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In Vivo Metabolic Activity of CYP2C19 and CYP3A in Relation to CYP2C19 Genetic Polymorphism in Chronic Liver Disease

From the Department of Laboratory Medicine, Daisan Hospital, Jikei University School of Medicine, Tokyo, Japan (Dr Ohnishi, Dr Akizuki), the Division of Gastroenterology & Hepatology, Daisan Hospital, Jikei University School of Medicine, Tokyo, Japan (Dr Murakami, Dr Mochizuki, Dr Takagi), and the Department of Pharmacotherapy, Meiji Pharmaceutical University, Tokyo, Japan (Dr Echizen).

To study whether chronic liver disease (CLD) and genetic polymorphism affect the hepatic activity of cytochrome P450 (CYP) isoforms, we compared in vivo CYP2C19 and CYP3A activities using 3-hour omeprazole hydroxylation index (plasma concentration ratio of omeprazole to its 5-hydroxylated metabolite; a higher index indicates lower CYP2C19 activity) and partial formation clearance of cortisol to 6ß-hydroxycortisol (CL_{cortisol6ß-HC}) in 31 CLD patients (9 with chronic hepatitis; 22 with cirrhosis comprising 20 Child-Pugh type A, 1 type B, and 1 type C) and 30 healthy subjects with different CYP2C19 genotypes. The mean (±SEM) omeprazole hydroxylation index in CLD patients with homozygous extensive metabolizer (EM) genotype (*1/*1, n = 8), heterozyous EM (*1/*2, n = 11; *1/*3, n = 6) genotypes and poor metabolizer (PM) genotypes (*2/*2, n = 3; *3/*3, n = 3) were 17.15 ± 2.12, 20.02 ± 2.63, and 26.04 ± 3.15, respectively, which were significantly higher compared with control subjects with the corresponding CYP2C19 genotypes (0.81 ± 0.09, 1.55 ± 0.20, and 15.5 ± 1.52). CLD patients with PM genotype had significantly (P < .05) higher omeprazole hydroxylation indexes than did those with homozygous EM genotype, and those with heterozygous EM genotypes had intermediate values. The mean CL_{cortisol6ß-HC} decreased significantly (P < .001) in CLD patients compared with control subjects (1.19 ± 0.12 versus 2.26 ± 0.24 mL/min). Multiple regression analysis showed that CLD, serum albumin level, and CYP2C19 genotype correlated significantly (P < .05) with the omeprazole hydroxylation index, whereas no significant correlation was observed between CL_{cortisol6ß-HC} and other variables, except CLD. Because CLD and genetic polymorphism of CYP2C19 act additively to reduce CYP2C19 activity, genotyping these patients may be of value in averting adverse reactions of drugs that depend on CYP2C19 for elimination.

Key Words: Chronic liver disease • cirrhosis • cytochrome P450 • CYP2C19 • CYP3A

Address for reprints: Akihiro Ohnishi, MD, PhD, Department of Laboratory Medicine, Daisan Hospital, Jikei University School of Medicine, 4-11-1 Izumihonchyo, Komae, Tokyo 201-8601.

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