Drug transporters in pharmacokinetics

Petzinger, Ernst; Geyer, Joachim

doi:10.1007/s00210-006-0042-9

Cited by 92 publications

(46 citation statements)

References 138 publications

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“…In both scores, plasma bilirubin is a parameter that monitors, among others, transport capacity of hepatocytes and biotransformation, i.e., the detoxifying capacity of the liver. Hepatocyte-mediated detoxification involves four phases: phase 0 represents the uptake of substances into hepatocytes, phase I metabolism of substances, phase II, conjugation and phase III export of substances and/or metabolites from hepatocytes (Petzinger and Geyer, 2006;Vavricka et al, 2002). Hence, transport proteins are key molecular components of the hepatocellular detoxification system (phase 0 and phase III) and consequently of liver function tests.…”

Section: Introductionmentioning

confidence: 99%

The emerging role of transport systems in liver function tests

Stieger

Heger

Graaf

et al. 2012

European Journal of Pharmacology

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Liver function tests are of critical importance for the management of patients with severe or terminal liver disease. They are also used as prognostic tools for planning liver resections. In recent years many transport systems have been identified that also transport substances employed in liver function tests. Such substances include endogenous bilirubin or exogenously administered indocyanine green, agents for magnetic resonance imaging, agents for single photon emission computed tomography or agents for breath tests. The increasing functional and molecular information on the respective transport systems should improve the management and as a result the outcome of patients scheduled for liver surgery or transplantation. To achieve the latter goal, clinical studies that assess individual patients' liver function over the course of their disease with liver function tests are needed to firmly establish and validate recently introduced and novel liver function markers. The emerging role of transport systems in liver function tests Bruno Stieger is supported by grant # 31003A_124652 from the Swiss National Science foundation. AbstractLiver function tests are of critical importance for the management of patients with severe or terminal liver disease. They are also used as prognostic tools for planning liver resections. In recent years many transport systems have been identified, that also transport substances employed in liver function tests. Such substances include endogenous bilirubin or exogenously administered indocyanine green, agents for magnetic resonance imaging, agents for single photon emission computed tomography or agents for breath tests. The increasing functional and molecular information on the respective transport systems should improve the management and as a result the outcome of patients scheduled for liver surgery or transplantation. To achieve the latter goal, clinical studies that assess individual patients liver function over the course of their disease with liver function testes are needed to firmly establish and validate recently introduced and novel liver function markers.

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Section: Introductionmentioning

confidence: 99%

The emerging role of transport systems in liver function tests

Stieger

Heger

Graaf

et al. 2012

European Journal of Pharmacology

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“…Carrier-mediated uptake processes by solute carrier (SLC) transporters are being increasingly recognized as a major determinant of drug absorption, tissue distribution, and elimination (Ho and Kim, 2005;Petzinger and Geyer, 2006). Members of the organic anion-transporting polypeptide (OATP) superfamily (SLCO gene family) mediate sodium-independent transport of amphipathic organic compounds including many endobiotics, such as bile acids, steroid conjugates, and thyroid hormones, and several classes of pharmacological agents, in particular HMG-CoA reductase inhibitors (Ho and Kim, 2005).…”

Section: Introductionmentioning

confidence: 99%

pH Dependence of Organic Anion-Transporting Polypeptide 2B1 in Caco-2 Cells: Potential Role in Antiretroviral Drug Oral Bioavailability and Drug–Drug Interactions

Kis

Zastre²,

Ramaswamy³

et al. 2010

J Pharmacol Exp Ther

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Human intestinal epithelium expresses a number of drug efflux and influx transporters that can restrict and/or facilitate intestinal drug uptake during absorption. Organic anion-transporting polypeptide 2B1 (OATP2B1), a multispecific organic anion uptake transporter localized at the brush-border membrane of intestinal epithelial cells, is known to transport many endogenous substrates (e.g., steroid conjugates) and xenobiotics (e.g., statins). At present, limited information is available on the mechanism of HIV protease inhibitor (PIs) intestinal uptake. In this study, we examined the interaction of PIs with the OATP2B1 transport system in Caco-2 cells, an in vitro model of human intestinal epithelium, and Madin-Darby canine kidney II cells stably transfected with OATP2B1. The expression of OATP2B1 transcript and protein was confirmed by reverse transcription-polymerase chain reaction and immunoblot analysis, respectively. Estrone-3-sulfate (E3S) uptake demonstrated biphasic saturation kinetics in Caco-2 cells, with dissociation constants (K M ) of 6 Ϯ 2 M and 1.5 Ϯ 0.2 mM. Several PIs potently inhibited OATP2B1-mediated transport in Caco-2 cells at clinically relevant IC 50 concentrations for ritonavir (0.93 M), atazanavir (2.2 M), lopinavir (1.7 M), tipranavir (0.77 M), and nelfinavir (2.2 M). An inwardly directed proton gradient was identified as the driving force of E3S uptake through NH 4 Cl intracellular acidification studies with a H ϩ :E3S stoichiometry for OATP2B1 of 1:1. In contrast, although atazanavir and ritonavir uptake by Caco-2 cells was stimulated by low extracellular pH, this process was not mediated by OATP2B1 and was not affected by an outwardly directed H ϩ gradient. Because OATP2B1 exhibits an increasing number of drug substrates, including several statins, alterations of its function by PIs could result in clinically significant drug-drug interactions in the intestine.

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“…In addition to metabolism, elimination of drugs can be strongly dependent on hepatic and/or renal transport processes and drug-drug interactions can be transporter-related as well (Petzinger and Geyer, 2006;Poirier et al, 2007). In the liver, the interplay between uptake and export processes influences the drug intracellular concentration and thereby the amount of drug available for metabolic elimination and/or biliary excretion.…”

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confidence: 99%

Design, Data Analysis, and Simulation of in Vitro Drug Transport Kinetic Experiments Using a Mechanistic in Vitro Model

Poirier

Lavé²,

Portmann³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The use of in vitro data for quantitative predictions of transportermediated elimination in vivo requires an accurate estimation of the transporter Michaelis-Menten parameters, V max and K m , as a first step. Therefore, the experimental conditions of in vitro studies used to assess hepatic uptake transport were optimized regarding active transport processes, nonspecific binding, and passive diffusion (P dif ). A mechanistic model was developed to analyze and accurately describe these active and passive processes. This twocompartmental model was parameterized to account for nonspecific binding, bidirectional passive diffusion, and active uptake processes based on the physiology of the cells. The model was used to estimate kinetic parameters of in vitro transport data from organic anion-transporting peptide model substrates (e.g., cholecystokinin octapeptide deltorphin II, fexofenadine, and pitavastatin). Data analysis by this mechanistic model significantly improved the accuracy and precision in all derived parameters [mean coefficient of variations (CVs) for V max and K m were 19 and 23%, respectively] compared with the conventional kinetic method of transport data analysis (mean CVs were 58 and 115%, respectively, using this method). Furthermore, permeability was found to be highly temperature-dependent in Chinese hamster ovary (CHO) control cells and artificial membranes (parallel artificial membrane permeability assay). Whereas for some compounds (taurocholate, estrone-3-sulfate, and propranolol) the effect was moderate (1.5-6-fold higher permeability at 37°C compared with that at 4°C), for fexofenadine a 16-fold higher passive permeability was seen at 37°C. Therefore, P dif was better predicted if it was evaluated under the same experimental conditions as V max and K m , i.e., in a single incubation of CHO overexpressed cells or rat hepatocytes at 37°C, instead of a parallel control evaluation at 4°C.

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Drug transporters in pharmacokinetics

Cited by 92 publications

References 138 publications

The emerging role of transport systems in liver function tests

The emerging role of transport systems in liver function tests

pH Dependence of Organic Anion-Transporting Polypeptide 2B1 in Caco-2 Cells: Potential Role in Antiretroviral Drug Oral Bioavailability and Drug–Drug Interactions

Design, Data Analysis, and Simulation of in Vitro Drug Transport Kinetic Experiments Using a Mechanistic in Vitro Model

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