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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Developmental Expression of the Major Human Hepatic CYP3A Enzymes

Pfizer, Pharmacokinetics, Dynamics, and Metabolism (J.C.S., C.G., P.J.T., M.J.Z.), and Global Nonclinical Biostatistics (J.R.M.), Kalamazoo, Michigan; and Medical College of Wisconsin (R.N.H., S.B.K.), Milwaukee, Wisconsin

The human cytochrome P4503A forms show expression patterns subject to developmental influence. CYP3A7 and CYP3A4 are generally classified as the major fetal and adult liver forms, respectively. However, characterization of CYP3A4, -3A5, and -3A7 developmental expression has historically been confounded by the lack of CYP3A isoform-specific antibodies or marker enzyme activities. Therefore, the objective of this study was to characterize the developmental expression of hepatic CYP3A forms from early gestation to 18 years of age using up to 212 fetal and pediatric liver samples. Based on immunoquantitation, CYP3A5 protein expression was found to be highly variable, generally independent of age, and more frequently observed for African-American individuals. For differentiation of CYP3A4 and -3A7 levels, dehydroepiandrosterone metabolite patterns for expressed CYP3A forms were characterized and used for simultaneous quantitation of protein levels within liver microsome samples. The major metabolite formed by CYP3A4, 7-hydroxy-dehydroepiandrosterone, was identified based on cochromatography and mass spectra matching with the authentic standard. Kinetic analysis showed a 34-fold greater intrinsic clearance of 7-hydroxy-dehydroepiandrosterone by CYP3A4 versus -3A7, whereas CYP3A7 showed the highest 16-hydroxy-dehydroepiandrosterone intrinsic clearance. Metabolite profiles for the expressed enzymes were fit to a multiple response model and CYP3A4 and -3A7 levels in fetal and pediatric liver microsome samples were calculated. Fetal liver microsomes showed extremely high CYP3A7 levels (311-158 pmol/mg protein) and significant expression through 6 months postnatal age. Low CYP3A4 expression was noted for fetal liver (10 pmol/mg), with mean levels increasing with postnatal age.

Address correspondence to: Dr. Jeffrey C. Stevens, Pfizer, Pharmacokinetics, Dynamics, and Metabolism, 301 Henrietta St., 7265-300-306, Kalamazoo, MI 49007. E-mail: jeffrey.c.stevens{at}pfizer.com

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