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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Developmental Expression of Human Hepatic CYP2C9 and CYP2C19

Department of Pediatrics, Birth Defects Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin (S.B.K., D.G.M., R.N.H.); Pfizer, Pharmacokinetics, Dynamics, and Metabolism, Kalamazoo, Michigan (J.R.M., S.A.M., J.C.S.); and Department of Medicinal Chemistry, University of Washington, Seattle, Washington (A.E.R.)

The CYP2C subfamily is responsible for metabolizing many important drugs and accounts for about 20% of the cytochrome P450 in adult liver. To determine developmental expression patterns, liver microsomal CYP2C9 and -2C19 were measured (n = 237; ages, 8 weeks gestation-18 years) by Western blotting and with diclofenac or mephenytoin, respectively, as probe substrates. CYP2C9-specific content and catalytic activity were consistent with expression at 1 to 2% of mature values (i.e., specific content, 18.3 pmol/mg protein and n = 79; specific activity, 549.5 pmol/mg/min and n = 72) during the first trimester, with progressive increases during the second and third trimesters to levels approximately 30% of mature values. From birth to 5 months, CYP2C9 protein values varied 35-fold and were significantly higher than those observed during the late fetal period, with 51% of samples exhibiting values commensurate with mature levels. Less variable CYP2C9 protein and activity values were observed between 5 months and 18 years. CYP2C19 protein and catalytic activities that were 12 to 15% of mature values (i.e., specific content, 14.6 pmol/mg and n = 20; specific activity, 18.5 pmol/mg/min and n = 19) were observed as early as 8 weeks of gestation and were similar throughout the prenatal period. CYP2C19 expression did not change at birth, increased linearly over the first 5 postnatal months, and varied 21-fold from 5 months to 10 years. Adult CYP2C19 protein and activity values were observed in samples older than 10 years. The ontogeny of CYP2C9 and -2C19 were dissimilar among both fetal and 0- to 5-months postnatal samples, implying different developmental regulatory mechanisms.

Address correspondence to: Dr. Ronald N. Hines, Medical College of Wisconsin, Department of Pediatrics, Birth Defects Research Center, 8701 Watertown Plank Road, Milwaukee, WI 53226-4801. E-mail: rhines{at}mail.mcw.edu

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