CYP3A activity measured by the midazolam test is not related to 3435 C>T polymorphism in the multiple drug resistance transporter gene

A recent study with 69 Japanese liver transplants treated with tacrolimus found that the MDR13435 C>T polymorphism, but not the MDR12677 G>T polymorphism, was associated with differences in the intestinal expression level of CYP3A4 mRNA. In the present study, over 6 h, we measured the kinetics of a 75 mug oral dose of midazolam, a CYP3A substrate, in 21 healthy subjects genotyped for the MDR13435 C>T and 2677 G>T polymorphism. No statistically significant differences were found in the calculated pharmacokinetic parameters between the three 3435 C>T genotypes (TT, CT and CC group, respectively: C-max (mean +/- SD: 0.30 +/- 0.08 ng/ml, 0.31 +/- 0.09 ng/ml and 0.31 +/- 0.11 ng/ml; Apparent clearance: 122 +/- 29 1/h, 156 +/- 92 1/h and 111 +/- 35 1/h; t(1/2):1.9 +/- 1.1 h, 1.6 +/- 0.90 h and 1.7 +/- 0.7 h). In addition, the 30-min 1'OH midazolam to midazolam ratio, a marker of CYP3A activity, determined in 74 HIV-positive patients before the introduction of antiretroviral treatment, was not significantly different between the three 3435 C>T genotypes (mean ratio SD: 3.65 +/- 2.24,4.22 +/- 3.49 and 4.24 +/- 2.03, in the TT, CT and CC groups, respectively). Similarly, no association was found between the MDR12677 G>T polymorphism and CYP3A activity in the healthy subjects or in the HIV-positive patients. The existence of a strong association between the activity of CYP3A and MDR13435 C>T and 2677 G>T polymorphisms appears unlikely, at least in Caucasian populations and/or in the absence of specific environmental factors. Pharmacogenetics 14:255-260 (C) 2004 Lippincott Williams Wilkins