BIOTRANSFORMATION OF TIRILAZAD IN HUMAN .2. EFFECT OF KETOCONAZOLE ONTIRILAZAD CLEARANCE AND ORAL BIOAVAILABILITY

The effect of ketoconazole, a CYP3A inhibitor, on the oral bioavailabi lity of tirilazad mesylate was assessed in 12 healthy subjects, who re ceived the following treatments in a crossover design: a) 10 mg/kg tir ilazad mesylate solution orally on the fourth day of a 7-day regimen o f 200 mg ketoconazole once daily, b) 10 mg/kg tirilazad mesylate solut ion orally, c) 2 mg/kg i.v. tirilazad mesylate solution on the fourth day of a 7-day regimen of 200 mg ketoconazole once daily and d) 2 mg/k g i.v. tirilazad mesylate solution. Plasma concentrations of tirilazad mesylate and its active reduced metabolites (U-89678 and U-87999) wer e measured by high-performance liquid chromatography. Urinary ratios o f 6 beta-hydroxycortisol to cortisol (6 beta-OHC/C) were measured as a n index of hepatic CYP3A activity. Ketoconazole increased mean tirilaz ad mesylate area under the curve (AUC) values by 67% and 309% for i.v. and oral administration, respectively. Mean AUC values for U-89678 we re increased 472% and 720% by ketoconazole coadministration with i.v. and oral tirilazad, respectively, whereas increases of > 10-fold in me an U-87999 AUC values were observed. These differences were statistica lly significant. These results indicate that ketoconazole inhibits the metabolism of these three compounds, which suggests that all of the c ompounds are substrates for CYP3A. Urinary 6 beta-OHC/C ratios did not reflect this level of effect of ketoconazole on CYP3A; this probe may not be useful for assessing the effect of CYP3A inhibitors. The absol ute bioavailability of oral tirilazad was 8.7 +/- 4.8%; ketoconazole i ncreased the bioavailability to 20.9 +/- 6.5%. Ketoconazole increased tirilazad mesylate bioavailability by decreasing the first-pass liver and gut wall metabolism of tirilazad mesylate to similar degrees.