Publications by authors named "Gina Song"

23 Publications

  • Page 1 of 1

Physiologically Based Pharmacokinetic Modeling in Risk Assessment: Case Study With Pyrethroids.

Toxicol Sci 2020 08;176(2):460-469

ScitoVation, LLC, Durham, North Carolina 27713.

The assessment of potentially sensitive populations is an important application of risk assessment. To address the concern for age-related sensitivity to pyrethroid insecticides, life-stage physiologically based pharmacokinetic (PBPK) modeling supported by in vitro to in vivo extrapolation was conducted to predict age-dependent changes in target tissue exposure to 8 pyrethroids. The purpose of this age-dependent dosimetry was to calculate a Data-derived Extrapolation Factor (DDEF) to address age-related pharmacokinetic differences for pyrethroids in humans. We developed a generic human PBPK model for pyrethroids based on our previously published rat model that was developed with in vivo rat data. The results demonstrated that the age-related differences in internal exposure to pyrethroids in the brain are largely determined by the differences in metabolic capacity and in physiology for pyrethroids between children and adults. The most important conclusion from our research is that, given an identical external exposure, the internal (target tissue) concentration is equal or lower in children than in adults in response to the same level of exposure to a pyrethroid. Our results show that, based on the use of the life-stage PBPK models with 8 pyrethroids, DDEF values are essentially close to 1, resulting in a DDEF for age-related pharmacokinetic differences of 1. For risk assessment purposes, this indicates that no additional adjustment factor is necessary to account for age-related pharmacokinetic differences for these pyrethroids.
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http://dx.doi.org/10.1093/toxsci/kfaa070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416317PMC
August 2020

Quantitative bias analysis of the association between subclinical thyroid disease and two perfluoroalkyl substances in a single study.

Environ Res 2020 03 9;182:109017. Epub 2019 Dec 9.

Ramboll, Raleigh, NC, USA.

Exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) has been associated with the occurrence of thyroid disease in some epidemiologic studies. We hypothesized that in a specific epidemiologic study based on the National Health and Nutrition Examination Survey, the association of subclinical thyroid disease with serum concentration of PFOA and PFOS was due to reverse causality. Thyroid hormone affects glomerular filtration, which in turn affects excretion of PFOA and PFOS. We evaluated this by linking a model of thyroid disease status over the lifetime to physiologically based pharmacokinetic models of PFOA and PFOS. Using Monte Carlo methods, we simulated the target study population and analyzed the data using multivariable logistic regression. The target and simulated populations were similar with respect to age, estimated glomerular filtration rate, serum concentrations of PFOA and PFOS, and prevalence of subclinical thyroid disease. Our findings suggest that in the target study the associations with subclinical hypothyroidism were overstated and the results for subclinical hyperthyroidism were, in general, understated. For example, for subclinical hypothyroidism in men, the reported odds ratio per ln(PFOS) increase was 1.98 (95% CI 1.19-3.28), whereas in the simulated data the bias due to reverse causality gave an odds ratio of 1.19 (1.16-1.23). Our results provide evidence of bias due to reverse causality in a specific cross-sectional study of subclinical thyroid disease with exposure to PFOA and PFOS among adults.
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http://dx.doi.org/10.1016/j.envres.2019.109017DOI Listing
March 2020

Development and Application of a Life-Stage Physiologically Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans.

Toxicol Sci 2020 01;173(1):86-99

ScitoVation, LLC, Research Triangle Park, North Carolina 27709.

To address concerns around age-related sensitivity to pyrethroids, a life-stage physiologically based pharmacokinetic (PBPK) model, supported by in vitro to in vivo extrapolation (IVIVE) was developed. The model was used to predict age-dependent changes in target tissue exposure of 8 pyrethroids; deltamethrin (DLM), cis-permethrin (CPM), trans-permethrin, esfenvalerate, cyphenothrin, cyhalothrin, cyfluthrin, and bifenthrin. A single model structure was used based on previous work in the rat. Intrinsic clearance (CLint) of each individual cytochrome P450 or carboxylesterase (CES) enzyme that are active for a given pyrethroid were measured in vitro, then biologically scaled to obtain in vivo age-specific total hepatic CLint. These IVIVE results indicate that, except for bifenthrin, CES enzymes are largely responsible for human hepatic metabolism (>50% contribution). Given the high efficiency and rapid maturation of CESs, clearance of the pyrethroids is very efficient across ages, leading to a blood flow-limited metabolism. Together with age-specific physiological parameters, in particular liver blood flow, the efficient metabolic clearance of pyrethroids across ages results in comparable to or even lower internal exposure in the target tissue (brain) in children than that in adults in response to the same level of exposure to a given pyrethroid (Cmax ratio in brain between 1- and 25-year old = 0.69, 0.93, and 0.94 for DLM, bifenthrin, and CPM, respectively). Our study demonstrated that a life-stage PBPK modeling approach, coupled with IVIVE, provides a robust framework for evaluating age-related differences in pharmacokinetics and internal target tissue exposure in humans for the pyrethroid class of chemicals.
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http://dx.doi.org/10.1093/toxsci/kfz211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944222PMC
January 2020

Evaluation of Age-Related Pyrethroid Pharmacokinetic Differences in Rats: Physiologically-Based Pharmacokinetic Model Development Using In Vitro Data and In Vitro to In Vivo Extrapolation.

Toxicol Sci 2019 06;169(2):365-379

ScitoVation, LLC, Research Triangle Park, North Carolina, 27709.

An in vitro to in vivo (IVIVE) extrapolation based-physiologically based pharmacokinetic (PBPK) modeling approach was demonstrated to understand age-related differences in kinetics and how they potentially affect age-related differences in acute neurotoxic effects of pyrethroids. To describe the age-dependent changes in pyrethroid kinetics, it was critical to incorporate age-dependent changes in metabolism into the model. As such, in vitro metabolism data were collected for 3 selected pyrethroids, deltamethrin (DLM), cis-permethrin, and trans-permethrin, using liver microsomes and cytosol, and plasma prepared from immature and adult rats. Resulting metabolism parameters, maximum rate of metabolism (Vmax) and Michaelis-Menten constant (Km), were biologically scaled to respective in vivo parameters for use in the age-specific PBPK model. Then, age-dependent changes in target tissue exposure, i.e., brain Cmax, to a given pyrethroid were simulated across ages using the model. The PBPK model recapitulated in vivo time-course plasma and brain concentrations of the 3 pyrethroids in immature and adult rats following oral administration of both low and high doses of these compounds. A single model structure developed for DLM was able to describe the kinetics of the other 2 pyrethroids when used with compound- and age-specific metabolism parameters, suggesting that one generic model for pyrethroids as a group can be used for early age-sensitivity evaluation if appropriate metabolic parameters are used. This study demonstrated the validity of applying IVIVE-based PBPK modeling to development of age-specific PBPK models for pyrethroids in support of pyrethroid risk assessment of potentially sensitive early age populations in humans.
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http://dx.doi.org/10.1093/toxsci/kfz042DOI Listing
June 2019

Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients.

Cancer Chemother Pharmacol 2019 01 16;83(1):61-70. Epub 2018 Oct 16.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC, 27599-7361, USA.

Purpose: Obesity may alter mononuclear phagocyte system (MPS) function and the pharmacology and efficacy of nanoparticles therapies, such as PEGylated liposomal doxorubicin (PLD). We aimed to evaluate the relationships between hormone and chemokine mediators of MPS function and the pharmacokinetic (PK) exposure of PLD in obese and normal weight patients with ovarian and endometrial cancer.

Methods: Hormone and chemokine mediators in obese and normal weight ovarian and endometrial cancer patients were measured. A separate pharmacology study was performed that evaluated the relationship between serum hormone concentrations, MPS function, and PK disposition of PLD in refractory ovarian cancer patients.

Results: Univariate analysis revealed a significant relationship between serum estradiol and body mass index (OR 8.64, 95% CI 2.67-28.0, p < 0.001). Estrone and testosterone concentrations were positively correlated with MPS function (ρ = 0.57 and 0.53, p = 0.14 and 0.18, respectively) and inversely correlated with PLD PK exposure (ρ = - 0.75 and - 0.76, respectively, p = 0.02 for both).

Conclusions: Higher MPS function resulting in reduced PLD exposure is a potential mechanism for reduced efficacy of PLD and other nanoparticles observed in obese patients with cancer. PK simulations suggest higher doses of PLD are required in obese patients to achieve similar exposures as standard dosing in normal weight patients.
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http://dx.doi.org/10.1007/s00280-018-3702-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370499PMC
January 2019

Physiologically-based pharmacokinetic modeling suggests similar bioavailability of Mn from diet and drinking water.

Toxicol Appl Pharmacol 2018 11 20;359:70-81. Epub 2018 Sep 20.

ScitoVation, LLC., Research Triangle Park, NC, USA; ToxStrategies, Inc., Cary, NC, USA. Electronic address:

Due to concerns for enhanced absorption of manganese (Mn) from drinking water compared to diet, bioavailability of Mn from drinking water remains a major data gap in understanding Mn kinetics. In this study, PBPK models for adult rats and humans were updated with a drinking water exposure route and were used to assess the homeostatic control of Mn uptake, excretion and tissue kinetics between the two different ingestion modes. Drinking water model parameters were estimated from tissue kinetic data from a drinking water study in rats. The published study included a 10 ppm-Mn diet with additional Mn added to drinking water to give a total ingested Mn dose equivalent to that from a 200 ppm diet. The 200 ppm diet and equivalent mixed drinking water/diet exposures provided Mn concentrations for brain (striatum, olfactory bulb, and cerebellum), liver and bone after 7 and 61 days of Mn exposure. Modeling of these data sets indicated that (1) the oral Mn bioavailability is similar for diet or drinking water and (2) homeostatic control of gut uptake of Mn occurs with either drinking water or dietary ingestion. This updated description for absorption and distribution of Mn from gut was added to a human Mn-PBPK model to simulate Mn exposure from multiple routes of exposure (i.e. dietary intake, drinking water, and inhalation). This increases the utility of the Mn PBPK model by allowing for the simulation of multiple Mn exposure scenarios, including variable daily food and drinking water exposures in a human population.
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http://dx.doi.org/10.1016/j.taap.2018.09.023DOI Listing
November 2018

An in vitro approach for prioritization and evaluation of chemical effects on glucocorticoid receptor mediated adipogenesis.

Toxicol Appl Pharmacol 2018 09 19;355:112-126. Epub 2018 May 19.

ScitoVation, 6 Davis Drive, PO Box 12878, Research Triangle Park, NC 27709, United States; ToxStrategies, Inc, 1249 Kildaire Farm Road #134, Cary, NC 27511, United States. Electronic address:

Rising obesity rates worldwide have socio-economic ramifications. While genetics, diet, and lack of exercise are major contributors to obesity, environmental factors may enhance susceptibility through disruption of hormone homeostasis and metabolic processes. The obesogen hypothesis contends that chemical exposure early in development may enhance adipocyte differentiation, thereby increasing the number of adipocytes and predisposing for obesity and metabolic disease. We previously developed a primary human adipose stem cell (hASC) assay to evaluate the effect of environmental chemicals on PPARG-dependent adipogenesis. Here, the assay was modified to determine the effects of chemicals on the glucocorticoid receptor (GR) pathway. In differentiation cocktail lacking the glucocorticoid agonist dexamethasone (DEX), hASCs do not differentiate into adipocytes. In the presence of GR agonists, adipocyte maturation was observed using phenotypic makers for lipid accumulation, adipokine secretion, and expression of key genes. To evaluate the role of environmental compounds on adipocyte differentiation, progenitor cells were treated with 19 prioritized compounds previously identified by ToxPi as having GR-dependent bioactivity, and multiplexed assays were used to confirm a GR-dependent mode of action. Five chemicals were found to be strong agonists. The assay was also modified to evaluate GR-antagonists, and 8/10 of the hypothesized antagonists inhibited adipogenesis. The in vitro bioactivity data was put into context with extrapolated human steady state concentrations (Css) and clinical exposure data (Cmax). These data support using a human adipose-derived stem cell differentiation assay to test the potential of chemicals to alter human GR-dependent adipogenesis.
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http://dx.doi.org/10.1016/j.taap.2018.05.016DOI Listing
September 2018

Metabolism of deltamethrin and cis- and trans-permethrin by human expressed cytochrome P450 and carboxylesterase enzymes.

Xenobiotica 2019 May 4;49(5):521-527. Epub 2018 Jun 4.

a Concept Life Sciences (formerly CXR Biosciences Ltd.) , Dundee , UK.

The metabolism of the pyrethroids deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes. DLM, CPM and TPM were metabolised by human CYP2B6 and CYP2C19, with the highest apparent intrinsic clearance (CL) values for pyrethroid metabolism being observed with CYP2C19. Other CYP enzymes contributing to the metabolism of one or more of the three pyrethroids were CYP1A2, CYP2C8, CYP2C9*1, CYP2D6*1, CYP3A4 and CYP3A5. None of the pyrethroids were metabolised by CYP2A6, CYP2E1, CYP3A7 or CYP4A11. DLM, CPM and TPM were metabolised by both human CES1 and CES2 enzymes. Apparent CL values for pyrethroid metabolism by CYP and CES enzymes were scaled to per gram of adult human liver using abundance values for microsomal CYP enzymes and for CES enzymes in liver microsomes and cytosol. TPM had the highest and CPM the lowest apparent CL values for total metabolism (CYP and CES enzymes) per gram of adult human liver. Due to their higher abundance, all three pyrethroids were extensively metabolised by CES enzymes in adult human liver, with CYP enzymes only accounting for 2%, 10% and 1% of total metabolism for DLM, CPM and TPM, respectively.
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http://dx.doi.org/10.1080/00498254.2018.1474283DOI Listing
May 2019

Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages.

Drug Metab Dispos 2017 05 22;45(5):468-475. Epub 2017 Feb 22.

The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); ScitoVation, LLC, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.); Medical College of Wisconsin, Milwaukee, Wisconsin (D.G.M.); Centre for Toxicology, University of Surrey, Surrey, United Kingdom (B.G.L.); Science Strategies, LLC, Charlottesville, Virginia (T.G.O.); and Valent USA Corporation, Walnut Creek, California (M.R.C.)

Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s and carboxylesterase enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme are needed to support in vitro to in vivo extrapolation (IVIVE). This study was designed to determine age-dependent human hepatic CYP2C8 expression, for which only limited ontogeny data are available, and to further define CYP1A2 ontogeny. CYP2C8 and 1A2 protein levels were measured by quantitative Western blotting using liver microsomal samples prepared from 222 subjects with ages ranging from 8 weeks gestation to 18 years after birth. The median CYP2C8 expression was significantly greater among samples from subjects older than 35 postnatal days ( 122) compared with fetal samples and those from very young infants (fetal to 35 days postnatal, 100) (0.00 vs. 13.38 pmol/mg microsomal protein; < 0.0001). In contrast, the median CYP1A2 expression was significantly greater after 15 months postnatal age ( 55) than in fetal and younger postnatal samples (fetal to 15 months postnatal, 167) (0.0167 vs. 2.354 pmol/mg microsomal protein; < 0.0001). CYP2C8, but not CYP1A2, protein levels significantly correlated with those of CYP2C9, CYP2C19, and CYP3A4 ( < 0.001), consistent with CYP2C8 and CYP1A2 ontogeny probably being controlled by different mechanisms. This study provides key data for the physiologically based pharmacokinetic model-based prediction of age-dependent pyrethroid metabolism, which will be used for IVIVE to support pyrethroid risk assessment for early life stages.
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http://dx.doi.org/10.1124/dmd.116.074583DOI Listing
May 2017

Glucagon increases insulin levels by stimulating insulin secretion without effect on insulin clearance in mice.

Peptides 2017 02 21;88:74-79. Epub 2016 Dec 21.

Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA. Electronic address:

Circulating insulin is dependent on a balance between insulin appearance through secretion and insulin clearance. However, to what extent changes in insulin clearance contribute to the increased insulin levels after glucagon administration is not known. This study therefore assessed and quantified any potential effect of glucagon on insulin kinetics in mice. Prehepatic insulin secretion in mice was first estimated following glucose (0.35g/kg i.v.) and following glucose plus glucagon (10μg/kg i.v.) using deconvolution of plasma C-peptide concentrations. Plasma concentrations of glucose, insulin, and glucagon were then measured simultaneously in individual mice following glucose alone or glucose plus glucagon (pre dose and at 1, 5, 10, 20min post). Using the previously determined insulin secretion profiles and the insulin concentration-time measurements, a population modeling analysis was applied to estimate the one-compartment kinetics of insulin disposition with and without glucagon. Glucagon with glucose significantly enhanced prehepatic insulin secretion (Cmax and AUC) compared to that with glucose alone (p<0.0001). From the modeling analysis, the population mean and between-animal SD of insulin clearance was 6.4±0.34mL/min for glucose alone and 5.8±1.5mL/min for glucagon plus glucose, with no significant effect of glucagon on mean insulin clearance. Therefore, we conclude that the enhancement of circulating insulin after glucagon administration is solely due to stimulated insulin secretion.
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http://dx.doi.org/10.1016/j.peptides.2016.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272823PMC
February 2017

Quantitative bias analysis for epidemiological associations of perfluoroalkyl substance serum concentrations and early onset of menopause.

Environ Int 2017 Feb 5;99:245-254. Epub 2016 Dec 5.

RAMBOLL ENVIRON, RTP, NC, USA. Electronic address:

An association between increased serum concentrations of perfluoroalkyl substances (PFAS) such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and early menopause has been reported (Knox et al., 2011; Taylor et al., 2014). This association may be explained by the fact that women who underwent menopause no longer excrete PFAS through menstruation. Our objective was to assess how much of the epidemiologic association between PFAS and altered timing of menopause might be explained by reverse causality. We extended a published population life-stage physiologically-based pharmacokinetic (PBPK) model of PFOS and PFOA characterized by realistic distributions of physiological parameters including age at menopause. We then conducted Monte Carlo simulations to replicate the Taylor population (Taylor et al., 2014) and the Knox population (Knox et al., 2011). The analysis of the simulated data overall showed a pattern of results that was comparable to those reported in epidemiological studies. For example, in the simulated Knox population (ages 42-51) the odds ratio (OR) for menopause in the fifth quintile of PFOA compared to those in the first quintile was 1.33 (95% CI 1.26-1.40), whereas the reported OR was 1.4 (95% CI 1.1-1.8). Using our model structure, a substantial portion of the associations reported can be explained by pharmacokinetics.
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http://dx.doi.org/10.1016/j.envint.2016.11.030DOI Listing
February 2017

Profiling the relationship between tumor-associated macrophages and pharmacokinetics of liposomal agents in preclinical murine models.

Nanomedicine 2017 02 5;13(2):471-482. Epub 2016 Oct 5.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

The mononuclear phagocyte system (MPS) has previously been shown to significantly affect the clearance, tumor delivery, and efficacy of nanoparticles (NPs). This study profiled MPS cell infiltration in murine preclinical tumor models and evaluated how these differences may affect tumor disposition of PEGylated liposomal doxorubicin (PLD) in models sensitive and resistant to PLD. Significant differences in MPS presence existed between tumor types (e.g. ovarian versus endometrial), cell lines within the same tumor type, and location of tumor implantation (i.e. flank versus orthotopic xenografts). Further, the differences in MPS presence of SKOV-3 ovarian and HEC1A endometrial orthotopic cancer models may account for the 2.6-fold greater PLD tumor exposure in SKOV-3, despite similar plasma, liver and spleen exposures. These findings suggest that profiling the presence of MPS cells within and between tumor types is important in tumor model selection and in tumor types and patients likely to respond to NP treatment.
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http://dx.doi.org/10.1016/j.nano.2016.09.015DOI Listing
February 2017

Pharmacokinetic bias analysis of the epidemiological associations between serum polybrominated diphenyl ether (BDE-47) and timing of menarche.

Environ Res 2016 10 16;150:541-548. Epub 2016 Jul 16.

Ramboll Environ, Research Triangle Park, NC, USA.

Background: Associations between serum levels of polybrominated diphenyl ether (PBDE) and timing of pubertal development in adolescent girls (e.g., menarche) have been reported in both a cross-sectional and in a longitudinal study. The associations may be biased by growth dilution and pharmacokinetic changes during pubertal development.

Objectives: To use a physiologically-based pharmacokinetic (PBPK) model to assess how much of the epidemiologic association between PBDE and altered timing of menarche might be attributable to growth dilution and pubertal maturation.

Methods: We developed a PBPK model of BDE-47, a major congener of PBDE, to perform Monte Carlo (MC) simulation of plasma BDE-47 levels in a hypothetical target population aged 2 to 22 years old. The model used realistic distributions of physiological parameters including timing of growth spurts and menarche. The simulated data were analyzed as if they had come from an epidemiologic study. We compared the results based on the simulated population to those reported.

Results: The population characteristics, including age and body mass index (BMI) were similar between the simulated and reported groups. In the cross-sectional study design, the association between proportion of subjects with menarche before age 12 years and BDE-47 serum concentration was inverse in our simulated population, whereas the reported association was positive. In the longitudinal study design, simulated data were not suggestive of an association, whereas a delay in pubertal onset with higher concentrations of BDE-47 was observed in the epidemiologic study.

Conclusion: Results of our simulation suggest that in the previous cross-sectional study there was a small negative bias due to pharmacokinetics in the reported relationship between BDE-47 and age at menarche. However, in the longitudinal study there was little evidence of bias. Our study showed how PBPK modeling can be used to quantify the potential bias in epidemiological studies and also suggested that further studies on the optimal approach to modeling exposure are warranted to better understand and quantify the potential bias in the epidemiological associations with BDE-47 due to pharmacokinetics.
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http://dx.doi.org/10.1016/j.envres.2016.07.004DOI Listing
October 2016

Gulp1 is associated with the pharmacokinetics of PEGylated liposomal doxorubicin (PLD) in inbred mouse strains.

Nanomedicine 2016 10 9;12(7):2007-2017. Epub 2016 Jun 9.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

Nanoparticles (NP) including liposomes are cleared by phagocytes of the mononuclear phagocyte system. High inter-patient variability in pharmacokinetics of PEGylated liposomal doxorubicin (PLD) has been reported. We hypothesized that genetic factors may be associated with the variable disposition of PLD. We evaluated plasma and tissue disposition of doxorubicin after administration of PLD at 6mg/kg IV ×1 via tail vein in 23 different male inbred mouse strains. An approximately 13-fold difference in plasma clearance of PLD was observed among inbred strains. We identified a correlation between strain-specific differences in PLD clearance and genetic variation within a genomic region encoding GULP1 (PTB domain containing engulfment adapter 1) protein using haplotype associated mapping and the efficient mixed-model association algorithms. Our results also show that Gulp1 expression in adipose tissue was associated with PLD disposition in plasma. Our findings suggest that genetic variants may be associated with inter-individual pharmacokinetic differences in NP clearance.
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http://dx.doi.org/10.1016/j.nano.2016.05.019DOI Listing
October 2016

Technetium Tc 99m sulfur colloid phenotypic probe for the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin in women with ovarian cancer.

Cancer Chemother Pharmacol 2016 Mar 28;77(3):565-73. Epub 2016 Jan 28.

Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill-Eshelman School of Pharmacy, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC, 27599-7361, USA.

Purpose: Significant variability in the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin (PLD) exists. PLD undergoes clearance via the mononuclear phagocyte system (MPS). Technetium Tc 99m sulfur colloid (TSC) is approved for imaging MPS cells. We investigated TSC as a phenotypic probe of PLD pharmacokinetics and pharmacodynamics in women with epithelial ovarian cancer.

Methods: TSC 10 mCi IVP was administered and followed by dynamic planar and SPECT/CT imaging and blood pharmacokinetics sampling. PLD 30-40 mg/m(2) IV was administered with or without carboplatin, followed by plasma pharmacokinetics sampling.

Results: There was a linear relationship between TSC clearance and encapsulated doxorubicin clearance (R(2) = 0.61, p = 0.02), particularly in patients receiving PLD alone (R(2) = 0.81, p = 0.04). There was a positive relationship (ρ = 0.81, p = 0.01) between maximum grade palmar-plantar erythrodysesthesia toxicity developed and estimated encapsulated doxorubicin concentration in hands.

Conclusions: TSC is a phenotypic probe for PLD pharmacokinetics and pharmacodynamics and may be used to individualize PLD therapy in ovarian cancer and for other nanoparticles in development.
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http://dx.doi.org/10.1007/s00280-015-2945-yDOI Listing
March 2016

Roles of chemokines CCL2 and CCL5 in the pharmacokinetics of PEGylated liposomal doxorubicin in vivo and in patients with recurrent epithelial ovarian cancer.

Nanomedicine 2015 Oct 17;11(7):1797-807. Epub 2015 Jun 17.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

Unlabelled: Nanoparticles (NPs) are cleared by monocytes and macrophages. Chemokines CCL2 and CCL5 are key mediators for recruitment of these immune cells into tumors and tissues. The purpose of this study was to investigate effects of CCL2 and CCL5 on the pharmacokinetics (PKs) of NPs. Mice deficient in CCL2 or CCL5 demonstrated altered clearance and tissue distribution of polyethylene glycol tagged liposomal doxorubicin (PLD) compared to control mice. The PK studies using mice bearing SKOV3 ovarian cancer xenografts revealed that the presence of tumor cells and higher expression of chemokines were significantly associated with greater clearance of PLD compared to non-tumor bearing mice. Plasma exposure of encapsulated liposomal doxorubicin positively correlated with the total exposure of plasma CCL2 and CCL5 in patients with recurrent epithelial ovarian cancer treated with PLD. These data emphasize that the interplay between PLD and chemokines may have an important role in optimizing PLD therapy.

From The Clinical Editor: The use of nanoparticles as drug delivery carriers is gaining widespread acceptance in the clinical setting. However, the underlying pharmacokinetics of these novel drugs has not really been elucidated. In this interesting article, the authors carried out experiments using mice deficient in CCL2 or CCL5 to study the clearance of liposomal system. They showed the important role the immune system played and would enable better designs of future drug delivery systems.
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http://dx.doi.org/10.1016/j.nano.2015.05.007DOI Listing
October 2015

The effects of nanoparticle drug loading on the pharmacokinetics of anticancer agents.

Nanomedicine (Lond) 2015 Feb;10(3):447-63

Division of Pharmacotherapy & Experimental Therapeutics, University of North Carolina at Chapel Hill (UNC) Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA.

Major advances in carrier-mediated agents, which include nanoparticles, nanosomes and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages, such as greater solubility, duration of exposure and delivery to the site of action over their small-molecule counterparts, there is substantial variability in systemic clearance and distribution, tumor delivery and pharmacologic effects (efficacy and toxicity) of these agents. This review provides an overview of factors that affect the pharmacokinetics and pharmacodynamics of carrier-mediated agents in preclinical models and patients.
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http://dx.doi.org/10.2217/nnm.14.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594874PMC
February 2015

Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.

Clin Cancer Res 2014 Dec 17;20(23):6083-95. Epub 2014 Sep 17.

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, Chapel Hill, North Carolina. Carolina Center of Cancer Nanotechnology Excellence, UNC at Chapel Hill, Chapel Hill, North Carolina. Center for Pharmacogenomics and Individualized Therapy, UNC at Chapel Hill, Chapel Hill, North Carolina.

Purpose: Tumor cells are surrounded by a complex microenvironment. The purpose of our study was to evaluate the role of heterogeneity of the tumor microenvironment in the variability of nanoparticle (NP) delivery and efficacy.

Experimental Designs: C3(1)-T-Antigen genetically engineered mouse model (C3-TAg) and T11/TP53(Null) orthotopic syngeneic murine transplant model (T11) representing human breast tumor subtypes basal-like and claudin-low, respectively, were evaluated. For the pharmacokinetic studies, non-liposomal doxorubicin (NL-doxo) or polyethylene glycol tagged (PEGylated) liposomal doxorubicin (PLD) was administered at 6 mg/kg i.v. x1. Area under the concentration versus time curve (AUC) of doxorubicin was calculated. Macrophages, collagen, and the amount of vasculature were assessed by IHC. Chemokines and cytokines were measured by multiplex immunochemistry. NL-doxo or PLD was administered at 6 mg/kg i.v. weekly x6 in efficacy studies. Analyses of intermediary tumor response and overall survival were performed.

Results: Plasma AUC of NL-doxo and PLD encapsulated and released doxorubicin was similar between two models. However, tumor sum total AUC of PLD was 2-fold greater in C3-TAg compared with T11 (P < 0.05). T11 tumors showed significantly higher expression of CC chemokine ligand (CCL) 2 and VEGF-a, greater vascular quantity, and decreased expression of VEGF-c compared with C3-TAg (P < 0.05). PLD was more efficacious compared with NL-doxo in both models.

Conclusion: The tumor microenvironment and/or tumor cell features of breast cancer affected NP tumor delivery and efficacy, but not the small-molecule drug. Our findings reveal the role of the tumor microenvironment in variability of NP delivery and therapeutic outcomes.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-0493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565518PMC
December 2014

Nanoparticles and the mononuclear phagocyte system: pharmacokinetics and applications for inflammatory diseases.

Curr Rheumatol Rev 2014 ;10(1):22-34

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 120 Mason Farm Road, suite 1013, CB 7361, Chapel Hill, NC 27599-7361, USA.

Nanoparticles (NPs) provide several advantages over the small molecule drugs including prolonged circulation time and enhanced delivery to targeted sites. Once a NP enters the body, it interacts with host's immune system and is engulfed by cells of the mononuclear phagocyte system (MPS). The interaction between NPs and the immune cells can result in immunosuppression or immunostimulation, which may enhance or reduce the treatment effects of NPs. Therefore, it is critical to understand the interactions between NPs and the immune system in order to optimize the treatment benefit and minimize the undesirable toxicities of NPs. This review elaborates on the interaction between NP and the MPS and its impacts on the pharmacokinetics (PK) and pharmacodynamics (PD) of NPs and applications for inflammatory diseases. This review also encompasses an overview of NPs being developed for treatment of inflammatory diseases.
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http://dx.doi.org/10.2174/1573403x10666140914160554DOI Listing
June 2015

Factors affecting the pharmacokinetics and pharmacodynamics of liposomal drugs.

J Liposome Res 2012 Sep 15;22(3):177-92. Epub 2012 Feb 15.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

Various attempts to increase the therapeutic index of the drug while minimizing side effects have been made in drug delivery systems. Among several promising strategies, liposomes represent an advanced technology to target active molecules to the site of action. Rapid clearance of circulating liposomal drugs administered intravenously has been a critical issue because circulation time in the blood affects drug exposure at the target site. The clinical use of liposomal drugs is complicated by large intra- and interindividual variability in their pharmacokinetics (PK) and pharmacodynamics (PD). Thus, it is important to understand the factors affecting the PK/PD of the liposomal formulation of drugs and to elucidate the mechanisms underlying the variability in the PK/PD of liposomal drugs. In this review article, we describe the characteristics of liposome formulations and discuss the effects of various factors, including liposome-associated factors, host-associated factors, and treatment on the PK/PD of liposomal agents.
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http://dx.doi.org/10.3109/08982104.2012.655285DOI Listing
September 2012

Risk of catecholamine crisis in patients undergoing resection of unsuspected pheochromocytoma.

Int Braz J Urol 2011 Jan-Feb;37(1):35-40;discussion 40-1

Department of Radiology, University of California, San Francisco, CA, USA.

Purpose: To report the risk of catecholamine crisis in patients undergoing resection of unsuspected pheochromocytoma.

Materials And Methods: Over a four-year period, we retrospectively identified four patients who underwent resection of adrenal pheochromocytoma in whom the diagnosis was unsuspected based on preoperative clinical, biochemical, and imaging evaluation.

Results: None of the patients exhibited preoperative clinical features of catecholamine excess. Preoperative biochemical screening in two patients was normal. CT scan performed in all patients demonstrated a nonspecific enhancing adrenal mass. During surgical resection of the adrenal mass, hemodynamic instability was observed in two of four patients, and one of these two patients also suffered a myocardial infarct.

Conclusion: Both surgeons and radiologists should maintain a high index of suspicion for pheochromocytoma, as the tumor can be asymptomatic, biochemically negative, and have nonspecific imaging features. Resection of such unsuspected pheochromocytomas carries a substantial risk of intraoperative hemodynamic instability.
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http://dx.doi.org/10.1590/s1677-55382011000100005DOI Listing
December 2011

Infarct morphology identifies patients with substrate for sustained ventricular tachycardia.

J Am Coll Cardiol 2005 Apr;45(7):1104-8

Department of Medicine, Divisions of Cardiology and Radiology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.

Objectives: We sought to evaluate whether infarct size characterization by cardiac magnetic resonance imaging (MRI) is a better predictor of inducible ventricular tachycardia (VT) than left ventricular ejection fraction (LVEF).

Background: Inducibility of VT at electrophysiologic study (EPS) and low LVEF can identify patients with a substrate for VT. Magnetic resonance imaging has been shown to identify, with high precision, areas of myocardial infarction and may therefore be a better tool to evaluate for a substrate for VT.

Methods: We studied 48 patients with known coronary artery disease who were referred for EPS using cine and gadolinium-enhanced MRI. Wall motion and infarct characteristics were determined blindly and compared among patients with no inducible ventricular arrhythmias (n = 21), those with inducible monomorphic VT (MVT, n = 18), and those with either inducible polymorphic VT or ventricular fibrillation (n = 9).

Results: Patients with MVT had larger infarcts than patients who did not have inducible arrhythmias (mass: 49 +/- 5 g [SE] vs. 28 +/- 5 g, p < 0.005; surface area: 172 +/- 15 cm(2) vs. 93 +/- 14 cm(2), p < 0.0005). Patients with polymorphic VT/fibrillation had intermediate values (mass: 36 +/- 7 g; surface area: 115 +/- 22 cm(2)). Ejection fraction was inversely related to infarct mass and surface area, with R(2) values ranging from 0.21 to 0.27. Logistic regression and receiver-operating characteristic analysis demonstrated that infarct mass and surface area were better predictors of inducibility of MVT than LVEF.

Conclusions: Infarct surface area and mass, as measured by cardiac MRI, are better identifiers of patients who have a substrate for MVT than LVEF. Further evaluation of infarct size characterization by cardiac MRI as a predictor of sudden cardiac death is warranted.
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http://dx.doi.org/10.1016/j.jacc.2004.12.057DOI Listing
April 2005

Safety of gadolinium contrast angiography in patients with chronic renal insufficiency.

J Vasc Surg 2003 Aug;38(2):313-8

Department of Surgery, Division of Vascular Surgery, Northwestern Memorial Hospital, Feinberg Northwestern University Medical School, 201 E Huron Street, Chicago, IL 60611, USA.

Objective: To prevent iodinated contrast medium-induced nephrotoxicity, gadolinium has been used increasingly for magnetic resonance angiography (MRA) or conventional digital subtraction angiography (DSA) to visualize arterial anatomy in patients undergoing vascular surgery who are considered at high risk because of chronic renal insufficiency. We assessed the safety of gadolinium-based contrast medium as a substitute for iodinated contrast medium-enhanced examinations. We determined the incidence of gadolinium-induced nephrotoxicity in a clinical setting and searched for contributing risk factors. Patients and methods In a single-center retrospective study from December 1999 to January 2001, 218 inpatients underwent MRA and 42 inpatients underwent DSA, with gadolinium as the sole contrast agent. Patient comorbid conditions, indications for vascular imaging, contrast dose, urine output, baseline and post-procedure serum creatinine concentration (SCr), and outcome were recorded for all patients in whom gadolinium-induced renal failure developed.

Results: Of 260 patients who received gadolinium-based contrast agents, at a dose of 0.25 mmol/kg or more, 195 patients (75%) had pre-test baseline chronic renal insufficiency. In 7 of 195 patients (3.5%) acute renal failure developed after gadolinium-based contrast medium administration, for MRA (n = 153) in 3 patients (1.9%) and DSA (n = 42) in 4 patients (9.5%). Average baseline SCr in the 195 patients with chronic renal insufficiency was 38.2 +/- 1.6 mL/min/1.73 m(2), and in the 7 patients in whom acute renal failure developed, baseline SCr was 32.5 +/- 7.8 mL/min/1.73 m(2) (P =.33). Respective intravenous and intra-arterial gadolinium doses in these 7 patients ranged from 0.31 to 0.41 mmol/kg for MRA and 0.27 to 0.42 mmol/kg for DSA. Acute renal failure did not develop in any of 65 patients with normal baseline SCr.

Conclusion: Despite reports of negligible nephrotoxicity, rarely gadolinium-based contrast agents can cause acute renal failure in patients with underlying chronic renal insufficiency. Estimation of creatinine clearance alone does not enable prediction of which patients are likely to have acute renal failure. Patients at high-risk should be identified, and prophylactic measures should be taken to reduce the risk for nephrotoxicity.
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http://dx.doi.org/10.1016/s0741-5214(03)00315-xDOI Listing
August 2003