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*22-CYP3A5*3/*3) and 28.0% (95% CI: -33.3 to -22.6; p < 0.001) for intermediate (CYP3A4*1/*1-CYP3A5*3/*3) metabolizers, compared with extensive (CYP3A4*1/*1-CYP3A5*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.
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 cancerpatients 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*22-CYP3A5*3/*3) and 28.0% (95% CI: -33.3 to -22.6; p < 0.001) for intermediate (CYP3A4*1/*1-CYP3A5*3/*3) metabolizers, compared with extensive (CYP3A4*1/*1-CYP3A5*1) CYP3A metabolizers. CYP3A4erythromycin 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.
Authors: Laure Elens; Rachida Bouamar; Nauras Shuker; Dennis A Hesselink; Teun van Gelder; Ron H N van Schaik Journal: Br J Clin Pharmacol Date: 2014-04 Impact factor: 4.335
Authors: D Meulendijks; E A Rozeman; A Cats; K Sikorska; M Joerger; M J Deenen; J H Beijnen; J H M Schellens Journal: Pharmacogenomics J Date: 2016-12-20 Impact factor: 3.550
Authors: Jessica K Roberts; Chad D Moore; Robert M Ward; Garold S Yost; Christopher A Reilly Journal: J Pharmacol Exp Ther Date: 2013-03-19 Impact factor: 4.030