FK 506 metabolism in male and female rat liver microsomes.

The main metabolite of the immunosuppressant FK 506 in hepatic microsomes from male and female Sprague-Dawley rats was identified by mass spectrometry as an O-desmethyl derivative. The rate of formation of the metabolite exhibited saturation kinetics in the range of 0.6-40 microM with Vmax and KM equal to 0.66 +/- 0.47 nmol/min/mg protein and 24 +/- 18 microM, respectively, for microsomes from male rats, and 0.28 +/- 0.15 nmol/min/mg protein and 24 +/- 16 microM, respectively, for microsomes from female rats. CYP3A enzymes are thought to be responsible for metabolizing FK 506 in male rats. Because untreated female rats show no classical CYP3A activity, our work suggests that other CYP enzymes metabolize FK 506 in untreated female rats. O-Desmethyl FK 506 did not cross-react in the standard clinical ELISA assay for FK 506. This suggests that demethylation had occurred at the C13-methoxy group.