L C Wienkers
Affiliation: Pharmacia and Upjohn
- Factors confounding the successful extrapolation of in vitro CYP3A inhibition information to the in vivo conditionLarry C Wienkers
Global Drug Metabolism, Pharmacia, 301 Henrietta St, Kalamazoo, MI 49009, USA
Eur J Pharm Sci 15:239-42. 2002..The focus of the current report is to describe some of the confounding factors associated with in vitro drug inhibition studies and the impact of these issues on in vitro/in vivo extrapolations...
- Cytochrome P-450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomesL C Wienkers
Department of Drug Metabolism, Pharmacia and Upjohn, Kalamazoo, Michigan 49007, USA
Drug Metab Dispos 27:1334-40. 1999..5 and 11 microM, respectively). Based on the results of the study, it is concluded that the metabolism of both reboxetine enantiomers in humans is principally mediated via CYP3A...
- Interaction of delavirdine with human liver microsomal cytochrome P450: inhibition of CYP2C9, CYP2C19, and CYP2D6R L Voorman
Drug Metabolism Research, Pharmacia Corporation, Kalamazoo, Michigan 49007, USA
Drug Metab Dispos 29:41-7. 2001..These results, along with previously reported experiments, indicate that delavirdine can partially inhibit CYP2C9, -2C19, -2D6, and -3A4, although the degree of inhibition in vivo would be subject to a variety of additional factors...
- Covalent alteration of the CYP3A4 active site: evidence for multiple substrate binding domainsM L Schrag
Global Metabolism and Investigative Sciences, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, Michigan, 49007, USA
Arch Biochem Biophys 391:49-55. 2001..These results provide physical evidence, which supports the hypothesis that the active site of CYP3A4 contains spatially distinct substrate-binding domains within the enzyme active site...
- Problems associated with in vitro assessment of drug inhibition of CYP3A4 and other P-450 enzymes and its impact on drug discoveryL C Wienkers
Pharmacia Corporation, 301 Henrietta Street, 7265 300 319, Kalamazoo, MI 49007, USA
J Pharmacol Toxicol Methods 45:79-84. 2001..Moreover, some of these enzyme-based interactions appear to be substrate specific. In this presentation, several issues associated with the generation of accurate DDI information will be discussed...
- Characterization of bropirimine O-glucuronidation in human liver microsomesM A Wynalda
Global Drug Metabolism, Pharmacia, Kalamazoo, MI 49007, USA
Xenobiotica 33:999-1011. 2003..4. The results demonstrate that UGT1A9 and to a lesser extent UGT1A1 are responsible for the majority of bropirimine O-glucuronidation in man...
- Bioactivation of the anticancer agent CPT-11 to SN-38 by human hepatic microsomal carboxylesterases and the in vitro assessment of potential drug interactionsJ G Slatter
Drug Metabolism Research, Pharmacia and Upjohn Co, Kalamazoo, MI 49007, USA
Drug Metab Dispos 25:1157-64. 1997..Therefore, CPT-11-sensitive carboxylesterase isoforms may account for only 20% of total alpha-NA hydrolases. Thus, CPT-11 is unlikely to significantly inhibit high turnover, nonselective substrates of carboxylesterases...
- In vitro metabolism of clindamycin in human liver and intestinal microsomesMichael A Wynalda
Global Drug Metabolism, Pharmacia Corporation, Kalamazoo, MI 49007, USA
Drug Metab Dispos 31:878-87. 2003..Thus, it is concluded that CYP3A4 appears to account for the largest proportion of the observed P450 catalytic clindamycin S-oxidase activity in vitro, and this activity may be extrapolated to the in vivo condition...
- Inhibition of cytochrome P450 3A4 by a pyrimidineimidazole: Evidence for complex heme interactionsJ Matthew Hutzler
Pharmacokinetics, Dynamics and Metabolism PDM, Department of Medicinal Chemistry, Pfizer Global Research and Development, 700 Chesterfield Parkway West T3A, Chesterfield, Missouri 63017, USA
Chem Res Toxicol 19:1650-9. 2006....
- Mechanism of inactivation of human cytochrome P450 2B6 by phencyclidineMonica I Jushchyshyn
Pfizer Inc, Pharmacokinetics and Drug Metabolism, St. Louis, Missouri, USA
Drug Metab Dispos 34:1523-9. 2006....
- Multiple cytochrome P450 enzymes responsible for the oxidative metabolism of the substituted (S)-3-phenylpiperidine, (S,S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride, in human liver microsomesLarry C Wienkers
Global Drug Metabolism, Pharmacia, Kalamazoo, Michigan 49007, USA
Drug Metab Dispos 30:1372-7. 2002..Thus, it is concluded that (-)-OSU6162 is metabolized by several p450 enzymes and that CYP2D6 accounts for the majority of the observed p450 N-depropylase activity in vitro...
- Time-dependent inactivation of P450 3A4 by raloxifene: identification of Cys239 as the site of apoprotein alkylationBrian R Baer
Amgen, Department of Pharmacokinetics and Drug Metabolism, 1201 Amgen Court West, Seattle, Washington 98119, USA
Chem Res Toxicol 20:954-64. 2007....
- CYP2C9 protein interactions with cytochrome b(5): effects on the coupling of catalysisCharles W Locuson
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
Drug Metab Dispos 35:1174-81. 2007..Together, these findings suggest that cyt b5 can alter multiple steps in the P450 catalytic cycle via complex interactions with P450 and P450 reductase...
- The in vitro drug interaction potential of dietary supplements containing multiple herbal componentsRobert S Foti
Biochemistry Biophysics Group, Amgen Pharmacokinetics and Drug Metabolism, Seattle, Washington 98119, USA
Drug Metab Dispos 35:185-8. 2007..Based on the data presented, it is concluded that mixtures of herbal components may exhibit multiple modes of P450 inhibition, indicating the potential for complex herbal-drug interaction scenarios to occur...
- Predicting in vivo drug interactions from in vitro drug discovery dataLarry C Wienkers
Amgen, 1201 Amgen Court West, Seattle, Washington 98119, USA
Nat Rev Drug Discov 4:825-33. 2005....
- Catalytic turnover of pyrene by CYP3A4: evidence that cytochrome b5 directly induces positive cooperativityMonica I Jushchyshyn
PDM, Pfizer Inc, St. Louis, MO, USA
Arch Biochem Biophys 438:21-8. 2005..This demonstrated that b5 could directly induce positive cooperativity on CYP3A4 and that this biological factor needs to be carefully considered when included in in vitro P450 reactions...
- Predicting drug-drug interactions in drug discovery: where are we now and where are we going?Matthew Hutzler
Pfizer PGRD Pharmacokinetics, Dynamics and Metabolism, Chesterfield, MO 63017, USA
Curr Opin Drug Discov Devel 8:51-8. 2005....
- Mechanism-based inactivation of cytochrome P450 2D6 by 1-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]- 4-[4-(trifluoromethyl)-2-pyridinyl]piperazine: kinetic characterization and evidence for apoprotein adductionJ Matthew Hutzler
Pfizer, Pharmacokinetics, Dynamics, and Metabolism (PDM, St. Louis, Missouri, USA
Chem Res Toxicol 17:174-84. 2004..Overall, evidence suggests that nucleophilic attack of an imidazo-methide-like intermediate by a P450 2D6 active site residue leads to apoprotein adduction and consequent inactivation...
- Pyrene.pyrene complexes at the active site of cytochrome P450 3A4: evidence for a multiple substrate binding siteMichael J Dabrowski
Department of Medicinal Chemistry, Box 357610, University of Washington, Seattle, WA 98195-7610, USA
J Am Chem Soc 124:11866-7. 2002..Functional implications include the possibility that turnover rate, regioselectivity, and stereoselectivity of the reaction are determined by the substrate.substrate complex rather than individual substrates...
- Activation of cytochrome P450 2C9-mediated metabolism: mechanistic evidence in support of kinetic observationsJ Matthew Hutzler
Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Health Sciences Center, HSN, Morgantown, WV 26506, USA
Arch Biochem Biophys 410:16-24. 2003....
- Identification of phenylisoxazolines as novel and viable antibacterial agents active against Gram-positive pathogensMichael R Barbachyn
Combinatorial and Medicinal Chemistry, Pharmacia Corporation, 7000 Portage Road, Kalamazoo, Michigan 49001, USA
J Med Chem 46:284-302. 2003..Many of the analogues exhibited interesting levels of antibacterial activity. The piperazine derivative 54 displayed especially promising in vitro activity and in vivo efficacy comparable to the activity and efficacy of linezolid...
- Differential time-dependent inactivation of P450 3A4 and P450 3A5 by raloxifene: a key role for C239 in quenching reactive intermediatesJosh T Pearson
Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc Seattle, WA 98119 3105, USA
Chem Res Toxicol 20:1778-86. 2007....