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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

  1. Author:
    Lepper, E. R.
    Baker, S. D.
    Permenter, M.
    Ries, N.
    van Schaik, R. H. N.
    Schenk, P. W.
    Price, D. K.
    Ahn, D.
    Smith, N. F.
    Cusatis, G.
    Ingersoll, R. G.
    Bates, S. E.
    Mathijssen, R. H. J.
    Verweij, J.
    Figg, W. D.
    Sparreboom, A.

  2. Author Address

    NCI, Clin Pharmacol Res Core, Bethesda, MD 20892 USA. Sci Applicat Int Corp, Frederick, MD USA. NCI, Mol Pharmacol Sect, Bethesda, MD 20892 USA. NCI, Can Therapeut Branch, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21218 USA. Erasmus Med Ctr, Dept Clin Chem, Rotterdam, Netherlands. Erasmus Med Ctr, Daniel Hoed Canc Ctr, Dept Clin Chem, Rotterdam, Netherlands Sparreboom, A, NCI, Clin Pharmacol Res Core, Room 5A01,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA
    1. Year: 2005
    2. Date: OCT 15
  2. Journal: Clinical Cancer Research
    1. 11
    2. 20
    3. Pages: 7398-7404
  4. Type of Article: Article
  1. 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 >= 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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  2. WOS: 000232739200026

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