Abstract
The effect of oral finasteride, an inhibitor of 5α-reductase, on the clearance of tirilazad, a membrane lipid peroxidation inhibitor, was assessed in eight healthy men who received: 1) 10 mg/kg tirilazad mesylate solution orally on the 7th day of a 10-day regimen of 5 mg finasteride 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 finasteride once daily and 4) 2 mg/kg tirilazad mesylate i.v., in a four-way cross-over design. Plasma concentrations of tirilazad and its active reduced metabolites (U-89678 and U-87999) were measured by liquid chromatography with tandem mass spectrometry (LC-MS-MS). Finasteride increased mean tirilazad areas under the curve by 21 and 29% for i.v. and p.o. tirilazad, respectively. Mean U-89678 areas under the curve were decreased 92 and 75% by finasteride administration with i.v. and p.o. tirilazad, respectively, and decreases of 94 and 85% in mean U-87999 area under the curve values were observed. These differences were statistically significant. These results indicate that finasteride inhibits the metabolism of tirilazad to U-89678. However, this inhibition has only a moderate effect on the overall clearance of tirilazad. These results thus confirm earlierin vitro work that showed that tirilazad is predominantly metabolized by CYP3A4. Although the major circulating metabolites of tirilazad are formed via reduction, this represents a minor route of tirilazad elimination in man.
Footnotes
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Send reprint requests to: Dr. Joseph C. Fleishaker, Clinical Pharmacokinetics Unit, 7215-24-205, Pharmacia and Upjohn, Inc., Kalamazoo, MI 49007.
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↵1 This work was supported financially by Pharmacia and Upjohn, Inc.
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↵2 Current address: Merck and Co., West Point, PA.
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↵3 Current address: Astra Pharmaceuticals LP Wayne, PA.
- Abbreviations:
- SAH
- subarachnoid hemorrhage
- t½
- half-life
- AUC0–∞
- area under the plasma concentration-time curve
- AUMC0–∞
- area under the first moment curve
- MRT
- mean residence time
- T
- infusion duration
- CL
- systemic clearance
- CLPO
- oral clearance
- Vss
- volume of distribution at steady-state
- Cinf
- concentration at the end of infusion
- Cmax
- maximal plasma concentration
- Tmax
- time of maximal plasma concentration
- F
- absolute bioavailability
- ANOVA
- analysis of variance
- E
- extraction ratio
- Fh
- fractional availability through the liver
- Fa
- fraction absorbed
- Fg
- fractional availability through the gut
- CLint
- intrinsic clearance
- Q
- hepatic blood flow
- CLh
- hepatic clearance
- CV
- coefficient of variation
- λz
- terminal elimination rate constant
- Received January 26, 1998.
- Accepted May 6, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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