title: Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism.
abstract: The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.).
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Tracy
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.).
authors.forename: Amarjit S
authors.initials: AS
authors.lastname: Chaudhry
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.).
authors.forename: Bhagwat
authors.initials: B
authors.lastname: Prasad
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.).
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.).
authors.forename: Erin G
authors.initials: EG
authors.lastname: Schuetz
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.).
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Zhong
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.).
authors.forename: Yun-Chen
authors.initials: YC
authors.lastname: Tien
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.) yjeong@uic.edu.
authors.forename: Hyunyoung
authors.initials: H
authors.lastname: Jeong
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.).
authors.forename: Xian
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.).
authors.forename: Laura M
authors.initials: LM
authors.lastname: Shireman
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Tay-Sontheimer
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (T.S.T.); Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (A.S.C., E.G.S.); Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (B.P., K.E.T., L.M.S., J.T.-S., Y.S.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.Z., Y.-C.T); and Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois (H.J., X.P.).
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Lin
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D004347:Drug Interactions / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D010641:Phenotype; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System