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Effect of Common CYP3A4 and CYP3A5 Variants on the Pharmacokinetics of the Cytochrome P450 3A Phenotyping Probe Midazolam in Cancer Patients

Authors' Affiliations: ¹ Science Applications International Corporation-Frederick, ² Molecular Pharmacology Section, ³ Cancer Therapeutics Branch, ⁴ Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, Maryland; ⁵ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, ⁶ Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Departments of ⁷ Clinical Chemistry, Erasmus MC and ⁸ Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands

Requests for reprints: Alex Sparreboom, Clinical Pharmacology Research Core, National Cancer Institute, Room 5A01, Building 10, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-402-9498; Fax: 301-402-8606; E-mail: SparrebA{at}mail.nih.gov.

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 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 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.

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