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Utility of drug de
Utility of drug de
D RUG M ETABOLISM AND D ISPOSITION Vol. 40, No. 8Copyright (C)2012by The American Society for Pharmacology and Experimental Therapeutics 6DMD 40:,2012
Utility of Drug Depletion-Time Profiles in Isolated Hepatocytes for
Accessing Hepatic Uptake Clearance:Identifying Rate-Limiting
Steps and Role of Passive Processes
Emilie Jigorel 1and J. Brian Houston
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester,
Manchester, United Kingdom
Received March 16, 2012; accepted May 16, 2012ABSTRACT:
Drug depletion-time profiles in isolated hepatocytes, as well as elimination within the hepatocyte, which is distinct from the time microsomes, have become a standard method of assessing he-profile in a conventional incubation, and show higher clearances. patic metabolic clearance in vitro. There is a previously described The four other compounds (clarithromycin,saquinavir, erythromy-adaptation of the depletion approach to allow determination of cin, and repaglinide) show identical depletion-time profiles (andhepatic uptake by transporters in addition to metabolism (Drug clearances) in both sets of incubations. Whether or not the bipha-Metab Dispos 35:859–865,2007). Dual incubations are performed sic nature (andhigher clearance) is evident, indicating transporter where one set of incubations undergo conventional methodology, activity for a particular drug, appears to be dependent on its pas-whereas for the second set, cells and media are separated for sive permeability. Using the parameter K pu to reflect the relative determination of drug loss from the media. The utility of this dual importance of hepatic transporters versus passive diffusion, a incubation approach has been assessed using eight drugs (ator-value of 10was identified as a cutoff for whether the biphasic vastatin, clarithromycin, erythromycin, fexofenadine, pitavastatin, those compounds in excess of 10show this repaglinide, rosuvastatin, and saquinavir) with a range of active characteristic clearly. There appears to be no relationship between uptake, passive permeability, cell binding, and metabolic charac-the presence of the biphasic nature and any other parameter, teristics. Four of these compounds (fexofenadine,rosuvastatin, including cellular binding, extent of metabolism, or the magnitude pitavastatin, and atorvastatin) show a biphasic time profile when of active uptake.
assessing drug loss from media indicative of hepatic uptake before
Introduction of this process, in a way analogous to an in vivo pharmacokinetic
The use of isolated hepatocytes, either in suspension or as a study. The popularity of in vitro systems to make quantitative predic-monolayer, has allowed many aspects of qualitative and quantitative tions of in vivo clearance has led to similar investigations using drug metabolism to be assessed (Hewittet al., 2007; Soars et al., hepatic microsomes (Obach2001; Riley et al., 2005). This substrate 2007a). Investigations performed as early as the mid 1970s (Inabaet depletion approach is widely used because formal kinetic character-al., 1975; Yih and van Rossum, 1977) demonstrated the use of the ization and metabolite quantification are not required, allowing the substrate depletion-time profile within an incubation of isolated hepa-rapid screening of compounds.
tocytes to estimate clearance and to characterize the nonlinear nature The basis of predicting in vivo clearance values from in vitro
kinetic parameters is the use of Michaelis-Menten kinetics and expe-
riential data obtained under initial rate conditions (Houston,1994).
This work was supported by a consortium of pharmaceutical companies For a number of drugs with simple metabolic pathways, it has been (GlaxoSmithKline,Lilly, Pfizer, and Servier) within the Centre of Applied Pharma-demonstrated that drug depletion and metabolite formation can pro-cokinetic Research at the University of Manchester.
1Current affiliation:UCB Pharma SA, Drug Metabolism and Pharmacokinetics, vide equivalent clearance terms (Jonesand Houston, 2004; Sjo ¨gren et
Braine l’Alleud,Belgium. al., 2009; Stringer et al., 2009). However, Jones and Houston (2004)
This work was previously published in part in the following publication:Jigorel have also indicated the importance of enzyme stability for longer E and Houston JB (2009)Involvement of drug uptake in hepatic clearance. Drug incubation times because instability may generate biphasic depletion-Metab Rev 41(Suppl1):66. time profiles. The drug depletion method assumes that the concentra-Article, publication date, and citation information can be found at tions of drug in media and cells are the same, which may not be true http://www.wendangku.net/doc/5df.html .because of transporter protein activity. The most common approach to http://www.wendangku.net/doc/5df.html /10.1124/dmd.112.045732.measure hepatic uptake is analogous to the Michaelis-Menten ap-ABBREVIATIONS:CL active , cleara CL met , cle CL obs , observed in vitro clearance (eitherby uptake or by metabolism); CL uptake , total uptake clearance by active a fu cell , fraction of unbound dr k dep , initial dep K p total , tissue-to-medium total drug K p u , hepatocyte-to-medium unbound drug OATP, organic anion tra P diff , pass LC-MS/MS,liquid chromatography-tandem mass spectrometry.
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