Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

Pfeifer, Nathan D.; Yang, Kunlun; Brouwer, Kim L. R.

doi:10.1124/jpet.113.207472

Cited by 89 publications

(110 citation statements)

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“…Uptake and efflux studies of TCA were performed in human and rat SCH as previously described (Pfeifer et al, 2013). In brief, on day 4 (rat) or day 7 (human) of culture, SCH were preincubated for 10 minutes in 1.5 ml/well (rat) or 0.…”

Section: Methodsmentioning

confidence: 99%

“…The purpose of the present studies was to characterize taurocholic acid (TCA) hepatobiliary disposition (basolateral uptake, basolateral efflux, biliary excretion, flux from canalicular networks) in human and rat sandwich-cultured hepatocytes (SCH) using a novel uptake and efflux protocol developed by our laboratory combined with pharmacokinetic modeling (Pfeifer et al, 2013). Results from the current investigation revealed that species differences exist in cellular TCA efflux pathways in human versus rat SCH; simulations suggested differential hepatobiliary TCA disposition in human and rat SCH due to inhibitors of canalicular excretion and/or basolateral efflux.…”

Section: Introductionmentioning

confidence: 99%

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Species Differences in Hepatobiliary Disposition of Taurocholic Acid in Human and Rat Sandwich-Cultured Hepatocytes: Implications for Drug-Induced Liver Injury

Yang

Pfeifer

Köck

et al. 2015

J Pharmacol Exp Ther

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The bile salt export pump (BSEP) plays an important role in bile acid excretion. Impaired BSEP function may result in liver injury. Bile acids also undergo basolateral efflux, but the relative contributions of biliary (CL Bile ) versus basolateral efflux (CL BL ) clearance to hepatocellular bile acid excretion have not been determined. In the present study, taurocholic acid (TCA; a model bile acid) disposition was characterized in human and rat sandwich-cultured hepatocytes (SCH) combined with pharmacokinetic modeling. In human SCH, biliary excretion of TCA predominated (CL Bile 5 0.14 6 0.04 ml/min per g liver; CL BL 5 0.042 6 0.019 ml/min per g liver), whereas CL Bile and CL BL contributed approximately equally to TCA hepatocellular excretion in rat SCH (CL Bile 5 0.34 6 0.07 ml/min per g liver; CL BL 5 0.26 6 0.07 ml/min per g liver).Troglitazone decreased TCA uptake, CL Bile , and CL BL ; membrane vesicle assays revealed for the first time that the major metabolite, troglitazone sulfate, was a noncompetitive inhibitor of multidrug resistance-associated protein 4, a basolateral bile acid efflux transporter. Simulations revealed that decreased CL Bile led to a greater increase in hepatic TCA exposure in human than in rat SCH. A decrease in both excretory pathways (CL Bile and CL BL ) exponentially increased hepatic TCA in both species, suggesting that 1) drugs that inhibit both pathways may have a greater risk for hepatotoxicity, and 2) impaired function of an alternate excretory pathway may predispose patients to hepatotoxicity when drugs that inhibit one pathway are administered. Simulations confirmed the protective role of uptake inhibition, suggesting that a drug's inhibitory effects on bile acid uptake also should be considered when evaluating hepatotoxic potential. Overall, the current study precisely characterized basolateral efflux of TCA, revealed species differences in hepatocellular TCA efflux pathways, and provided insights about altered hepatic bile acid exposure when multiple transport pathways are impaired.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Species Differences in Hepatobiliary Disposition of Taurocholic Acid in Human and Rat Sandwich-Cultured Hepatocytes: Implications for Drug-Induced Liver Injury

Yang

Pfeifer

Köck

et al. 2015

J Pharmacol Exp Ther

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“…However, because of significant species differences in the function, substrate specificity, and regulation of transporter proteins, it is difficult to directly extrapolate animal hepatobiliary data quantitatively to humans (Ishizuka et al, 1999;Wang and LeCluyse, 2003;Ghibellini et al, 2006;Swift et al, 2010). In vitro models have begun to emerge to characterize hepatobiliary elimination (Pfeifer et al, 2013) and predict the extent of biliary excretion of drugs in humans. Establishing IVIVC of biliary excretion in humans remains a challenge in part because of the lack of high-quality and quantitative biliary excretion data in humans.…”

Section: Prediction From Preclinical Species and In Vitro Systemslearmentioning

confidence: 99%

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Bohnert¹,

Patel²,

Templeton³

et al. 2016

Drug Metabolism and Disposition

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Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (f CL ), estimation of fractional contribution of metabolizing enzyme toward metabolism (f m ), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify f CL and f m , 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.

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“…Additionally, some ABC transporters such as MRP3 and MRP4 are expressed on the basolateral membrane and export compounds into the bloodstream (Klaassen and Aleksunes, 2010). MRP3 and MRP4 have been indicated to play a central role in basolateral efflux of sulfate-and glucoronide-conjugated drug metabolites (ZamekGliszczynski et al, 2006) and have been shown to be involved in basolateral efflux of fexofenadine and rosuvastatin (Tian et al, 2008a;Pfeifer et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Functional ATP-Binding Cassette Drug Efflux Transporters in Isolated Human and Rat Hepatocytes Significantly Affect Assessment of Drug Disposition

et al. 2014

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Freshly isolated hepatocytes are considered the gold standard for in vitro studies of hepatic drug disposition. To ensure a reliable supply of cells, cryopreserved human hepatocytes are often used. ABC-superfamily drug efflux transporters are key elements in hepatic drug disposition. These transporters are often considered lost after isolation of hepatocytes. In the present study, the expression and activity of ABC transporters BCRP, BSEP, P-gp, MRP2, MRP3, and MRP4 in human and rat cryopreserved hepatocytes were investigated. In commercially available human cryopreserved hepatocytes, all drug efflux transporters except human BCRP (hBCRP) exhibited similar expression levels as in fresh liver biopsies. Expression levels of hBCRP were 60% lower in cryopreserved human hepatocytes than in liver tissue, which could lead to, at most, a 2.5-fold reduction in hBCRP-mediated efflux. Fresh rat hepatocytes showed significantly lower levels of rat BCRP compared with liver expression levels; expression levels of other ABC transporters were unchanged. ABC transporters in human cryopreserved cells were localized to the plasma membrane. Functional studies could demonstrate P-gp and BCRP activity in both human cryopreserved and fresh rat hepatocytes. Inhibiting P-gp-mediated efflux by elacridar in in vitro experiments significantly decreased fexofenadine efflux from hepatocytes, resulting in an increase in apparent fexofenadine uptake. The results from the present study clearly indicate that ABC transporter-mediated efflux in freshly isolated as well as cryopreserved rat and human hepatocytes should be taken into account in in vitro experiments used for modeling of drug metabolism and disposition.

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Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

Cited by 89 publications

References 43 publications

Species Differences in Hepatobiliary Disposition of Taurocholic Acid in Human and Rat Sandwich-Cultured Hepatocytes: Implications for Drug-Induced Liver Injury

Species Differences in Hepatobiliary Disposition of Taurocholic Acid in Human and Rat Sandwich-Cultured Hepatocytes: Implications for Drug-Induced Liver Injury

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Functional ATP-Binding Cassette Drug Efflux Transporters in Isolated Human and Rat Hepatocytes Significantly Affect Assessment of Drug Disposition

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