, risk assessment studies on DiBP and MiBP, which have not yet been reported in detail, are needed. The aim of this study was to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for DiBP and MiBP in rats and extend this to human risk assessment based on human exposure. Pharmacokinetic studies were performed in male rats following the administration of 5-100 mg/kg DiBP, and these results were used for the development and validation of the PBPK model. In addition, the previous pharmacokinetic results in female rats following DiBP administration and the pharmacokinetic results in both males and females according to multiple exposures to DiBP were used to develop and validate the PBPK model. The metabolism of DiBP to MiBP in the body was very significant and rapid, and the biodistribution of MiBP was broad and major. Furthermore, the amount of MiBP in the body showed a correlation with DiBP exposure, and from this, a PBPK model was developed to evaluate the external exposure of DiBP from the internal exposure of MiBP. The predicted rat plasma, urine, fecal, and tissue concentrations using the developed PBPK model fitted well with the observed values. The established PBPK model for rats was extrapolated to a human PBPK model of DiBP and MiBP based on human physiological parameters and allometric scaling. The reference dose of 0.512 mg/kg/day of DiBP and external doses of 6.14-280.90 μg/kg/day DiBP for human risk assessment were estimated using Korean biomonitoring values. Valuable insight and approaches to assessing human health risks associated with DiBP exposure were provided by this study.
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http://dx.doi.org/10.1007/s00204-021-03057-5DOI Listing
July 2021

The complete chloroplast genome of a traditional medicinal plant.

Mitochondrial DNA B Resour 2021 Apr 5;6(4):1332-1334. Epub 2021 Apr 5.

Tradition Korean Medicine Research Team, National Development Institute of Korean Medicine, Jangheung, South Korea.

is a rare native plant attributed with analgesic, gallbladder-supportive, and other functions in China and the Republic of Korea. However, the complete chloroplast genome sequence of the native plant has not been determined. In this study, we sequenced the complete chloroplast genome sequence, and examined the molecular phylogeny and genetic information of . The total chloroplast genome of was 154,871 bp in length with a large single-copy region (85,089 bp), small single-copy region (17,714 bp), and pair of inverted repeats regions (26,034 bp). The chloroplast genome encoded a total of 176 genes, including 131 protein-coding genes, 37 tRNA genes, and eight rRNA genes. The phylogenetic tree indicated that was the most closely related to
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http://dx.doi.org/10.1080/23802359.2021.1907802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023639PMC
April 2021

The complete chloroplast genome of a traditional medicinal plant.

Mitochondrial DNA B Resour 2021 Mar 15;6(3):870-871. Epub 2021 Mar 15.

National Development Institute of Korean Medicine, Jangheung, South Korea.

is a rare native plant attributed with analgesic, gallbladder-supportive, and other functions in China and the Republic of Korea. However, the complete chloroplast genome sequence of the native plant has not been determined. In this study, we sequenced the complete chloroplast genome sequence, and examined the molecular phylogeny and genetic information of . The total chloroplast genome of was 154,871 bp in length with a large single-copy region (85,089 bp), small single-copy region (17,714 bp), and pair of inverted repeats regions (26,034 bp). The chloroplast genome encoded a total of 176 genes, including 131 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. The phylogenetic tree indicated that was most closely related to
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http://dx.doi.org/10.1080/23802359.2021.1886006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971250PMC
March 2021

Characteristics and phylogenetic analysis of the complete chloroplast genome of (Paeoniaceae).

Mitochondrial DNA B Resour 2021 Mar 11;6(3):734-735. Epub 2021 Mar 11.

National Development Institute of Korean Medicine, Jangheung-gun, South Korea.

, distributed throughout Asia, is a traditional medicinal herb in Korea, with many potential beneficial effects including pain-relieving, anti-inflammatory, and anti-cancer activities. Despite its high pharmacological value, the genetic information on remains limited. In this study, the chloroplast genome of was sequenced using next-generation sequencing (NGS) technology and genome and phylogeny were analyzed using multiple tools. The chloroplast genome of was 152,731 bp in length with an inverted repeat region of 26,656 bp, including a large single-copy region of 84,389 bp and a small single copy region of 17,030 bp. The chloroplast genome included 113 genes comprising 80 protein-coding genes, 27 tRNA, and 5 rRNA genes. Phylogenetic analysis indicated that and share a close evolutionary relationship.
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http://dx.doi.org/10.1080/23802359.2020.1860718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954510PMC
March 2021

In vivo and in vitro studies of Banhahoobak-tang tablets using UPLC-ESI-MS/MS with polarity switching.

J Pharm Biomed Anal 2021 Mar 28;196:113931. Epub 2021 Jan 28.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea. Electronic address:

Banhahoobak-tang is the most prescribed herbal drug in East Asia when individuals experience sudden symptoms such as sore throat or neurological symptoms. The low toxicity and high in-vivo safety of this herbal medicine has made it more attractive to patients, and it has recently been formulated as tablets. In addition, Banhahoobak-tang tablets are registered as health insurance drugs in South Korea, and clinical prescriptions and demand are increasing. However, there are very few clinical trial data as well as very little accurate content analysis and results for Banhahoobak-tang tablets. The purpose of this study was to perform in-vitro and in-vivo studies on Banhahoobak-tang tablets, including content analysis, pharmacokinetics in humans, and plasma protein binding. For this study, a UPLC-ESI-MS/MS method with polarity switching was developed for simultaneous analysis of 18 components of Banhahoobak-tang. To separate the analytes, a C reverse-phase column was used as the stationary phase, 0.1 % aqueous formic acid and acetonitrile as the mobile phase, and ionization and multiple reaction monitoring for quantification. The developed method was able to isolate and quantify the 18 components with good sensitivity and selectivity and was fully validated according to international analytical standards. Stability tests were also conducted on the analytes. Finally, the method was applied to in-vitro and in-vivo studies of Banhahoobak-tang tablets, and the tablet components were 52.49 ng/g to 91.00 μg/g on average. The detected components showed rapid oral absorption in humans as well as high plasma protein binding ratio overall. These results and methods can be useful not only for effectiveness and safety evaluation but also for quality control of Banhahoobak-tang tablets.
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http://dx.doi.org/10.1016/j.jpba.2021.113931DOI Listing
March 2021

Characterization of the complete chloroplast genome of (Asparagaceae: Nolinoideae) isolated in Korea.

Mitochondrial DNA B Resour 2020 Jul 20;5(3):2874-2875. Epub 2020 Jul 20.

National Development Institute of Korean Medicine, Jangheung-gun, South Korea.

is used as an important medicinal plant for fatigue, cough, and inflammation in South Korea. Here, we report the complete chloroplast genome of . The total genome size of the chloroplast is 157,076 bp with a large single-copy region (LSC: 85,374 bp), a small single-copy region (SSC: 18,748 bp), and inverted repeat regions (IRa and IRb: 26,477 bp). The GC content of the chloroplast was 37.6%. The cp genome encoded a set of 129 genes, including 83 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. The phylogenetic tree analysis indicated that is closely related to .
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http://dx.doi.org/10.1080/23802359.2020.1787898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782188PMC
July 2020

Splenic infarction and infectious diseases in Korea.

BMC Infect Dis 2020 Dec 2;20(1):915. Epub 2020 Dec 2.

Division of Infectious Diseases, Department of Internal Medicine, Inha University School of Medicine, Incheon, 22212, Republic of Korea.

Background: The spleen contains immune cells and exhibits a pattern of infarction different from other organs; as such, splenic infarction (SI) may provide important clues to infection. However, the nature of the relationship between SI and infectious disease(s) is not well understood. Accordingly, this retrospective study investigated the relationship between SI and infection.

Methods: Hospital records of patients with SI, who visited Inha University Hospital (Incheon, Republic of Korea) between January 2008 and December 2018, were reviewed. Patient data regarding clinical presentation, causative pathogens, risk factors, and radiological findings were collected and analyzed.

Results: Of 353 patients with SI, 101 with infectious conditions were enrolled in this study, and their data were analyzed to identify associations between SI and infection. Ten patients were diagnosed with infective endocarditis (IE), and 26 exhibited bacteremia without IE. Twenty-seven patients experienced systemic infection due to miscellaneous causes (negative result on conventional automated blood culture), including the following intracellular organisms: parasites (malaria [n = 12], babesiosis [n = 1]); bacteria (scrub typhus [n = 5]); viruses (Epstein-Barr [n = 1], cytomegalovirus [n = 1]); and unidentified pathogen[s] (n = 7). Splenomegaly was more common among patients with miscellaneous systemic infection; infarction involving other organs was rare. Thirty-eight patients had localized infections (e.g., respiratory, intra-abdominal, or skin and soft tissue infection), and most (35 of 38) had other risk factors for SI.

Conclusions: In this study, various infectious conditions were found to be associated with SI, and intracellular organisms were the most common causative pathogens. Further studies are needed to examine other possible etiologies and the underlying pathophysiological mechanisms.
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http://dx.doi.org/10.1186/s12879-020-05645-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708890PMC
December 2020

Simultaneous determination of asarinin, β-eudesmol, and wogonin in rats using ultraperformance liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic studies following administration of standards and Gumiganghwal-tang.

Biomed Chromatogr 2021 Apr 30;35(4):e5021. Epub 2020 Nov 30.

College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea.

Asarinin, β-eudesmol, and wogonin have common antiangiogenic activities and have the potential for use in chemotherapy. Besides, they are multivalent substances that are combined in various herbal medicines. The purpose of this study was to develop a method for simultaneous analysis of asarinin, β-eudesmol, and wogonin, which are representative pharmacological components of Asarum heterotropoides, Atractylodes lancea, and Scutellaria baicalensis, respectively, in rat biosamples using ultraperformance liquid chromatography-tandem mass spectrometry. The three components were separated using 5 mm aqueous ammonium acetate containing 0.1% formic acid and acetonitrile as a mobile phase, equipped with a KINETEX core-shell C column. The analysis was quantitated on a triple-quadrupole mass-spectrometer employing electrospray ionization, and operated in the multiple reaction monitoring mode. The chromatograms showed high resolution, sensitivity, and selectivity with no interference with plasma, urine, and feces constituents. The developed analytical method satisfied international guidance criteria and could be successfully applied to the pharmacokinetic (PK) studies evaluating oral bioavailability of asarinin, β-eudesmol, and wogonin after oral and intravenous administration and their urinary and fecal excretion ratios after oral administration to rats. Furthermore, the analysis was extended to PK studies following oral administration of Gumiganghwal-tang. This study was the first simultaneous analysis of the aforesaid three constituents in rat plasma, urine, and feces that also determined their PK parameters.
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http://dx.doi.org/10.1002/bmc.5021DOI Listing
April 2021

Enhanced Lymphatic Delivery of Methotrexate Using W/O/W Nanoemulsion: In Vitro Characterization and Pharmacokinetic Study.

Pharmaceutics 2020 Oct 16;12(10). Epub 2020 Oct 16.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-Gu, Gwangju 61186, Korea.

Methotrexate, which is widely used in the treatment of cancer and immune-related diseases, has limitations in use because of its low bioavailability, short half-life, and tissue toxicity. Thus, in this study, a nano-sized water-in-oil-in-water (W/O/W) double emulsion containing methotrexate was prepared to enhance its lymphatic delivery and bioavailability. Based on the results from solubility testing and a pseudo-ternary diagram study, olive oil as the oil, Labrasol as a surfactant, and ethanol as a co-surfactant, were selected as the optimal components for the nanoemulsion. The prepared nanoemulsion was evaluated for size, zeta potential, encapsulation efficiency, pH, morphology, and in vitro release profiles. Furthermore, pharmacokinetics and lymphatic targeting efficiency were assessed after oral and intravenous administration of methotrexate-loaded nanoemulsion to rats. Mean droplet size, zeta potential, encapsulation efficiency, and pH of formulated nanoemulsion were 173.77 ± 5.76 nm, -35.63 ± 0.78 mV, 90.37 ± 0.96%, and 4.07 ± 0.03, respectively. In vitro release profile of the formulation indicated a higher dissolution and faster rate of methotrexate than that of free drug. The prepared nanoemulsion showed significant increases in maximum plasma concentration, area under the plasma concentration-time curve, half-life, oral bioavailability, and lymphatic targeting efficiency in both oral and intravenous administration. Therefore, our research proposes a methotrexate-loaded nanoemulsion as a good candidate for enhancing targeted lymphatic delivery of methotrexate.
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http://dx.doi.org/10.3390/pharmaceutics12100978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589886PMC
October 2020

Toxicokinetics of diisobutyl phthalate and its major metabolite, monoisobutyl phthalate, in rats: UPLC-ESI-MS/MS method development for the simultaneous determination of diisobutyl phthalate and its major metabolite, monoisobutyl phthalate, in rat plasma, urine, feces, and 11 various tissues collected from a toxicokinetic study.

Food Chem Toxicol 2020 Nov 11;145:111747. Epub 2020 Sep 11.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea. Electronic address:

The aim of this study was to explore the toxicokinetics of diisobutyl-phthalate (DiBP) and its major metabolite, monoisobutyl-phthalate (MiBP), by developing a UPLC-ESI-MS/MS method for simultaneously measuring DiBP and MiBP in rat plasma, urine, feces, and 11 different tissues. For the experiment, 0.1% (v/v) aqueous formic acid and acetonitrile mobile phase by gradient elution at a flow rate of 0.3 mL/min, equipped with a KINETEX core-shell C-column (50 × 2.1 mm, 1.7 μm), was used to completely separate analytes. The mass transitions were m/z 279.1 → 149.0 for DiBP, 221.0 → 77.0 for MiBP, and 283.2 → 153.0 for DiBP-d as an internal standard. The developed assay had lower limits of quantification of 0.01 ng/mL for DiBP and 0.1 ng/mL for MiBP at all biological matrices. Toxicokinetics of DiBP were characterized by extensive distribution, short half-life, and high clearance. DiBP was rapidly metabolized to MiBP, with MiBP levels consistently exceeding the DiBP levels. Distribution of MiBP to tissues was considerable. The developed analytical method satisfied international criteria and was successfully applied to toxicokinetic studies after oral and intravenous administration of DiBP to rats. Findings of this study may be useful for evaluating the external exposure and toxic potential of DiBP and its metabolite in risk assessment.
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http://dx.doi.org/10.1016/j.fct.2020.111747DOI Listing
November 2020

Ivabradine-Induced Torsade de Pointes in Patients with Heart Failure Reduced Ejection Fraction.

Int Heart J 2020 Sep 12;61(5):1044-1048. Epub 2020 Sep 12.

Department of Cardiology, Inha University Hospital Cardiovascular Center.

Ivabradine is a selective inhibitor of the sinoatrial node "funny" current, prolonging the slow diastolic depolarization. As it has the ability to block the heart rate selectively, it is more effective at a faster heart rate. It is recommended for the treatment of heart failure reduced ejection fraction in the presence of beta-blocker therapy for the further reduction of the heart rate. However, previous reports have shown the association of Torsade de pointes (TdP) with concurrent use of ivabradine and drugs resulting in QT prolongation or blockage of the metabolic breakdown of ivabradine. In this article, we report two cases of patients with heart failure reduced ejection fraction who developed TdP after ivabradine use. Our report highlights the need to exercise caution with the administration of ivabradine in the presence of a reduced repolarization reserve, such as QT prolongation or metabolic insufficiency.
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http://dx.doi.org/10.1536/ihj.20-073DOI Listing
September 2020

Simultaneous determination of three iridoid glycosides of Rehmannia glutinosa in rat biological samples using a validated hydrophilic interaction-UHPLC-MS/MS method in pharmacokinetic and in vitro studies.

J Sep Sci 2020 Nov 28;43(22):4148-4161. Epub 2020 Sep 28.

College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea.

The purpose of this study was to develop a method for simultaneous analysis of aucubin, catalpol, and geniposide, which are representative iridoid glycoside constituents of Rehmannia glutinosa, in rat plasma, urine, and feces using hydrophilic interaction ultra high-performance liquid chromatography with tandem mass spectrometry. The three components were separated using 10 mmol/L aqueous ammonium formate containing 0.01% (v/v) formic acid and acetonitrile as a mobile phase by gradient elution at a flow rate of 0.2 mL/min, equipped with a Kinetex HILIC column (50 × 2.1 mm, 2.6 μm). Quantitation of this analysis was performed on a triple quadrupole mass spectrometer employing electrospray ionization and operated in multiple reaction monitoring mode. The chromatograms showed high resolution, sensitivity, and selectivity with no interference with plasma constituents. In all three iridoid glycosides, both the intra- and interbatch precisions (coefficient of variation %) were less than 4.81%. The accuracy was 96.56-103.55% for aucubin, 95.23-106.21% for catalpol, and 94.50-104.16% for geniposide. The developed analytical method satisfied the criteria of international guidance and was successfully applied to pharmacokinetic studies including oral bioavailability of aucubin, catalpol, and geniposide, and their urinary and fecal excretion ratios after oral or intravenous administration to rats. The new method was also applied to measure plasma protein binding ratios in vitro.
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http://dx.doi.org/10.1002/jssc.202000809DOI Listing
November 2020

Pharmacokinetic Comparison of Three Different Administration Routes for Topotecan Hydrochloride in Rats.

Pharmaceuticals (Basel) 2020 Sep 2;13(9). Epub 2020 Sep 2.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju 61186, Korea.

Topotecan is actively used in clinic, with its primary use being in treatment of various types of cancer. The approved administration routes are oral and intravenous. The purpose of this study was to investigate and identify pharmacokinetic profiles of different administration routes. We conducted pharmacokinetic studies on three different routes of administration in rats. Five rats in each group received a single dose of 4 mg/kg of topotecan hydrochloride intravenously, orally, or subcutaneously, and the concentrations of lactone and total forms of the drug in plasma, urine, and feces were quantified. Various pharmacokinetic parameters were compared statistically. Plasma concentrations of both the lactone and total forms at elimination phase following subcutaneous administration, were two times higher than was seen with oral administration and 10 times higher than with intravenous administration. Subcutaneous administration of topotecan showed pharmacokinetic profiles similar to sustained release. In addition, subcutaneous administration showed bioavailability from 88.05% (for lactone form) to 99.75% (for total form), and these values were four-five times greater than those of oral administration. The results of this non-clinical study will not only provide greater understanding of the in vivo pharmacokinetics of topotecan, but also be useful for development of additional formulations and/or administration routes.
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http://dx.doi.org/10.3390/ph13090231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559546PMC
September 2020

Mechanical and Pharmacological Revascularization Strategies for Prevention of Microvascular Dysfunction in ST-Segment Elevation Myocardial Infarction: Analysis from Index of Microcirculatory Resistance Registry Data.

J Interv Cardiol 2020 9;2020:5036396. Epub 2020 Jul 9.

Division of Cardiology, Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea.

Objectives: We aimed to identify mechanical and pharmacological revascularization strategies correlated with the index of microcirculatory resistance (IMR) in ST-elevation myocardial infarction (STEMI) patients.

Background: Microvascular dysfunction (MVD) after STEMI is correlated with infarct size and poor long-term prognosis, and the IMR is a useful analytical method for the quantitative assessment of MVD. However, therapeutic strategies that can reliably reduce MVD remain uncertain.

Methods: Patients with STEMI who underwent primary percutaneous coronary intervention (PCI) were enrolled. The IMR was measured with a pressure sensor/thermistor-tipped guidewire immediately after primary PCI. High IMR was defined as values ≥66 percentile of IMR in enrolled patients (IMR > 30.9 IU).

Results: A total of 160 STEMI patients were analyzed (high IMR = 54 patients). Clinical factors for Killip class (=0.006), delayed hospitalization from symptom onset (=0.004), peak troponin-I level (=0.042), and multivessel disease (=0.003) were associated with high IMR. Achieving final thrombolysis in myocardial infarction myocardial perfusion grade 3 tended to be associated with low IMR (=0.119), whereas the presence of distal embolization was significantly associated with high IMR (=0.034). In terms of therapeutic strategies that involved adjusting clinical and angiographic factors associated with IMR, preloading of third-generation P2Y12 inhibitors correlated with reducing IMR value ( = -10.30, < 0.001). Mechanical therapeutic strategies including stent diameter/length, preballoon dilatation, direct stenting, and thrombectomy were not associated with low IMR value (all > 0.05), and postballoon dilatation was associated with high IMR ( = 8.30, =0.020).

Conclusions: In our study, mechanical strategies were suboptimal in achieving myocardial salvage. Preloading of third-generation P2Y12 inhibitors revealed decreased IMR value, indicative of MVD prevention.
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http://dx.doi.org/10.1155/2020/5036396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368229PMC
November 2020

An analysis of vascular properties using pulse wave analysis in patients with vasovagal syncope.

Clin Cardiol 2020 Jul 18;43(7):781-788. Epub 2020 Jun 18.

Department of Cardiology, Inha University Hospital Cardiovascular Center, Incheon, Republic of Korea.

Background: Vasovagal syncope (VVS) is a common cause of recurrent syncope. Nevertheless, the exact hemodynamic mechanism has not been elucidated. Pulse wave analysis (PWA) is widely used to evaluate vascular properties, as it reflects the condition of the entire arterial system.

Hypothesis: Cardiovascular autonomic modulation may influence the hemodynamic mechanism and result in different vascular properties between VVS patients and healthy individuals.

Methods: We enrolled consecutive patients diagnosed with VVS on head-up tilt testing from January 2014 to August 2019. Healthy subjects were enrolled as the control group. We performed PWA on all participants. Using propensity score matching, we assembled a study population with similar baseline characteristics and compared hemodynamic parameters.

Results: A total of 111 VVS patients (43 ± 18 years, 72 females) and 475 healthy control subjects (48 ± 13 years, 192 females) were enrolled. Compared to the healthy control subjects, the VVS patients had a higher augmentation index (AIx) adjusted to a heart rate of 75 beats per minute ([email protected], 20.5 ± 13.1% vs 16.7 ± 11.9%, P = .003). After 1:1 matched comparison (111 matched control), VVS patients consistently showed higher [email protected] (20.5 ± 13.1% vs 16.7 ± 12.9%, P = .02) than the matched control group. According to age distribution, VVS patients showed significantly higher [email protected] (10.6 ± 11.7% vs 2.5 ± 11.1%, P = .01) in a young age (15-33 years) group.

Conclusions: VVS patients had greater arterial stiffness than healthy subjects. This is one of the plausible mechanisms of the pathophysiology of VVS.
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http://dx.doi.org/10.1002/clc.23380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368349PMC
July 2020

A 13-week repeated oral dose toxicity evaluation and a 4-week recovery evaluation of the Sam So Eum (SSE) in male and female rats.

J Ethnopharmacol 2020 Oct 22;260:112988. Epub 2020 May 22.

Department of Traditional Korean Medicine Resource Development, National Development Institute of Korean Medicine, Jangheung-gun, 59338, South Korea; College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, South Korea. Electronic address:

Ethnophamacological Relevance: Sam So Eum (SSE), used in traditional Korean medicine, has been prescribed for the treatment of various ailments including emesis, and fever for centuries. SSE is known by several different names (Shen Su Yin in traditional Chinese medicine; Jin So In traditional Japanese Kampo medicine). It is a mixture of medicinal plants including Panax ginseng C. A. Mey., Perilla frutescens (L.) Britton, and Peucedanum praeruptorum Dunn. Studies have revealed that SSE has many pharmacological effects including anti-inflammatory, anti-cancer, and anti-allergic properties, but its toxic effects have not been evaluated in vivo. Recently, the use of traditional medicinal herbs to treat various diseases has increased, owing to increased number of studies supporting their efficacy. However, safety evaluations for toxicity and other adverse effects have not been extensive. It is commonly considered that natural products extracted from traditional medicinal herbs are safer than synthetic drugs, but this lacks a scientific basis. Thus, in this study, we evaluated the toxicity of SSE in male and female rats.

Aim Of The Study: To evaluated the safety of SSE in male and female rats.

Materials And Methods: SSE was administered orally for 13 weeks at 1000, 2000, and 4000 mg kg·day, and then the rats were maintained for 4 weeks without SSE administration (recovery evaluation).

Results: We observed the animals for changes in clinical signs, including hematological parameters, and food consumption; serum chemistry profiling and urinalysis were also carried out. Creatinine levels in the serum were significantly increased following oral administration of SSE at 2000 and 4000 mg kg·day in male and female rats, but returned to the normal levels during the recovery period. In addition, SSE administration does not cause kidney and liver toxicity. Thus, we determined that the no-observed-adverse-effect level of SSE is 4000 mg kg·day. The no-observed-effect level of SSE was determined to be 1000 mg kg·day, because serum creatinine was increased by oral administration of SSE at 2000 and 4000 mg kg·day in male and female rats.

Conclusions: SSE administration does not cause toxicity at 4000 mg kg·day in male and female rats.
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http://dx.doi.org/10.1016/j.jep.2020.112988DOI Listing
October 2020

Population Pharmacokinetic Analysis of Tiropramide in Healthy Korean Subjects.

Pharmaceutics 2020 Apr 18;12(4). Epub 2020 Apr 18.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-Gu, Gwangju 61186, Korea.

The purpose of this study was to perform population pharmacokinetic (PPK) analysis of tiropramide in healthy Korean subjects, as well as to investigate the possible effects of various covariates on pharmacokinetic (PK) parameters of tiropramide. Although tiropramide is commonly used in digestive system-related diseases as an antispasmodic, PPK reporting and factors affecting PKs are not clearly reported. Thus, this study for healthy subjects is very significant because it could find new covariates in patients that had not been reported before or predict PPK for patients in the clinic by establishing PPK in healthy adults. By using Phoenix NLME, PK, demographic, and genetic data (collected to explain PK diversity of tiropramide in population) analyses were performed. As a basic model, a one-compartment with first-order absorption and lag-time was established and extended to include covariates that influenced the inter-subject variability. The total protein significantly influenced the distribution volume and systemic clearance of tiropramide, but genetic factors such as A (1236C>T, 2677G>T/A, and 3435C>T), (*1 and *10), (808G>T), and (1287G>C) genes did not show any significant association with PK parameters of tiropramide. The final PPK model of tiropramide was validated, and suggested that some of the PK diversity in the population could be explained. Herein, we first describe the establishment of the PPK model of tiropramide for healthy Korean subjects, which may be useful as a dosing algorithm for the diseased population.
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http://dx.doi.org/10.3390/pharmaceutics12040374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238185PMC
April 2020

Risk assessment for humans using physiologically based pharmacokinetic model of diethyl phthalate and its major metabolite, monoethyl phthalate.

Arch Toxicol 2020 07 17;94(7):2377-2400. Epub 2020 Apr 17.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 61186, Republic of Korea.

Diethyl phthalate (DEP) belongs to phthalates with short alkyl chains. It is a substance frequently used to make various products. Thus, humans are widely exposed to DEP from the surrounding environment such as food, soil, air, and water. As previously reported in many studies, DEP is an endocrine disruptor with reproductive toxicity. Monoethyl phthalate (MEP), a major metabolite of DEP in vivo, is a biomarker for DEP exposure assessment. It is also an endocrine disruptor with reproductive toxicity, similar to DEP. However, toxicokinetic studies on both MEP and DEP have not been reported in detail yet. Therefore, the objective of this study was to evaluate and develop physiologically based pharmacokinetic (PBPK) model for both DEP and MEP in rats and extend this to human risk assessment based on human exposure. This study was conducted in vivo after intravenous or oral administration of DEP into female (2 mg/kg dose) and male (0.1-10 mg/kg dose) rats. Biological samples consisted of urine, plasma, and 11 different tissues. These samples were analyzed using UPLC-ESI-MS/MS method. For DEP, the tissue to plasma partition coefficient was the highest in the kidney, followed by that in the liver. For MEP, the tissue to plasma partition coefficient was the highest in the liver. It was less than unity in all other tissues. Plasma, urine, and fecal samples were also obtained after IV administration of MEP (10 mg/kg dose) to male rats. All results were reflected in a model developed in this study, including in vivo conversion from DEP to MEP. Predicted concentrations of DEP and MEP in rat urine, plasma, and tissue samples using the developed PBPK model fitted well with observed values. We then extrapolated the PBPK model in rats to a human PBPK model of DEP and MEP based on human physiological parameters. Reference dose of 0.63 mg/kg/day (or 0.18 mg/kg/day) for DEP and external doses of 0.246 μg/kg/day (pregnant), 0.193 μg/kg/day (fetus), 1.005-1.253 μg/kg/day (adults), 0.356-0.376 μg/kg/day (adolescents), and 0.595-0.603 μg/kg/day (children) for DEP for human risk assessment were estimated using Korean biomonitoring values. Our study provides valuable insight into human health risk assessment regarding DEP exposure.
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http://dx.doi.org/10.1007/s00204-020-02748-9DOI Listing
July 2020

Simultaneous measurement of epinastine and its metabolite, 9,13b-dehydroepinastine, in human plasma by a newly developed ultra-performance liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic studies.

Biomed Chromatogr 2020 Sep 25;34(9):e4848. Epub 2020 Jun 25.

College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea.

Epinastine is an antiallergic drug with high selectivity for histamine receptors. It has been reported that 9,13b-dehydroepinastine is present as a metabolite in vivo in humans, but there was little information about their pharmacokinetics (PKs) in humans. Although several analytical methods have been reported for epinastine analysis in different matrices, none are available for its metabolite. Therefore, the purpose of this study was to develop an analytical method to simultaneously measure epinastine and its metabolite, 9,13b-dehydroepinastine, in human plasma samples using an ultra-performance liquid chromatography-tandem mass spectrometer. Analytes were separated on a C column. Quantification of this analysis was performed on a triple-quadrupole mass spectrometer. Chromatograms showed high sensitivity, selectivity, and resolution with no interference with plasma constituents. Calibration curves for both epinastine and 9,13b-dehydroepinastine in human plasma were 0.1-50 ng/ml and displayed excellent linearity with correlation coefficients (r ) >0.99. The developed analytical method satisfied the criteria of international guidance and was validated. The method could be successfully applied to pharmacokinetic studies of epinastine and, for the first time, the metabolite kinetics of epinastine to 9,13b-dehydroepinastine in humans after oral administration of 20 mg epinastine hydrochloride tablets. Our study is expected to be useful in future studies such as dosage settings and clinical pharmacotherapy.
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http://dx.doi.org/10.1002/bmc.4848DOI Listing
September 2020

Pharmacokinetic Comparison of Epinastine Using Developed Human Plasma Assays.

Molecules 2020 Jan 3;25(1). Epub 2020 Jan 3.

College of Pharmacy, Chonnam National University, 77 Yongbong-ro, Buk-Gu, Gwangju 61186, Korea.

The purpose of the study was to develop two new methods, HPLC-UV and UPLC-MS/MS, for quantifying epinastine in human plasma and to compare pharmacokinetic (PK) parameters obtained using them. Even in the same sample, there may be a difference in the quantitative value of drug depending on the assay, so that minor changes in PK parameter values may affect drug dose and usage settings. Therefore, selection and establishment of analytical methods are very important in PK studies of drugs, and a comparison of PK parameters according to analytical methods will be vital. For this study of PK parameter change, we newly developed two methods, HPLC-UV and UPLC-MS/MS, which are most commonly used to quantify epinastine concentrations in human plasma. All developed methods satisfied the international guidelines and criteria for successful application to PK study of 20 mg epinastine hydrochloride tablets after oral administration to twenty-six humans. A comparison of these two methods for in vivo analysis of epinastine was performed for the first time. This comparison study confirmed that different dose and usage settings might be possible based on PK parameters calculated using other analyses. Such changes in calculated PK parameters according to analytical methods would be crucial in the clinic.
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http://dx.doi.org/10.3390/molecules25010209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983027PMC
January 2020

Doxorubicin inhibits PD-L1 expression by enhancing TTP-mediated decay of PD-L1 mRNA in cancer cells.

Biochem Biophys Res Commun 2020 02 23;522(2):402-407. Epub 2019 Nov 23.

Meta-Inflammation Research Center, University of Ulsan, Ulsan, 680-749, South Korea. Electronic address:

Recent research revealed that doxorubicin (DOX) decreased expression of programmed death-ligand 1 (PD-L1) in cancer cells. However, the detailed mechanisms underlying this effect are not well established. Here, we demonstrate that doxorubicin down-regulates PD-L1 expression through induction of AU-rich element (ARE) binding protein tristetraprolin (TTP) in cancer cells. PD-L1 mRNA contain three AREs within its 3'UTR. Doxorubicin induced expression of TTP, increased TTP binding to the 3rd ARE of the PD-L1 3'UTR, and increased decay of PD-L1 mRNA. Inhibition of TTP abrogates the inhibitory effect of doxorubicin on PD-L1 expression. Our data suggest that TTP plays a key role in doxorubicin-mediated down-regulation of PD-L1 by enhancing degradation of PD-L1 mRNA in cancer cells.
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http://dx.doi.org/10.1016/j.bbrc.2019.11.106DOI Listing
February 2020

Tristetraprolin posttranscriptionally downregulates PFKFB3 in cancer cells.

Biochem Biophys Res Commun 2020 01 25;521(2):389-394. Epub 2019 Oct 25.

Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, South Korea. Electronic address:

The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases 3 (PFKFB3) catalyzes the first committed rate-limiting step of glycolysis and is upregulated in cancer cells. The mechanism of PFKFB3 expression upregulation in cancer cells has not been fully elucidated. The PFKFB3 3'-UTR is reported to contain AU-rich elements (AREs) that are important for regulating PFKFB3 mRNA stability. However, the mechanisms by which PFKFB3 mRNA stability is determined by its 3'-UTR are not well known. We demonstrated that tristetraprolin (TTP), an ARE-binding protein, has a critical function regulating PFKFB3 mRNA stability. Our results showed that PFKFB3 mRNA contains three AREs in the 3'-UTR. TTP bound to the 3rd ARE and enhanced the decay of PFKFB3 mRNA. Overexpression of TTP decreased PFKFB3 expression and ATP levels but increased GSH level in cancer cells. Overexpression of PFKFB3 cDNA without the 3'-UTR rescued ATP level and GSH level in TTP-overexpressing cells. Our results suggested that TTP post-transcriptionally downregulated PFKFB3 expression and that overexpression of TTP may contribute to suppression of glycolysis and energy production of cancer cells in part by downregulating PFKFB3 expression.
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http://dx.doi.org/10.1016/j.bbrc.2019.10.128DOI Listing
January 2020
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