The cytochrome P450 3A (CYP3A) subfamily is comprised of three genes CYP3A4, CYP3A5,and CYP3A7; with CYP3A4 expressed in majority of adults livers. Recently, CYP3A4 has been indentified in enterocytes. Thus, both intestinal and hepatic CYP3A play important roles in the oral availability of CYP3A substrates such as midazolam, nifedipine and cyclosporine. clairthromycin is potent mechanistic inhibitor of intestinal and hepatic CYP3A. Consequuently, the binding of clarithromycin to the heme of CYP3A in vivo effectively removes this enzyme from the catalytically active CYP3A pool and reduces the clearence of co-administered CYP3A substrates such as midazolam, ritonavir, and cisapride. Thus following cessation of an administered mechanistic inhibitor such as clarithromycin, the return to basel CYP3A activity in vivo will determined by the rate of enzyme degradation. The rate of CYP3A degradation in humans has not been determined. Therefore the prediction of the duration of drug-drug interactions following discontinuation of an administered mechanistic inhibitor, such as clarithromycin is not feasible. The duration of clarithromycin medicated CYP3A inhibition following cessation of clarithromycin dosing is therefore unknown. Clinically significant drug-drug interactions may still be observed days to weeks following the dosing discontinuation of a mechanistic inhibtor (e.g.clarithromycin). In an effort to better predict the duration of a drug-drug interaction and prevent the occurrence of unwanted adverse side effects, we plan to study the changes in intestinal and hepatic CYP3A activity before, during and after clarithromycin administration by examining the changes in the intravenous and oral pharmacokinetics of midazolam and its stable isotope, N-midazolam, respectively. This will allow us to quantify the duration of inhibition at hepatic and intestinal sites independently. Futhermore, we plan to examine the impact of gender and age on the rate of CYP3A degradation.
Showing the most recent 10 out of 767 publications
