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

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.

• Authors: Erin R Lepper, Sharyn D Baker, Matt Permenter, Nicole Ries, Ron H N van Schaik, Paul W Schenk, Douglas K Price, Danielle Ahn, Nicola F Smith, George Cusatis, Roxann G Ingersoll, Susan E Bates, Ron H J Mathijssen, Jaap Verweij, William D Figg, Alex Sparreboom
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 20 Pg. 7398-404 (Oct 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 16243813 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

• 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, pharmacokinetics)
• Middle Aged
• Neoplasms (genetics, metabolism)
• Phenotype
• Polymorphism, Single Nucleotide