BIOTRANSFORMATION OF TIRILAZAD IN HUMAN - 4 - EFFECT OF FINASTERIDE ON TIRILAZAD CLEARANCE AND REDUCED METABOLITE FORMATION

The effect of oral finasteride, an inhibitor of 5 alpha-reductase, on the clearance of tirilazad, a membrane lipid peroxidation inhibitor, w as assessed in eight healthy men who received: 1) 10 mg/kg tirilazad m esylate solution orally on the 7th day of a 10-day regimen of 5 mg fin asteride once daily, 2) 10 mg/kg tirilazad mesylate orally, 3) 2 mg/kg tirilazad mesylate i.v. on the 7th day of a 10-day regimen of 5 mg fi nasteride once daily and 4) 2 mg/kg tirilazad mesylate i.v., in a four -way cross-over design. Plasma concentrations of tirilazad and its act ive reduced metabolites (U-89678 and U-87999) were measured by liquid chromatography with tandem mass spectrometry (LG-MS-MS). Finasteride i ncreased mean tirilazad areas under the curve by 21 and 29% for i.v. a nd p.o. tirilazad, respectively. Mean U-89678 areas under the curve we re decreased 92 and 75% by finasteride administration with i.v. and p. o. tirilazad, respectively, and decreases of 94 and 85% in mean U-8799 9 area under the curve values were observed. These differences were st atistically significant. These results indicate that finasteride inhib its the metabolism of tirilazad to U-89678. However, this inhibition h as only a moderate effect on the overall clearance of tirilazad. These results thus confirm earlier in vitro work that showed that tirilazad is predominantly metabolized by CYP3A4. Although the major circulatin g metabolites of tirilazad are formed via reduction, this represents a minor route of tirilazad elimination in man.