Effect of common CYP3A4 and CYP3A5 variants on the pharmacokinetics of the cytochrome P450 3A phenotyping probe midazolam in cancer patients

Clin Cancer Res. 2005 Oct 15;11(20):7398-404. doi: 10.1158/1078-0432.CCR-05-0520.

Abstract

Purpose: To evaluate the effect of naturally occurring variants in genes encoding the cytochrome P450 (CYP) isoforms CYP3A4 and CYP3A5 in patients with cancer receiving midazolam as a phenotyping probe.

Experimental design: Five variants in CYP3A4 and CYP3A5 were evaluated in 58 patients (21 women and 37 men) receiving a short i.v. bolus of midazolam (dose, 0.0145 or 0.025 mg/kg). Midazolam concentrations in plasma were determined using liquid chromatography-mass spectrometry, and pharmacokinetic variables were calculated using noncompartmental analysis. Genomic DNA was characterized for the variants by PCR-RFLP, and all genotypes were confirmed by direct nucleotide sequencing.

Results: The mean clearance of midazolam was 24.4 +/- 9.12 L/h, and phenotypic CYP3A activity varied about 4-fold in this population (range, 10.8-44.3 L/h). There were six carriers of the CYP3A4*1B allele (allele frequency, 0.061). No variant alleles for CYP3A4*17, CYP3A4*18A, or CYP3A5*6 were identified. Forty-eight of the 58 patients were homozygous variant for CYP3A5*3C, eight were heterozygous, and two were homozygous wild type (allele frequency, 0.897). No associations were noted between any of the studied genotypes and the phenotypic measures (P > or = 0.16). Likewise, a common variant in exon 26 in the gene encoding P-glycoprotein [i.e., ABCB1 (MDR1) 3435C>T] that was previously reported to be linked to CYP3A4 mRNA levels was unrelated to any of the studied phenotypic measures (P > or = 0.49).

Conclusions: The studied genetic variants in CYP3A4 and CYP3A5 are unlikely to have an important functional significance to phenotypic CYP3A activity in patients with cancer.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Adult
  • Aged
  • Alleles
  • Area Under Curve
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • Female
  • Gene Frequency
  • Genotype
  • Humans
  • Linkage Disequilibrium
  • Male
  • Midazolam / blood
  • Midazolam / pharmacokinetics*
  • Middle Aged
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Phenotype
  • Polymorphism, Single Nucleotide*

Substances

  • ABCB10 protein, human
  • ATP-Binding Cassette Transporters
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Midazolam