Impact of CYP3A haplotypes on alprazolam kinetics with and without rifampicin induction

Human P-450 Cytochromes (CYP) of the 3A class are involved in metabolism of most commonly used drugs. Several genetic variations within the CYP3A gene locus have been described but intergenic haplotype structures of the adjacent genes have never been determined. Further more, poor data on clinical relevance of genetic variations is available. We intended to study the interindividual variability in CYP3A activity measured by alprazolam as a probe drug before and after enzyme induction by rifampicin and correlate the phenotype to genetic haplotypes within the CYP3A gene cluster. 1 mg alprazolam was administered to 103 healthy Caucasian before, and after 5 days of treatment with 450 mg rifampicin. Alprazolam concentrations were measured at 0, 1h, 10h, 20h after each alprazolam intake by reverse phase HPLC. DNA sequence analysis was performed for coding and adjacent non-coding regions within the CYP3A genes. A high degree of linkage desequilibrium was found in the CYP3A locus. Haplotypes were predicted with PHASE algorithm and Maximum Likelihood Methode (20 and 23 haplotypes, respectively). 4 haplotypes with frequencies of 0.5%, 0.5%, 1.5% and 1.5% contained the known variants CYP3A4*1B and CYP3A5*3. Influence on alprazolam kinetics was detected only for one rare haplotype: 3A4*3 which was correlated with higher native alprazolam concentrations before rifampicin induction. Additionally some rare haplotypes with so far unknown variants were found. Clinical Pharmacology & Therapeutics (2004) 75, P81–P81; doi: 10.1016/j.clpt.2003.11.311