Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women

Michael D. Floyd, Guillermo Gervasini, Andrew L. Masica, Gail Mayo, Alfred L. George, Kolari Bhat, Richard B. Kim, Grant R. Wilkinson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

221 Scopus citations

Abstract

CYP3A activity in adults varies between individuals and it has been suggested that this has a genetic basis, possibly related to variant alleles in CYP3A4 and CYP3A5 genes. Accordingly, genotype-phenotype associations were investigated under constitutive and induced conditions. Midazolam's systemic and oral clearances, and the erythromycin breath test (ERBT) were determined in 57 healthy subjects: 23 (11 men, 12 women) European- and 34 (14 men, 20 women) African-Americans. Studies were undertaken in the basal state and after 14-15 days pretreatment with rifampin. DNA was characterized for the common polymorphisms CYP3A4* 1B, CYP3A5* 3, CYP3A5* 6 and CYP3A5* 7 by direct sequencing, and for exon 21 and exon 26 variants of MDR1 by allele-specific, real-time polymerase chain reaction. In 95% of subjects, the basal systemic clearance of midazolam was unimodally distributed and variability was less than four-fold whereas, in 98% of the study population, oral clearance varied five-fold. No population or sex-related differences were apparent. Similar findings were observed with the ERBT. Rifampin pretreatment markedly increased the systemic (two-fold) and oral clearance (16-fold) of midazolam, and the ERBT (two-fold) but the variabilities were unchanged. No associations were noted between these phenotypic measures and any of the studied genotypes, except for oral clearance and its fold-increase after rifampin. These were related to the presence of CYP3A4* 1B and the inversely linked CYP3A5* 3 polymorphism, with the extent of induction being approximately 50% greater in CYP3A5* 3 homozygotes compared to wild-type subjects. In most healthy subjects, variability in intestinal and hepatic CYP3A activity, using midazolam as an in-vivo probe, is modest and common polymorphisms in CYP3A4 and CYP3A5 do not appear to have important functional significance.

Original languageEnglish (US)
Pages (from-to)595-606
Number of pages12
JournalPharmacogenetics
Volume13
Issue number10
DOIs
StatePublished - Oct 2003

Keywords

  • CYP3A
  • CYP3A4* 1B
  • CYP3A5* 3
  • CYP3A5* 6
  • CYP3A5* 7
  • Midazolam
  • Polymorphisms

ASJC Scopus subject areas

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

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