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CYP3A4 intron 6 C>T SNP (CYP3A4*22) encodes lower CYP3A4 activity in cancer patients, as measured with probes midazolam and erythromycin

    Laure Elens

    Department of Clinical Chemistry, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands

    Louvain Centre for Toxicology & Applied Pharmacology, Université Catholique de Louvain, Brussels, Belgium

    ,
    Annemieke Nieuweboer

    Department of Medical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

    ,
    Stephen J Clarke

    University of Sydney, Sydney, New South Wales, Australia

    ,
    Kellie A Charles

    University of Sydney, Sydney, New South Wales, Australia

    ,
    Anne-Joy de Graan

    Department of Medical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

    ,
    Vincent Haufroid

    Louvain Centre for Toxicology & Applied Pharmacology, Université Catholique de Louvain, Brussels, Belgium

    ,
    Ron HJ Mathijssen

    Department of Medical Oncology, Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

    &
    Ron HN van Schaik

    * Author for correspondence

    Department of Clinical Chemistry, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.

    Published Online:https://doi.org/10.2217/pgs.12.202

    Aim: The CYP3A4*22 allele was recently reported to be associated with reduced CYP3A4 activity. We investigated the impact of this allele on the metabolism of the CYP3A-phenotyping probes, midazolam (MDZ) and erythromycin. Patients & methods: Genomic DNA from 108 cancer patients receiving intravenous MDZ and 45 undergoing the erythromycin breath test was analyzed for CYP3A4*22 (rs35599367 C>T) and CYP3A5*3. Results: The MDZ metabolic ratio (1´-OH-MDZ:MDZ) was 20.7% (95% CI: -36.2 to -6.2) lower for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (p = 0.01). Combining CYP3A4*22 and CYP3A5*3 genotypes showed a 38.7% decrease (95% CI: -50.0 to -27.4; p < 0.001) in 1´-OH-MDZ:MDZ for poor (CYP3A4*22CYP3A5*3/*3) and 28.0% (95% CI: -33.3 to -22.6; p < 0.001) for intermediate (CYP3A4*1/*1CYP3A5*3/*3) metabolizers, compared with extensive (CYP3A4*1/*1CYP3A5*1) CYP3A metabolizers. CYP3A4 erythromycin N-demethylation activity was 40% lower in CYP3A4*22 carriers compared with CYP3A4*1/*1 patients (p = 0.032). Conclusion: The CYP3A4*22 allele is associated with decreased CYP3A4-mediated metabolism, as verified by CYP3A-phenotyping probes.

    Original submitted 10 September 2012; Revision submitted 3 December 2012

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

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