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Thiotepa), Clopidogrel, and Ticlopidine As Selective Inactivators of Human Cytochrome P450 2B6

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Thiotepa), Clopidogrel, and Ticlopidine As Selective Inactivators of Human Cytochrome P450 2B6 0090-9556/07/3511-2053–2059$20.00 DRUG METABOLISM AND DISPOSITION Vol. 35, No. 11 Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics 15883/3264007 DMD 35:2053–2059, 2007 Printed in U.S.A. -A Comparison of 2-Phenyl-2-(1-piperidinyl)propane (PPP), 1,1؅,1؆ Phosphinothioylidynetrisaziridine (ThioTEPA), Clopidogrel, and Ticlopidine as Selective Inactivators of Human Cytochrome P450 2B6 Robert L. Walsky and R. Scott Obach Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer, Inc., Groton, Connecticut Received March 22, 2007; accepted August 3, 2007 ABSTRACT: The use of selective chemical inhibitors of human cytochrome greater for clopidogrel because of a greater kinact value (1.9/min). ␮ Downloaded from P450 (P450) enzymes represents a powerful method by which the Ticlopidine was potent with KI and kinact values of 0.32 M and relative contributions of various human P450 enzymes to the me- 0.43/min, respectively. The selectivity of these four agents for tabolism of drugs can be determined. However, the identification CYP2B6 was determined by testing their effects on other human of CYP2B6 in the metabolism of drugs has been more challenging P450 enzyme activities using conditions that yield ϳ90% inactiva- because of the lack of a well established inhibitor of this enzyme. tion of CYP2B6 activity. The results showed that preincubation of In this report, we describe the selectivity of 2-phenyl-2-(1-piperidi- human liver microsomes with PPP at 30 ␮M for 30 min provided nyl)propane (PPP) as an inactivator of CYP2B6 and compare this more selective inhibition for CYP2B6 than thioTEPA, clopidogrel, dmd.aspetjournals.org selectivity versus other CYP2B6 inactivators: 1,1؅,1؆-phosphino- and ticlopidine. Furthermore, the use of clopidogrel is complicated thioylidynetrisaziridine (thioTEPA), clopidogrel, and ticlopidine. by the observation that this agent is not stable in the presence of ␮ Values of KI and kinact for PPP were 5.6 M and 0.13/min for human liver microsomes, even without addition of NADPH. There- bupropion hydroxylase catalyzed by pooled human liver micro- fore, PPP can serve as a selective chemical inactivator of CYP2B6 somes, and values for thioTEPA were similar (4.8 ␮M and 0.20/min, and be used to define the role of CYP2B6 in the metabolism of respectively). Intrinsic inactivation capability was considerably drugs. at ASPET Journals on March 9, 2016 Cytochrome P450 (P450) enzymes are the most important enzymes mide, ifosfamide, and sertraline (Chang et al., 1993; Granvil et al., 1999; in drug metabolism and are responsible for clearance of a majority of Kobayashi et al., 1999; Roy et al., 1999; Faucette et al., 2000; Hesse et drugs. Five of these enzymes, CYP1A2, CYP2C9, CYP2C19, al., 2000; Huang et al., 2000; Rae et al., 2002; Ward et al., 2003; Obach CYP2D6, and CYP3A4, have been considered as important drug- et al., 2005; Turpeinen et al., 2005). However, robust, well characterized metabolizing P450 enzymes in humans, and it has been proposed that inhibitors of CYP2B6 that are selective for this enzyme versus other these enzymes should be routinely examined as potential contributors human P450 enzymes have not been thoroughly evaluated. An early to the metabolism of new drugs using in vitro approaches (Bjornsson report on CYP2B6 described orphenadrine as a potential CYP2B6 inhib- et al., 2003). Well characterized, selective chemical inhibitors of these itor; however, the selectivity is not high (Guo et al., 1997). More recent five enzymes have been described and applied throughout the past work has described potent mechanism-based inactivation of CYP2B6 by several years in examinations of the metabolism of drugs and other clopidogrel (Richter et al., 2004), ticlopidine (Richter et al., 2004; Tur- xenobiotics (Madan et al., 2002). The most frequently used chemical peinen et al., 2004), and 1,1Ј,1Љ-phosphinothioylidynetrisaziridine (thio- inhibitors are furafylline (CYP1A2 inactivator), sulfaphenazole TEPA) (Harleton et al., 2004; Turpeinen et al., 2004; Richter et al., 2005). (CYP2C9-reversible inhibitor), S-mephenytoin (CYP2C19-competi- In studies designed to gain a better understanding of the biochemistry of tive substrate), quinidine (CYP2D6-reversible inhibitor), and ketocon- CYP2B6, Chun et al. (2000) identified an analog of phencyclidine, azole (CYP3A-reversible inhibitor), although there are others that 2-phenyl-2-(1-piperidinyl)propane (PPP) (Fig. 1), as a mechanism-based have also been successfully applied. inactivator of human CYP2B6. However, recently, some other human P450 enzymes have been The potential for PPP to be used as a tool in identifying a role for shown to play a major role in the metabolism of some drugs. Of the CYP2B6 in the metabolism of drugs has not been explored. This human P450 enzymes, CYP2B6 has recently emerged as one of increas- requires an examination of the potential for PPP to not affect other ing importance. CYP2B6 has been shown to be involved in the metab- olism of several drugs, including efavirenz, bupropion, cyclophospha- human P450 enzymes at inhibitor concentrations that would provide 90% or more inhibition of CYP2B6. In this report, the selectivity of Article, publication date, and citation information can be found at PPP, thioTEPA, clopidogrel, and ticlopidine as CYP2B6 inactivators http://dmd.aspetjournals.org. has been examined in an attempt to determine which, if any, would be doi:10.1124/dmd.107.015883. a superior CYP2B6 reaction phenotyping tool and to define experi- ABBREVIATIONS: P450, cytochrome P450; thioTEPA, 1,1Ј,1Љ-phosphinothioylidynetrisaziridine; PPP, 2-phenyl-2-(1-piperidinyl)propane; MS/MS, tandem mass spectrometry. 2053 2054 WALSKY AND OBACH N O OMe Cl N S PPP FIG. 1. Structures of the inactivators examined in this report. (2-phenyl-2-(1-piperdinyl)propane) Clopidogrel S Cl NPN N N Downloaded from S ThioTEPA (triethylenethiophosphoramide) Ticlopidine mental conditions under which these agents could be used in P450 NADPH (1.3 mM). After preincubation periods, aliquots of 20 ␮l were ␮ ϫ dmd.aspetjournals.org reaction phenotyping experiments. removed and added to a mixture of bupropion (800 M, 10 KM) and NADPH (1.3 mM) in 100 mM potassium phosphate buffer, pH 7.4, followed by Materials and Methods incubation at 37°C for 12 min. Incubations were terminated by acidification Materials. P450 substrates, metabolite standards, and internal standards upon addition of 0.02 ml of termination solvent (H2O/CH3CN/HCOOH; 92: 2 were obtained as previously described (Walsky and Obach, 2004). Ticlopidine 5:3) containing [ H6]hydroxybupropion as an internal standard, followed by and thioTEPA were obtained from Sigma Chemical Co. (St. Louis, MO). filtration and analysis by liquid chromatography/MS/MS. Clopidogrel was obtained from Sequoia Research Products (Oxford, UK). PPP Time-Dependent Inhibition (KI/kinact) CYP2B6 Assay (Clopidogrel). To was synthesized under contract by Syncom BV (Groningen, The Netherlands). reduce an observed instability of clopidogrel in the presence of human liver Human liver microsomes pooled from 53 donors were obtained under contract microsomes, a modified experimental procedure was followed. Preincubations at ASPET Journals on March 9, 2016 from Gentest, Inc. (Woburn, MA). consisted of the following conditions: MgCl2 (3.3 mM), NADPH (1.3 mM) in Reversible Inhibition of CYP2B6. Specific aspects of the incubation 100 mM potassium phosphate buffer, pH 7.4. Buffer and inhibitor were mixed conditions (e.g., protein concentration, incubation time, reaction termination and prewarmed at 37°C; preincubations were initiated by the addition of solvent, etc.) were previously reported (Walsky and Obach, 2004). The pooled human liver microsomes (0.5 mg/ml). After preincubation periods, ␮ ␮ Michaelis constant for bupropion hydroxylase was 82 Ϯ 1 ␮M for pooled liver aliquots of 20 l were removed and added to a mixture of bupropion (800 M, ϫ microsomes. In general, human liver microsomes (0.05 mg/ml) were mixed 10 KM) and NADPH (1.3 mM) in 100 mM potassium phosphate buffer, pH 7.4, followed by incubation at 37°C for 12 min. Incubations were terminated with buffer (100 mM KH2PO4, pH 7.4), MgCl2 (3.3 mM), and substrate (at by acidification upon addition of 0.02 ml of termination solvent (H O/CH CN/ KM) and then warmed to 37°C in a 96-well temperature-controlled heater 2 3 2 block. Aliquots of this mixture (0.18 ml) were delivered to each well of a HCOOH; 92:5:3) containing [ H6]hydroxybupropion as an internal standard, 96-well polypropylene polymerase chain reaction plate maintained at 37°C, followed by filtration and analysis by liquid chromatography/MS/MS. followed by addition of the inhibitor or control solvent (mixture of water and Determination of Selectivity for CYP2B6 Inactivation and Effect of Protein Concentration. After determination of inactivation kinetic parameters CH3CN) as applicable. The inhibitors, standards, and quality controls were prepared as 100ϫ stock solutions and 2-␮l aliquots dispensed to the appro- for CYP2B6, inactivators were tested for selectivity among other P450 en- priate incubations maintaining solvent concentrations at 1% (v/v) or less. zymes using a concentration and incubation time that yielded 90% inactivation Incubations were commenced with the addition of NADPH stock (assay of CYP2B6. PPP and thioTEPA (30 ␮M; 30 min), ticlopidine, and clopidogrel concentration ϭ 1.3 mM) to a final incubation volume of 0.2 ml and main- (3 ␮M; 10 min) were incubated with NADPH and human liver microsomes at tained at 37°C for 20 min. Incubations were terminated by acidification upon protein concentrations that were 10-fold greater than those required for the addition of 0.02 ml of termination solvent (H2O/CH3CN/HCOOH; 92:5:3) specific P450 assays. After this inactivation incubation, the mixtures were 2 containing [ H6]hydroxybupropion as an internal standard, followed by filtra- diluted 10-fold into the activity assays for CYP1A2, CYP2A6, CYP2C8, tion through a 45-␮m filter and analysis by high-performance liquid chroma- CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A according to described tography/tandem mass spectrometry (MS/MS) as previously described (Wal- methods (Walsky and Obach, 2004).
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