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Reduced Methylprednisolone Clearance Causing Prolonged Pharmacodynamics in a Healthy Subject Was Not Associated With CYP3A5*3 Allele or a Change in Diet Composition

From the Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (Dr Lee, Dr Goldstein); the Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York (Dr Jusko); the Clinical Center Nutrition Department, National Institutes of Health, Bethesda, Maryland (Ms Salaita); the Pharmacy Department, National Institutes of Health, Bethesda, Maryland (Dr Calis, Dr Hon); the Center for Clinical Research, Mercer University Southern School of Pharmacy, Atlanta, Georgia (Dr Jann, Dr Spratlin); and the Department of Clinical and Administrative Sciences, Mercer University Southern School of Pharmacy, Atlanta, Georgia (Dr Hon).

The influence of diet and genetics was investigated in a healthy white person who had distinctly low methylprednisolone clearance. Pharmacokinetic and pharmacodynamic parameter values were similar on 2 occasions during the consumption of a low-carbohydrate diet and a Weight Watchers diet, indicating that the decreased clearance was unlikely attributable to a change in diet composition. Although the subject was found to be homozygous for CYP3A5*3, genetic findings were not significant for a number of other CYP3A4 and CYP3A5 allelic variants. Because of the high prevalence of CYP3A5*3/*3 in whites and because 5 of 7 white control subjects are also homozygous for CYP3A5*3, this genotype cannot fully explain the reduced metabolism of the drug. Other genetic or contributing factors might have been involved. New polymerase chain reaction–based genotyping methods for functionally defective CYP3A5*6, *8, *9, and *10 alleles were developed in this study. These assays will be useful for CYP3A5 genotype analysis in future clinical studies.

Key Words: Methylprednisolone clearance • steroid pharmacodynamics • low-carbohydrate diet • CYP3A5*3 allele • genotyping method

Address for reprints: Yuen Yi Hon, PharmD, Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, National Institutes of Health, Bldg 10, Room 1N-257, MSC-1196, 10 Center Drive, Bethesda, MD 20892; e-mail: chon{at}cc.nih.gov.