EFFECT OF FLUOXETINE, NORFLUOXETINE, SERTRALINE AND DESMETHYL SERTRALINE ON HUMAN CYP3A CATALYZED 1'-HYDROXY MIDAZOLAM FORMATION IN-VITRO

The ability of fluoxetine, norfluoxetine, sertraline and desmethyl ser traline to inhibit the CYP3A subfamily of cytochromes P450 was examine d in vitro, using the formation of 1'-hydroxy midazolam as a probe for CYP3A catalytic activity. The inhibition observed with these four com pounds was modeled using competitive, noncompetitive, uncompetitive an d mixed competitive/noncompetitive relationships by nonlinear regressi on analysis. The best fit model of the inhibition of CYP3A-mediated 1' -hydroxy midazolam formation by all four compounds examined was determ ined to be mixed inhibition. The calculated Ki values were 65.7 +/- 12 .0 mu M for fluoxetine, 19.1 +/- 1.9 mu M for norfluoxetine, 64.4 +/- 11.6 mu M for sertraline and 48.1 +/- 1.16 mu M for desmethyl sertrali ne. Steady-state plasma levels of fluoxetine and norfluoxetine can app roach a concentration of 1 mu M (approximately 350 ng/ml of plasma). A ssuming an inhibitor concentration of 1 mu M and a concentration of th e substrate substantially below its K-m (at least 10-fold lower), the results reported predict that fluoxetine and norfluoxetine together wo uld inhibit CYP3A catalytic activity by less than 7% (less than 0.7% i f the unbound plasma concentration of fluoxetine is considered). By us ing the same assumptions and concentrations for sertraline and desmeth yl sertraline, these agents together would be predicted to inhibit the metabolic clearance of a coadministered CYP3A metabolized drug by les s than 4%. The observations reported here suggest that fluoxetine and sertraline would have little effect on CYP3A-mediated clearance of coa dministered drugs.