Publications by authors named "Teruo Murakami"

61 Publications

Factors and dosage formulations affecting the solubility and bioavailability of P-glycoprotein substrate drugs.

Expert Opin Drug Metab Toxicol 2021 May 8;17(5):555-580. Epub 2021 Apr 8.

Bodor Laboratories, Miami, Florida, USA.

: Expression of P-glycoprotein (P-gp) increases toward the distal small intestine, implying that the duodenum is the preferential absorption site for P-gp substrate drugs. Oral bioavailability of poorly soluble P-gp substrate drugs is low and varied but increases with high-fat meals that supply lipoidal components and bile in the duodenum.: Absorption properties of P-gp substrate drugs along with factors and oral dosage formulations affecting their solubility and bioavailability were reviewed with PubMed literature searches. An overview is provided from the viewpoint of the 'spring-and-parachute approach' that generates supersaturation of poorly soluble P-gp substrate drugs.: The oral bioavailability of P-gp substrate drugs is difficult to predict because of their low solubility, preferential absorption sites, and overlapping substrate specificities with CYP3A4, along with the scattered intestinal P-gp expression/function. To attain high and steady oral bioavailability of poorly soluble P-gp substrate drugs, physicochemical modification of drugs to improve solubility, or oral dosage formulations that generate long-lasting supersaturation in the duodenum, is preferred. In particular, supersaturable lipid-based drug delivery systems that can increase passive diffusion and/or lymphatic absorption are effective and applicable to many poorly soluble P-gp substrate drugs.
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http://dx.doi.org/10.1080/17425255.2021.1902986DOI Listing
May 2021

Modulation of expression/function of intestinal P-glycoprotein under disease states.

Expert Opin Drug Metab Toxicol 2020 Jan 10;16(1):59-78. Epub 2019 Dec 10.

Bodor Laboratories, Miami, FL, USA.

: ATP-binding cassette (ABC) transporters, especially P-glycoprotein (P-gp), and various metabolic enzymes, in particular, CYP3A, expressed in the small intestine cooperatively limit the absorption of orally administered P-gp substrate drugs. The expression and/or function of intestinal P-gp, however, is easily modulated by various factors.: Through extensive literature searches primarily utilizing PubMed, the authors reviewed factors that may cause inter- or intra-individual variations of the pharmacokinetics of orally administered P-gp substrate drugs due to the modulation of intestinal P-gp expression/function. The information on P-gp modulating factors can help to develop safer and more reliable oral formulations and pharmacotherapy.: In clinical pharmacotherapy with orally administered P-gp substrate drugs, the pharmacological action may exhibit a large interindividual variation among patients. Factors modulating intestinal P-gp expression/function listed here include: circadian rhythm (or drug dosing time), drug-drug interactions, formulation/excipients (vehicle, nonionic surfactants), food/supplements, gene polymorphism, obesity, colorectal carcinomas, diarrhea, hepatic failure, inflammation, inflammatory bowel disease, ischemia/reperfusion, organ transplant, renal failure, and others. We will discuss the methods for reducing the effect of modulated intestinal P-gp function on the pharmacokinetics of orally administered P-gp substrate drugs to achieve safer and more reliable oral formulations and pharmacotherapy.
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http://dx.doi.org/10.1080/17425255.2020.1701653DOI Listing
January 2020

Study on the infusion-site adverse events and vascular distribution of epirubicin in chemotherapy with epirubicin and fosaprepitant.

Mol Clin Oncol 2019 Jul 24;11(1):43-49. Epub 2019 Apr 24.

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan.

In breast cancer patients on a fluorouracil-epirubicin (EPI)-cyclophosphamide (FEC) regimen and intravenous fosaprepitant (FAP) during chemotherapy, infusion-site adverse events such as vascular pain and induration and/or phlebitis are observed. In the present study, adverse events induced by the FEC regimen and FAP, a prodrug of aprepitant (AP), were studied based on the vascular tissue distribution of EPI in rats. Rats were treated with intravenous FAP (3 mg/kg, 10 min-constant rate infusion) or oral AP (3 mg/kg) and then intravenous EPI (1 mg/kg, 5 min-constant rate infusion) as follows: FAP-S Group, FAP and then EPI was infused from the same site on the jugular vein; FAP-D Group, FAP and then EPI was infused from different jugular veins (left and right); and AP Group, AP was administered orally and EPI was infused from the jugular vein. Concentrations of EPI in vascular tissue at the EPI infusion sites and opposite sites of the jugular vein (left and right, respectively) were measured at 30 min and 24 h after EPI infusion. Histological observation of the EPI infusion site was also made separately. In rats, the tissue concentrations of EPI at the infusion site in the FAP-S group were higher than those in the FAP-D and AP groups. Inflammation and necrosis were observed at the EPI infusion-site vascular tissue of the FAP-S group, but not of the FAP-D and AP groups. These findings could aid the development of an approach to avoid infusion-site adverse events in anthracycline-based chemotherapy in the clinical practice.
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http://dx.doi.org/10.3892/mco.2019.1849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535639PMC
July 2019

Reduction in the rate of postoperative delirium by switching from famotidine to omeprazole in Japanese hepatectomized recipients.

J Pharm Health Care Sci 2019 7;5:10. Epub 2019 May 7.

Department of Pharmacy, Chugoku Rosai Hospital, 1-5-1 Hiro-tagaya, Kure, Hiroshima, 737-0193 Japan.

Background: Hepatectomy is a highly invasive procedure with a high probability of postoperative delirium. Treatment with antiulcer drugs is indispensable after hepatectomy for anastomotic ulcer management. The clinical pathway for hepatectomy was reviewed and the antiulcer drug used was switched from famotidine, a H-receptor antagonist, to omeprazole, a proton pump inhibitor, owing to the pharmacist's intervention.

Methods: Hepatectomized recipients over 65 years of age, except in the cases of laparoscopic surgery and intensive care unit entry, were treated with famotidine injections (10 patients) or omeprazole injections (11 patients), and the incidence rates and severity of delirium were compared between the famotidine and omeprazole groups. The delirium after hepatectomy was assessed using the Japanese version of the NEECHAM confusion scale.

Results: The incidence rates of delirium were 90% in the famotidine group and 27.3% in the omeprazole group. Four out of 9 recipients in the famotidine group were injected with haloperidol to treat for delirium, but no recipients needed this treatment in the omeprazole group.

Conclusions: Compared with famotidine, the use of omeprazole was found to be effective in reducing the incidence rate and severity of postoperative delirium in patients undergoing hepatectomy. Pharmacists should actively strive to mitigate the risks of delirium.
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http://dx.doi.org/10.1186/s40780-019-0139-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505269PMC
May 2019

Effect of Gamma Ray Irradiation on Friction Property of Poly(vinyl alcohol) Cast-Drying on Freeze-Thawed Hybrid Gel.

Gels 2018 Mar 29;4(2). Epub 2018 Mar 29.

Research Institute of Environment and Information Sciences, Yokohama National University, 79-7 Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan.

Poly(vinyl alcohol) (PVA) is a biocompatible polymer with low toxicity. It is possible to prepare physically cross-linked PVA gels having hydrogen bonds without using a cross-linking agent. The newly reported physically cross-linked PVA cast-drying (CD) on freeze-thawed (FT) hybrid gel has an excellent friction property, which is expected to be applied as a candidate material for artificial cartilage. Gamma ray sterilization for clinical applications usually causes additional chemical cross-linking and changes physical properties of gels. In this study, CD on FT hybrid gels were irradiated using gamma rays at a different dose rate and irradiance. The results showed the optimized irradiation conditions for gamma irradiated gels to retain excellent friction characteristics.
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http://dx.doi.org/10.3390/gels4020030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209256PMC
March 2018

Uptake and metabolism of mizoribine, an immunosuppressant, in L5178Y-R mouse lymphoma cells in vitro and peripheral blood mononuclear cells of rats and kidney transplant recipients in vivo.

Drug Metab Pharmacokinet 2018 Oct 25;33(5):232-239. Epub 2018 Aug 25.

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.

The cellular uptake of mizoribine (MZR), an immunosuppressant, and metabolism of MZR to MZR-5'- monophosphate (MZRP), an active metabolite, were evaluated in L5178Y-R mouse lymphoma cells and peripheral blood mononuclear cells (PBMCs) of rats and kidney transplant recipients (KTRs, n = 22). Real-time PCR analysis revealed the expression of ENT1 and ENT2 mRNAs, but not of CNTs, in L5178Y-R cells and rat's PBMCs. In L5178Y-R cells, the uptake of MZR was suppressed by adenosine, a substrate for ENT1 and ENT2, but not by 5-(4-nitrobenzyl)-6-thioinosine (0.1 μM), an ENT1 inhibitor. Saturable metabolism of MZR to MZRP was observed. In rats, peak plasma concentrations of MZR and peak concentrations of MZR and MZRP in PBMCs were observed 3 h after oral administration. MZR disappeared from PBMCs in parallel with plasma MZR, but the disappearance of MZRP from PBMCs appeared to be slow. In KTRs, the mean plasma concentration of MZR 3-4 h after ingestion was 3.14 μg/ml and the mean MZRP concentration in PBMCs was 16.8% of MZR, reflecting the involvement of ENT in the uptake of MZR. A linear relationship was observed between plasma MZR concentrations ranging from 1 to 6 μg/ml and PBMC's MZRP concentrations ranging from 90 to 200 ng/ml.
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http://dx.doi.org/10.1016/j.dmpk.2018.08.007DOI Listing
October 2018

Pharmacokinetic interaction of green tea beverage containing cyclodextrins and high concentration catechins with P-glycoprotein substrates in LLC-GA5-COL150 cells in vitro and in the small intestine of rats in vivo.

J Pharm Pharmacol 2017 Dec 4;69(12):1736-1744. Epub 2017 Oct 4.

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, Japan.

Objectives: Possible interaction of green tea beverage (GT) containing cyclodextrins and high concentration catechins, a drinking water, with P-glycoprotein (P-gp) substrates was examined in vitro and in vivo.

Methods: Effects of GT on the uptake of rhodamine 123 by LLC-GA5-COL150 cells and intestinal efflux of rhodamine 123 from blood, intestinal absorption of quinidine from ileum loop and oral absorption of digoxin were examined in rats. Effects of GT and GT components on digoxin solubility were also examined.

Key Findings: Green tea increased the uptake of rhodamine 123 by LLC-GA5-COL150 cells, suppressed the intestinal efflux of rhodamine 123 from blood and increased the absorption of quinidine in the ileum of rats. Also, GT increased the solubility of digoxin, and ingestion of GT significantly increased the oral absorption of digoxin given at a high dose in rats.

Conclusions: Green tea suppressed the P-gp-mediated efflux transport of hydrophilic compounds and increased the solubility of lipophilic compounds. Thus, GT may cause interaction with various P-gp substrates, due to the combined effects of catechins and cyclodextrins. Especially, cyclodextrin alone can cause interaction with various low-solubility compounds in vivo. In taking low-solubility drugs including low-solubility P-gp substrates, cyclodextrin-containing foods and beverages such as GT should be avoided.
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http://dx.doi.org/10.1111/jphp.12817DOI Listing
December 2017

Absorption sites of orally administered drugs in the small intestine.

Authors:
Teruo Murakami

Expert Opin Drug Discov 2017 12 17;12(12):1219-1232. Epub 2017 Sep 17.

a Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences , Hiroshima International University , Hiroshima , Japan.

Introduction: In pharmacotherapy, drugs are mostly taken orally to be absorbed systemically from the small intestine, and some drugs are known to have preferential absorption sites in the small intestine. It would therefore be valuable to know the absorption sites of orally administered drugs and the influencing factors. Areas covered:In this review, the author summarizes the reported absorption sites of orally administered drugs, as well as, influencing factors and experimental techniques. Information on the main absorption sites and influencing factors can help to develop ideal drug delivery systems and more effective pharmacotherapies. Expert opinion: Various factors including: the solubility, lipophilicity, luminal concentration, pKa value, transporter substrate specificity, transporter expression, luminal fluid pH, gastrointestinal transit time, and intestinal metabolism determine the site-dependent intestinal absorption. However, most of the dissolved fraction of orally administered drugs including substrates for ABC and SLC transporters, except for some weakly basic drugs with higher pKa values, are considered to be absorbed sequentially from the proximal small intestine. Securing the solubility and stability of drugs prior to reaching to the main absorption sites and appropriate delivery rates of drugs at absorption sites are important goals for achieving effective pharmacotherapy.
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http://dx.doi.org/10.1080/17460441.2017.1378176DOI Listing
December 2017

Modulation of multidrug resistance-associated proteins function in erythrocytes in glycerol-induced acute renal failure rats.

J Pharm Pharmacol 2017 Feb 18;69(2):172-181. Epub 2016 Nov 18.

Laboratory of Biopharmaceutics and Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Hiroshima International University, Kure, Japan.

Objectives: Evaluation of the function of multidrug resistance-associated proteins (MRPs) expressed in erythrocytes and screening of endogenous MRPs modulator(s) in glycerol-induced acute renal failure (ARF) rats.

Methods: Concentrations of 2,4-dinitrophenyl-S-glutathione (DNP-SG), a substrate for MRPs, in erythrocytes after administration of 1-chloro-2,4-dintrobenzene (CDNB), a precursor of DNP-SG, were determined in control and ARF rats. The screening of endogenous MRPs modulator(s) was performed using washed erythrocytes and inside-out erythrocyte membrane vesicles (IOVs) in vitro.

Key Findings: Accumulation of DNP-SG in erythrocytes was observed in ARF rats. Uraemic plasma components exhibited a greater inhibitory effect on DNP-SG uptake by IOVs than control plasma components and increased the DNP-SG accumulation significantly in washed erythrocytes. Several protein-bound uraemic toxins at clinically observed concentrations and bilirubin significantly inhibited DNP-SG uptake by IOVs. In washed erythrocytes, bilirubin (10 μm) and l-kynurenine (100 μm), a precursor of kynurenic acid being MRPs inhibitor, increased DNP-SG accumulation significantly.

Conclusions: Glycerol-induced ARF rats contain various MRPs inhibitors in plasma, and membrane-permeable MRP substrates/inhibitors including their precursors inhibit the MRPs function in erythrocytes cooperatively.
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http://dx.doi.org/10.1111/jphp.12664DOI Listing
February 2017

Dosage Adjustment of Dabigatran Etexilate Based on Creatinine Clearance in Patients With Cardioembolic Stroke or Atrial Fibrillation.

Ther Drug Monit 2016 12;38(6):670-676

*Department of Pharmacy, Chugoku Rosai Hospital; and †Laboratory of Biopharmaceutics and Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Hiroshima International University, Kure, Japan.

Background: A recommendation for dosage adjustment of dabigatran etexilate, a prodrug of dabigatran, seems to be desirable based on creatinine clearance to avoid bleeding and stroke.

Methods: Outpatients and inpatients having a history of cardioembolic stroke or atrial fibrillation were included. After taking dabigatran etexilate orally (75-150 mg twice daily) for at least 1 week, plasma trough concentration (Ctrough, ng/mL) of dabigatran and creatinine clearance (CLcr, mL/min) of patients according to Cockcroft and Gault equation were determined.

Results: Among the 38 patients studied, Ctrough of dabigatran and CLcr were scattered in a range from 31.4 to 329.5 ng/mL and 15.4-133.4 mL/min, respectively. Temporal CLtotal (Temp-CLtotal) of dabigatran, estimated by dividing the daily absorbed amount of dabigatran etexilate with Ctrough of dabigatran, was linearly correlated with CLcr of patients (P = 0.0018). Based on the findings, the daily dose of dabigatran etexilate that provides Ctrough of dabigatran at approximately 70 ng/mL was estimated.

Conclusions: A linear relationship was found between Temp-CLtotal of dabigatran and CLcr of patients. Depending on CLxr of patients, we recommend 4 different dosages of dabigatran etexilate to obtain Ctrough of dabigatran at approximately 70 ng/mL.
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http://dx.doi.org/10.1097/FTD.0000000000000336DOI Listing
December 2016

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability.

Authors:
Teruo Murakami

J Pharm Sci 2016 09 16;105(9):2515-2526. Epub 2016 Jun 16.

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima 737-0112, Japan. Electronic address:

Orally administered drugs are categorized into 4 classes depending on the solubility and permeability in a Biopharmaceutics Classification System. Prodrug derivatization is one of feasible approaches in modifying the physicochemical properties such as low solubility and low permeability without changing the in vivo pharmacological action of the parent drug. In this article, prodrug-targeted solute carrier (SLC) transporters were searched randomly by PubMed. Collected SLC transporters are amino acid transporter 1, bile acid transporter, carnitine transporter 2, glucose transporter 1, peptide transporter 1, vitamin C transporter 1, and multivitamin transporter. The usefulness of transporter-targeted prodrugs was evaluated in terms of membrane permeability, stability under acidic condition, and conversion to the parent drug. Among prodrugs collected, peptide transporter-targeted prodrugs exhibited the highest number, and some prodrugs such as valaciclovir and valganciclovir are clinically available. ATP-binding cassette efflux transporter, P-glycoprotein (P-gp), reduces the intestinal absorption of lipophilic P-gp substrate drugs, and SLC transporter-targeted prodrugs of P-gp substrate drugs circumvented the P-gp-mediated efflux transport. Thus, SLC transporter-targeted prodrug derivatization seems to be feasible approach to increase the oral bioavailability by overcoming various unwanted physicochemical properties of orally administered drugs, although the effect of food on prodrug absorption should be taken into consideration.
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http://dx.doi.org/10.1016/j.xphs.2016.05.012DOI Listing
September 2016

Biphasic and boundary lubrication mechanisms in artificial hydrogel cartilage: A review.

Proc Inst Mech Eng H 2015 Dec;229(12):864-78

Department of Materials Science and Research Institute of Environment and Information Sciences, Yokohama National University, Yokohama, Japan.

Various studies on the application of artificial hydrogel cartilage to cartilage substitutes and artificial joints have been conducted. It is expected in clinical application of artificial hydrogel cartilage that not only soft-elastohydrodynamic lubrication but biphasic, hydration, gel-film and boundary lubrication mechanisms will be effective to sustain extremely low friction and minimal wear in daily activities similar to healthy natural synovial joints with adaptive multimode lubrication. In this review article, the effectiveness of biphasic lubrication and boundary lubrication in hydrogels in thin film condition is focused in relation to the structures and properties of hydrogels. As examples, the tribological behaviors in three kinds of poly(vinyl alcohol) hydrogels with high water content are compared, and the importance of lubrication mechanism in biomimetic artificial hydrogel cartilage is discussed to extend the durability of cartilage substitute.
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http://dx.doi.org/10.1177/0954411915611160DOI Listing
December 2015

Hydrogels in Biomedical Use.

Authors:
Teruo Murakami

Proc Inst Mech Eng H 2015 Dec;229(12):825-7

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http://dx.doi.org/10.1177/0954411915616528DOI Listing
December 2015

Influences of dehydration and rehydration on the lubrication properties of phospholipid polymer-grafted cross-linked polyethylene.

Proc Inst Mech Eng H 2015 Jul 2;229(7):506-14. Epub 2015 Jun 2.

Research Center for Advanced Biomechanics, Kyushu University, Fukuoka, Japan.

Surface modification by grafting of biocompatible phospholipid polymer onto the surface of artificial joint material has been proposed to reduce the risk of aseptic loosening and improve the durability. Poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-grafted cross-linked polyethylene (CLPE) has shown promising results for reducing wear of CLPE. The main lubrication mechanism for the PMPC layer is considered to be the hydration lubrication. In this study, the lubrication properties of PMPC-grafted CLPE were evaluated in reciprocating friction test with rehydration process by unloading in various lubricants. The start-up friction of PMPC-grafted CLPE was reduced, and the damage of PMPC layer was suppressed by rehydration in water or hyaluronic acid solutions. In contrast, the start-up friction of PMPC-grafted CLPE increased in fetal bovine serum solution, and the damage for PMPC layer was quite noticeable. Interestingly, the start-up friction of PMPC-grafted CLPE was reduced in fetal bovine serum solution containing hyaluronic acid, and the damage of the PMPC layer was suppressed. These results indicate that the rehydration by unloading and hyaluronic acid are elemental in maximizing the lubrication effect of hydrated PMPC layer.
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http://dx.doi.org/10.1177/0954411915588969DOI Listing
July 2015

Interaction of magnesium oxide with gastric acid secretion inhibitors in clinical pharmacotherapy.

Eur J Clin Pharmacol 2014 Aug 13;70(8):921-4. Epub 2014 May 13.

Department of Pharmacy, Chugoku Rosai Hospital, 1-5-1 Hiro-Tagaya, Kure, Hiroshima, 737-0193, Japan,

Purpose: Magnesium oxide (MgO), a short-term osmotic laxative, is converted into MgCl2 under acidic condition in the stomach and then Mg(HCO3)2 in the intestinal tract, where Mg(HCO3)2 induces the water exudation into the intestine. This indicates that the laxative effect of MgO could be attenuated under the suppressed gastric acid secretion. In this study, the possible interaction of MgO with gastric acid secretion inhibitors was evaluated by using electronic patient records of MgO dosage levels.

Methods: Defecation was controlled with MgO alone in some patients after colon surgery (n = 67) and after total gastric resection (n = 4). Some other patients were treated with a combination use of MgO and H2 receptor antagonist (H2RA) (n = 14) or proton pump inhibitor (PPI) (n = 27). The possible drug interaction of MgO with H2RA or PPI was evaluated by comparing dosage levels of MgO used in controlling defecation.

Results: In controlling defecation, the daily dosage levels of MgO in patients taking H2RA or PPI and patients with total gastric resection were significantly higher than those patients taking MgO alone after colon surgery. The ratios of good constipation control (controlled well at the dosing level of 1,000 mg MgO) in patients taking H2RA or PPI were significantly lower than that in patients treated with MgO alone. In an in vitro study, the solubility of MgO at pH 4.5 was quite low, as compared with that at pH 1.2.

Conclusions: When patients received H2RA or PPI, the laxative effect of MgO is decreased possibly due to the low solubility of MgO at the higher gastric pH and less generation of MgCl2 and Mg(HCO3)2. Higher dosing level of MgO or another laxative should be used in patients taking H2RA or PPI, as well as the case of patients with total gastric resection.
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http://dx.doi.org/10.1007/s00228-014-1694-xDOI Listing
August 2014

Effect of genistein, a natural soy isoflavone, on the pharmacokinetics and intestinal toxicity of irinotecan hydrochloride in rats.

J Pharm Pharmacol 2013 Feb 21;65(2):280-91. Epub 2012 Sep 21.

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Japan.

Objectives: The effect of genistein, a natural soy isoflavone, on pharmacokinetics and intestinal toxicity, or late-onset diarrhoea, of irinotecan hydrochloride (CPT-11) was examined in rats.

Methods: Probenecid, a typical inhibitor of multidrug resistance-associated protein (MRP) 2, was also employed for comparison with genistein. Plasma concentration, biliary excretion and intestinal secretion of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38) and SN-38 glucuronide (SN-38G) were determined in untreated, genistein-treated and probenecid-treated rats. CPT-11 was administered repeatedly by intravenous injection (60 mg/kg/day for 4 days), and the effects of genistein and probenecid on CPT-11-induced intestinal toxicity were evaluated by measuring body weight, induction of diarrhoea, and alkaline phosphatase (ALP) activity in the intestinal mucosal membranes.

Key Findings: Genistein, as well as probenecid, significantly suppressed the MRP2-mediated biliary and intestinal secretion of CPT-11 and its metabolites and increased their plasma concentrations. Multiple administration of CPT-11 reduced body weight and ALP activity, and induced watery diarrhoea. Genistein, as well as probenecid, significantly suppressed the loss in body weight and the reduced mucosal ALP activity in the ileum, and ameliorated the symptoms of diarrhoea induced by CPT-11.

Conclusions: Intravenous genistein was effective in ameliorating CPT-11-induced late-onset diarrhoea, by suppressing MRP2-mediated biliary excretion of CPT-11 and its metabolites.
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http://dx.doi.org/10.1111/j.2042-7158.2012.01592.xDOI Listing
February 2013

Comparison of in vivo with in vitro pharmacokinetics of mercury between methylmercury chloride and methylmercury cysteine using rats and Caco2 cells.

Arch Environ Contam Toxicol 2012 Nov 30;63(4):628-36. Epub 2012 Aug 30.

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiro-koshingai, Kure, Hiroshima, Japan.

The in vivo and in vitro pharmacokinetics of mercury (Hg) were compared between methylmercury chloride (MeHg·Cl) and methylmercury cysteine (MeHg-Cys) using rats and Caco2 cells because humans can be exposed to MeHg compounds through dietary fish. The in vivo pharmacokinetics of Hg immediately after the digestion of MeHg compounds are still obscure. In Caco2 cells, membrane uptake and subcellular distribution of MeHg compounds were examined. When rats received it intravenously, MeHg·Cl showed 20-fold greater plasma and 2-fold greater blood concentrations of Hg than MeHg-Cys, indicating that their pharmacokinetic properties are different. One hour later, however, Hg concentrations in plasma and blood became virtually identical between MeHg·Cl and MeHg-Cys, although blood Hg concentrations were >100-fold greater than those in plasma. When administered into the closed rat's jejunum loop, MeHg·Cl and MeHg-Cys were rapidly and efficiently taken up by intestinal membranes, and Hg was retained in intestinal membranes for a relatively long time. When administered orally, no difference was observed in plasma and blood Hg concentrations between MeHg·Cl and MeHg-Cys: plasma and blood Hg concentrations increased gradually and reached steady levels at 8 h after administration. In Caco2 cells, uptake of MeHg-Cys was significantly suppressed by L-leucine, although this was not seen with MeHg·Cl. In Caco2 cells, 81 % of Hg was recovered from cytosol fractions and 13 % of Hg from nuclear fractions (including debris) after a 2-h incubation with MeHg-Cys. In conclusion, the mechanism of membrane uptake and volume of distribution in the initial distribution phase were clearly different between MeHg·Cl and MeHg-Cys. However, such pharmacokinetic differences between them disappeared 1 h after intravenous and after oral routes of administration, possibly due to the metabolism in the body.
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http://dx.doi.org/10.1007/s00244-012-9800-5DOI Listing
November 2012

Effects of both vitamin C and mechanical stimulation on improving the mechanical characteristics of regenerated cartilage.

Biochem Biophys Res Commun 2012 Aug 16;424(4):724-9. Epub 2012 Jul 16.

Department of Biomedical Engineering, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Miyagi, Japan.

The present work describes the influence of both vitamin C (VC) and mechanical stimulation on development of the extracellular matrix (ECM) and improvement in mechanical properties of a chondrocyte-agarose construct in a regenerating tissue disease model of hyaline cartilage. We used primary bovine chondrocytes and two types of VC, ascorbic acid (AsA) as an acidic form and ascorbic acid 2-phosphate (A2P) as a non-acidic form, and applied uniaxial compressive strain to the tissue model using a purpose-built bioreactor. When added to the medium in free-swelling culture conditions, A2P downregulated development of ECM and suppressed improvement of the tangent modulus more than AsA. By contrast, application of mechanical stimulation to the construct both increased the tangent modulus more than the free-swelling group containing A2P and enhanced the ECM network of inner tissue to levels nearly as high as the free-swelling group containing AsA. Thus, mechanical stimulation and strain appears to enhance the supply of nutrients and improve the synthesis of ECM via mechanotransduction pathways of chondrocytes. Therefore, we suggest that mechanical stimulation is necessary for homogenous development of ECM in a cell-associated construct with a view to implantation of a large-sized articular cartilage defect.
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http://dx.doi.org/10.1016/j.bbrc.2012.07.019DOI Listing
August 2012

Correlation between plasma concentration ratios of SN-38 glucuronide and SN-38 and neutropenia induction in patients with colorectal cancer and wild-type UGT1A1 gene.

Oncol Lett 2012 Mar 22;3(3):694-698. Epub 2011 Dec 22.

Department of Pharmacy, Osaka Rosai Hospital, Sakai, Osaka 591-8025.

In irinotecan (CPT-11)-based chemotherapy, neutropenia and diarrhea are often induced. In the present study, the clinical significance of the concentration ratios of 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronide (SN-38G) and SN-38 in the plasma in predicting CPT-11-induced neutropenia was examined. A total of 17 patients with colorectal cancer and wild-type UDP-glucuronosyltransferase (UGT)1A1 gene were enrolled and treated with CPT-11 as part of the FOLFIRI regimen [CPT-11 and fluorouracil (5-FU)]. Blood was taken exactly 15 min following a 2-h continuous infusion of CPT-11. Plasma concentrations of SN-38, SN-38G and CPT-11 were determined by a modified high-performance liquid chromatography (HPLC) method. The median, maximum and minimum values of plasma SN-38G/SN-38 ratios were 4.25, 7.09 and 1.03, respectively, indicating that UGT activities are variable among patients with the wild-type UGT1A1 gene. The plasma SN-38G/SN-38 ratios decreased with an increase in the trial numbers of chemotherapy (r=0.741, p=0.000669), suggesting that CPT-11 treatment suppresses UGT activity, and the low plasma SN-38G/SN-38 ratios resulted in the induction of greater neutropenia. However, in this analysis, 2 clearly separated regression lines were observed between plasma SN-38G/SN-38 ratios and neutropenia induction. In conclusion, UGT activity involved in SN-38 metabolism is variable among patients with the wild-type UGT1A1 gene, and each CPT-11 treatment suppresses UGT activity. One-point determination of the plasma SN-38G/SN-38 ratio may provide indications for the prediction of CPT-11-induced neutropenia and adjustment of the optimal dose, although further studies are required.
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http://dx.doi.org/10.3892/ol.2011.533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362497PMC
March 2012

Involvement of Multiple Transporters-mediated Transports in Mizoribine and Methotrexate Pharmacokinetics.

Pharmaceuticals (Basel) 2012 Aug 10;5(8):802-36. Epub 2012 Aug 10.

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.

Mizoribine is administered orally and excreted into urine without being metabolized. Many research groups have reported a linear relationship between the dose and peak serum concentration, between the dose and AUC, and between AUC and cumulative urinary excretion of mizoribine. In contrast, a significant interindividual variability, with a small intraindividual variability, in oral bioavailability of mizoribine is also reported. The interindividual variability is mostly considered to be due to the polymophisms of transporter genes. Methotrexate (MTX) is administered orally and/or by parenteral routes, depending on the dose. Metabolic enzymes and multiple transporters are involved in the pharmacokinetics of MTX. The oral bioavailability of MTX exhibits a marked interindividual variability and saturation with increase in the dose of MTX, with a small intraindividual variability, where the contribution of gene polymophisms of transporters and enzymes is suggested. Therapeutic drug monitoring of both mizoribine and MTX is expected to improve their clinical efficacy in the treatment of rheumatoid arthritis.
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http://dx.doi.org/10.3390/ph5080802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763673PMC
August 2012

Role of phosphatidylserine binding in tissue distribution of amine-containing basic compounds.

Expert Opin Drug Metab Toxicol 2011 Mar;7(3):353-64

Hiroshima International University, Faculty of Pharmaceutical Sciences, Laboratory of Biopharmaceutics and Pharmacokinetics, 5-1-1 Hiro-koshingai Kure Hiroshima, Kure 737-0112, Japan.

Introduction: Amine-containing basic compounds with pK(a) values of ≥ 7 for at least one functional group, or moderately strong amines, typically exhibit large distribution volumes with a marked interorgan variation. Understanding the tissue distribution mechanisms of various basic compounds is important for drug design.

Areas Covered: This review focuses on the role of tissue phosphatidylserine (PS) binding in the characteristic tissue distribution of amine-containing basic compounds. The mechanisms underlying tissue distribution, including intercellular and intracellular distribution, and effects of pK(a) values and lipophilicity on the extent of tissue distribution of various basic compounds are clarified.

Expert Opinion: The extent of tissue distribution of membrane-permeable moderately strong amines depends on tissue PS concentrations and binding affinities to PS. A linear relationship is observed between the extent of tissue distribution of each compound and tissue PS concentrations in various tissues. In contrast, very weakly basic compounds with pK(a) values of < 6.5 distribute to various tissues at almost comparable magnitudes, independent of tissue PS concentrations. Understanding the tissue distribution mechanisms and predicting Kp values for each tissue is essential in controlling pharmacological and/or toxic effects in pharmacotherapy with various amine-containing basic compounds, as well as in drug design.
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http://dx.doi.org/10.1517/17425255.2011.548805DOI Listing
March 2011

Modulated pharmacokinetics and increased small intestinal toxicity of methotrexate in bilirubin-treated rats.

J Pharm Pharmacol 2011 Feb;63(2):206-13

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima, Japan.

Objectives: The effect of bilirubin treatment on the pharmacokinetics and small intestinal toxicity of methotrexate was evaluated in rats, since bilirubin and its glucuronide conjugates can suppress multidrug resistance-associated protein-mediated transport.

Methods: Rats were treated intravenously with bilirubin and the various clearances and tissue distribution of methotrexate were estimated under a steady-state plasma concentration. Intestinal toxicity induced by methotrexate was also evaluated by measuring the leakage of alkaline phosphatase (ALP) activity. Probenecid, an inhibitor for multidrug resistance-associated protein and organic anion transporters, was used for comparison.

Key Findings: The treatment with bilirubin increased the steady-state plasma concentration and reduced biliary excretion clearance, urinary excretion clearance and intestinal exsorption clearance of methotrexate, as did treatment with probenecid. The intestinal absorption and jejunum distribution of methotrexate also significantly increased in bilirubin- and probenecid-treated rats. A greater leakage of ALP activity to the luminal fluid, with a lower ALP activity in the intestinal mucosal membrane after intestinal perfusion of methotrexate, was observed in bilirubin- and probenecid-treated rats.

Conclusions: Hyperbilirubinemia, which is involved under various disease states, may increase the small intestinal accumulation and toxicities of methotrexate, since high plasma concentrations of conjugated bilirubin can suppress the function of multidrug resistance-associated proteins, which facilitate the efflux of methotrexate out of cells.
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http://dx.doi.org/10.1111/j.2042-7158.2010.01213.xDOI Listing
February 2011

Modulated function of tissue efflux transporters under hyperbilirubinemia in rats.

Eur J Pharmacol 2010 Jun 1;636(1-3):166-72. Epub 2010 Apr 1.

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.

The effect of hyperbilirubinemia on the function of tissue efflux transporters such as multidrug resistance-associated proteins (Mrps) and organic anion transporting polypeptides (Oatps) was examined by measuring tissue accumulation of 2,4-dinitrophenyl-S-glutathione (DNP-SG) after intravenous administration of 1-chloro-2,4-dinitrobenzene (CDNB), a precursor of DNP-SG, in rats. DNP-SG is known as a substrate of both Mrps and Oatps. Hyperbilirubinemia was induced by a bolus intravenous administration of bilirubin. Treatment with probenecid, an inhibitor for both Mrps and Oatps, significantly increased DNP-SG concentrations in the brain, heart, liver, kidney, jejunum, spleen and skeletal muscle as compared with those in control rats, suggesting the expression of some probenecid-sensitive efflux transporters in these tissues. Rats with more than 70 microM of unconjugated/conjugated bilirubin in plasma exhibited significantly higher DNP-SG concentrations in the brain, liver, jejunum, and skeletal muscle. These results suggested that probenecid-sensitive efflux transporters in tissues were suppressed functionally under hyperbilirubinemia. In conclusion, hyperbilirubinemia accompanied by obstructive jaundice is caused by various disease states, which may increase harmful toxicities of exogenously administered Mrps and/or Oatps substrate drugs at various tissues, by suppressing the efflux transporter's function systemically.
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http://dx.doi.org/10.1016/j.ejphar.2010.03.042DOI Listing
June 2010

Study on intestinal absorption sites of mizoribine and ribavirin, substrates for concentrative nucleoside transporter(s), in rats.

Eur J Pharmacol 2010 Feb 2;628(1-3):214-9. Epub 2009 Dec 2.

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, Japan.

The absorption sites of mizoribine (an imidazole nucleoside) and ribavirin (a purine nucleoside) in the small intestine were evaluated in rats. The intestinal absorption of mizoribine is known to be mediated by rat concentrative nucleoside transporter (CNT)1 and CNT2. In contrast, the absorption mechanism of ribavirin in rats is not yet fully understood. Thus, the intestinal absorption of ribavirin was characterized firstly. In in-situ jejunum loop studies, the absorption percentage of ribavirin at a dose of 25mg/kg was significantly lower than those after 1mg/kg and 5mg/kg doses. Coadministration of adenosine, inosine and mizoribine, but not thymidine and gemcitabine, significantly suppressed the intestinal absorption of ribavirin, indicating that ribavirin absorption is mediated by CNT2 in rats. In in-situ loop studies, mizoribine and ribavirin were absorbed to the same extents both in the proximal and distal small intestine. In vivo study was carried out using mizoribine, in which the gastric emptying rates altered by a subcutaneous injection of metoclopramide or scopolamine butylbromide exerted no significant effects on the values of peak plasma level (Cmax), area under the plasma concentration-time profile from 0 to 6h (AUC(0-6)), and urinary excretion percentage of mizoribine given orally, though the time to reach Cmax (Tmax) of mizoribine was altered by each treatment. In conclusion, mizoribine and ribavirin were found to be absorbed efficiently to the same extents from the whole small intestine. Also, the altered gastric emptying rates exerted no significant effects on the oral bioavailabilities of mizoribine and ribavirin.
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http://dx.doi.org/10.1016/j.ejphar.2009.11.048DOI Listing
February 2010

Site-specific contribution of proton-coupled folate transporter/haem carrier protein 1 in the intestinal absorption of methotrexate in rats.

J Pharm Pharmacol 2009 Jul;61(7):911-8

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima, Japan.

Objectives: Methotrexate is reportedly a substrate for proton-coupled folate transporter/haem carrier protein 1 (PCFT/HCP1) and reduced folate carrier 1 (RFC1). In this study, we examined the contribution of PCFT/HCP1 and RFC1 in the intestinal absorption of methotrexate in rats.

Methods: Western blot analysis was carried out to evaluate the protein levels of PCFT/HCP1 and multidrug resistance-associated protein 2 in brush-border membrane of rat small intestine. Mucosal uptake of methotrexate was studied in the rat everted small intestine and an in-situ intestinal perfusion study of methotrexate was also carried out in rats.

Key Findings: In transport studies using everted intestine, the mucosal methotrexate influx rate in proximal intestine at pH 5.5 was significantly greater than that at pH 7.4. Coadministration of folate or its analogues, such as folinate and 5-methyltetrahydrofolate, substrates for both PCFT/HCP1 and RFC1, significantly suppressed the methotrexate influx at pH 5.5, whereas thiamine pyrophosphate, an inhibitor for RFC1 alone, exerted no significant effect. Western blot analysis showed higher PCFT/HCP1 expression in proximal than distal small intestine. In distal small intestine, methotrexate influx rate was low and was not pH dependent. Also, folate and its analogues exerted no significant effect on methotrexate absorption.

Conclusions: Based on the present and our previous results, the site-specific contributions of various transporters including PCFT/HCP1 in methotrexate intestinal absorption were discussed. The variation in luminal pH and the involvement of multiple transporters in methotrexate absorption may cause variation in oral bioavailability among patients.
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http://dx.doi.org/10.1211/jpp/61.07.0010DOI Listing
July 2009

Intestinal efflux transporters and drug absorption.

Expert Opin Drug Metab Toxicol 2008 Jul;4(7):923-39

Hiroshima International University, Faculty of Pharmaceutical Sciences, Laboratory of Biopharmaceutics and Pharmacokinetics, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.

Background: The intestinal epithelial membrane expresses ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), multi-drug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP), in addition to various solute carrier (SLC) transporters. These ABC transporters affect the oral bioavailability of their substrate drugs.

Objective: To review the contribution of ABC efflux transporters such as P-gp, MRP2, MRP3, and BCRP in the intestinal absorption of substrate drugs.

Methods: Discussion was made by focusing on the site-specific expression and function of these ABC transporters, and the solubility and permeability of their substrate compounds.

Results/conclusion: The increase in the solubility and permeability of orally administered drugs could be the key to escape barrier function of ABC transporters, especially P-gp.
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http://dx.doi.org/10.1517/17425255.4.7.923DOI Listing
July 2008

Characterization of intestinal absorption of mizoribine mediated by concentrative nucleoside transporters in rats.

Eur J Pharmacol 2008 May 26;586(1-3):52-8. Epub 2008 Feb 26.

Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima 737-0112, Japan.

Mizoribine, an imidazole nucleoside, is an inhibitor of purine synthesis and has been used as an orally available immunosuppressive agent in human renal transplantation. In the present study, the intestinal absorption of mizoribine was characterized by examining the contribution of concentrative nucleoside transporters (CNT1, CNT2) in rats. When mizoribine was administered orally in conscious rats, the bioavailability of mizoribine estimated by urinary excretion percentage of unchanged mizoribine was a dose dependent: 53.1+/-6.0% at 5 mg/kg and 24.0+/-5.1% at 20 mg/kg. In in-situ loop studies, the disappearance rate, or absorption rate, of mizoribine from the intestinal lumen was comparable between 1 and 5 mg/kg, but significantly lower at 25 mg/kg. Coadministration of adenosine (a substrate of both CNT1 and CNT2), thymidine (a CNT1 substrate) and inosine (a CNT2 substrate) significantly suppressed the intestinal mizoribine absorption, depending on the nucleoside concentrations coadministered. Gemcitabine (a pyrimidine nucleoside analogue, a CNT1 substrate) and ribavirin (a purine nucleoside analog, a CNT2 substrate) also significantly suppressed the mizoribine intestinal absorption. Bile salts such as sodium cholate and sodium glycocholate (10 mM) also significantly suppressed the intestinal mizoribine absorption, but not ribavirin absorption. Mizoribine is an amphoteric compound, however, the suppression of intestinal absorption by bile salts was not ascribed to the electrostatic interaction or micellar formation between mizoribine and bile salts. In conclusion, the intestinal absorption of mizoribine is mediated by CNT1 and CNT2, and nucleoside-derived drugs such as gemcitabine and ribavirin can suppress the intestinal absorption of mizoribine. Bile salts such as sodium glycocholate were also found to cause interaction with mizoribine.
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http://dx.doi.org/10.1016/j.ejphar.2008.02.043DOI Listing
May 2008

Detoxication treatment for carbamazepine and lithium overdose.

Yakugaku Zasshi 2008 Jan;128(1):165-70

Department of Pharmaceutical Services, Hiroshima University Hospital, Minami-ku, Hiroshima, Japan.

This article reports detoxication treatments of a case of combined overdose of carbamazepine and lithium in a 38-year-old female with bipolar disorder. She was brought to the emergency unit after the family found her unresponsive and lying near empty packages for carbamazepine (corresponded to 7.7 g) and lithium carbonate (corresponded to 6.6 g) tablets. On admission, her blood pressure, heart rate and respiratory rate were 80/55 mmHg, 90 per minute and 13 per minute, respectively. Her GCS was 3 (E1, M1, V1). She received gastric lavage after intratracheal intubation, followed by administration of activated charcoal via gastric tube, and a large volume (800 ml/h) of lactate Ringer's solution by intravenous infusion. The serum levels of carbamazepine and lithium approximately 5 h after ingestion were 56.0 mug/ml and 3.56 mEq/l, respectively. The carbamazepine overdose was mainly treated by a 3 h charcoal hemoperfusion (CHP). The CHP treatment decreased serum carbamazepine levels by approximately 30-40% as compared with the levels simulated by Bayesian analysis using 1-point or 2-points serum level(s) (without detoxication treatment). For lithium overdose continuous infusion of Ringer's solution was effective, which increased serum sodium gradually and facilitated the elimination of lithium. In conclusion, the treatments with CHP and continuous infusion of Ringer's solution were considered to be effective for detoxification of carbamazepine and lithium overdose, respectively, when compared with those drug levels without detoxication treatment that simulated by Bayesian analysis method.
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http://dx.doi.org/10.1248/yakushi.128.165DOI Listing
January 2008

Role of intestinal efflux transporters in the intestinal absorption of methotrexate in rats.

J Pharm Pharmacol 2007 Sep;59(9):1263-70

Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.

The role of intestinal efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in intestinal absorption of methotrexate was examined in rats. In everted intestine, the mucosal efflux of methotrexate after application to serosal side was higher in jejunum than ileum, and the efflux in jejunum was suppressed by pantoprazole, a BCRP inhibitor, and probenecid, an MRP inhibitor, but not by verapamil, a P-gp inhibitor. The mucosal methotrexate efflux in ileum was suppressed by pantoprazole, but not by other inhibitors. On the other hand, the serosal efflux of methotrexate after application to mucosal side was greater in ileum than jejunum, and was suppressed by probenecid. In in-vivo rat studies, the intestinal absorption of methotrexate was significantly higher when methotrexate was administered to ileum than jejunum. Pantoprazole increased methotrexate absorption from jejunum and ileum. Probenecid increased the absorption of methotrexate from jejunum but decreased the absorption from ileum, as evaluated by peak plasma methotrexate levels. In conclusion, BCRP and MRPs are involved in the regional difference in absorption of methotrexate along the intestine, depending on their expression sites.
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http://dx.doi.org/10.1211/jpp.59.9.0011DOI Listing
September 2007

Membrane transport of andrographolide in artificial membrane and rat small intestine.

Pak J Biol Sci 2007 Jun;10(12):2078-85

Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand.

In the present study, the possible drug interactions of andrographolide with co-administering drugs such as acetaminophen, amoxycillin, aspirin, chlorpheniramine and norfloxacin to treat various infectious and inflammatory diseases that may be induced during absorption process were examined using artificial lipophilic membrane and everted rat intestine. The membrane transport of andrographolide across the artificial membrane was not affected by different pH of the medium (simulated gastric and intestinal fluids), different concentrations of andrographolide and co-administered drugs examined. In everted rat intestine, above co-administered drugs examined showed no significant effect on andrographolide membrane transport. The participation of efflux transporters such as P-glycoprotein and MRP2 in andrographolide transport was then examined, since andrographolide is a diterpene compound and some diterpene compounds are known as P-glycoprotein substrates. Cyclosporine, a P-glycoprotein/MRP2 inhibitor, significantly suppressed the efflux transport of andrographolide in distal region of intestine, whereas probenecid, an MRP inhibitor, showed no significant effect in both proximal and distal regions of intestine. These results suggest that P-glycoprotein, but not MRP, is participated in the intestinal absorption of andrographolide and P-glycoprotein-mediated drug interactions occur depending on the co-administered drugs and its concentrations.
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http://dx.doi.org/10.3923/pjbs.2007.2078.2085DOI Listing
June 2007