CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4*1B5'-promoter region polymorphism.

Wandel C, Witte JS, Hall JM, Stein CM, Wood AJ, Wilkinson GR
Clin Pharmacol Ther. 2000 68 (1): 82-91

PMID: 10945319 · DOI:10.1067/mcp.2000.108506

OBJECTIVE - Cytochrome P4503A (CYP3A) activity exhibits considerable interindividual variability. Possible differences in CYP3A activity were investigated in European American and African American men with the use of midazolam as an in vivo probe.

METHODS - Midazolam was simultaneously administered intravenously (1 mg, [15N3]-labeled) and orally (2 mg, unlabeled in capsule form) to 15 young healthy European American men and a similar group of men of African American descent. Plasma concentration-time curves were measured. The subjects were subsequently genotyped with respect to the CYP3A4*B1 polymorphism (A-290G) in the 5'-promoter (nifedipine-specific element) region.

RESULTS - The oral bioavailability of midazolam was about equally determined by intestinal and hepatic extraction with CYP3A activity at the former site exhibiting greater variability. Oral bioavailability was related to intestinal metabolism (r = 0.98), whereas hepatic CYP3A activity contributed little to the interindividual variability (r = 0.03). A lower systemic clearance (265+/-54 versus 310+/-56 mL/min; P = .04), but not oral clearance, was observed in African Americans. With one exception, the African Americans possessed a variant CYP3A4*1B allele (4 heterozygotes A/G and 10 homozygote G/G), whereas all of the European Americans were wild-type homozygotes (A/A). Hepatic CYP3A activity and the systemic clearance of midazolam were about 30% lower in G/G homozygotes than in A/A homozygotes (252+/-53 versus 310+/-54 mL/min; P = .02), and a gene-dose effect was present (P = .01). There was no genotype/phenotype relationship with respect to the oral clearance of midazolam.

CONCLUSION - Comparison of CYP3A activity between populations is complicated by frequency distribution differences in the regulatory CYP3A4*1B polymorphism and lower hepatic CYP3A activity associated with the variant allele. However, this reduction is modest; therefore no major and clinically important difference in CYP3A activity is present between Americans of African or European descent.

MeSH Terms (23)

Administration, Oral Adult African Continental Ancestry Group Aged Area Under Curve Aryl Hydrocarbon Hydroxylases Biological Availability Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System European Continental Ancestry Group GABA Modulators Genotype Humans Hypnotics and Sedatives Infusions, Intravenous Male Midazolam Middle Aged Oxidoreductases, N-Demethylating Polymorphism, Genetic Promoter Regions, Genetic Reference Values Time Factors

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