Phenobarbital and phenytoin reduce serum levels of tirilazadmesilate whereas ketoconazole increases them. Finasteride inhibits metabolism of tirilazad to its active metabolite
Clinical evidence,mechanism, importance and management
A study in 16 healthy men found that cimetidine 300mg every 6 hrs for 4 days had no effect on pharmacokinetics of a single 2-mg/kg dose of tirilazad mesilate, given by infusion over 10 minutes on day 2, nor on U-89678, its active metabolite (See reference number 1). No special precautions would seem necessary if cimetidine is given with tirilazad mesilate.
In a study,8 healthy men were given finasteride 5mg daily for 10 days, with tirilazad mesilate 10 mg/kg orally or 2 mg/kg intravenously on day 7. Finasteride increased AUCs of intravenous and oral tirilazad by 21 % and 29%, respectively. Oral finasteride reduced AUCs of active metabolite (U-89678) by 92 % when tirilazad was given intravenously and by 75 % when tirilazad was given orally. Although metabolism of tirilazad to U-89678 was inhibited there was only a moderate effect on overall clearance of tirilazad and interaction was considered unlikely to be of clinical significance (See reference number 2).
Tirilazad mesilate,10 mg/kg orally or 2 mg/kg intravenously, was given to 12 healthy men and women, either alone or on day 4 of a 7-day regimen of ketoconazole 200mg daily. The ketoconazole more than doubled absolute bioavailability of oral tirilazad mesilate (from 8.7 % to 20.9%), apparently because its metabolism by cytochrome P450 isoenzyme CYP3A in gut wall and during first pass through liver was inhibited (See reference number 3). The clinical importance of this interaction awaits assessment.
In a single-dose study in 12 healthy men,there was no pharmacokinetic or pharmacodynamic interaction between intravenous tirilazad mesilate 2 mg/kg and oral nimodipine 60mg (See reference number 4). No special precautions would seem necessary if nimodipine is given with tirilazad mesilate
The pharmacokinetics of tirilazad mesilate (1.5 mg/kg as 10 minute intravenous infusions every 6 hrs for 29 doses) were studied in 15 healthy subjects before and after they took phenobarbital 100mg daily for 8 days. The phenobarbital increased clearance of tirilazad by 25 % in male subjects and 29 % in female, and AUC of active metabolite of tirilazad (U-89678) was reduced by 51 % in males and 69 % in females. The reason is thought to be that phenobarbital acts as an enzyme inducer, which increases metabolism of tirilazad (See reference number 5). The clinical importance of these reductions awaits assessment,but be alert for evidence of reduced effects if both drugs are given. It is doubtful if full enzyme-inducing effects of phenobarbital would have been reached in this study after only one week, so anticipate a greater effect if it is given for a longer period.
After taking phenytoin 200mg every 8 hrs for 11 doses then 100mg every 8 hrs for 5 doses, AUC0-6 of tirilazad mesilate was reduced by 35 % in 12 healthy subjects. The AUC of active metabolite, U-89678, was reduced by 87 % (See reference number 6). Another report by same group of workers(See reference number 7)found that phenytoin every 8 hrs for 7 days (9 doses of 200mg followed by 13 doses of 100 mg) reduced clearance of tirilazad by 92 % and of U-89678 by 93%. In another report authors noted that phenytoin increased metabolism of tirilazad and its metabolite in men and women to similar extents (See reference number 8). The clinical importance of these reductions is still to be assessed,but be alert for any evidence of reduced tirilazad effects if both drugs are given.
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Fleishaker JC,Pearson PG, Wienkers LC, Pearson LK, Moore TA, Peters GR. Biotransformation of tirilazad in human: 4. effect of finasteride on tirilazad clearance and reduced metabolite formation. J Pharmacol Exp Ther. (1998) 287, 591–7.
Fleishaker JC,Pearson PG, Wienkers LC, Pearson LK, Peters GR. Biotransformation of tirilazad in humans: 2. Effect of ketoconazole on tirilazad clearance and oral bioavailability. J Pharmacol Exp Ther (1996) 277, 991–8.
Fleishaker JC,Hulst LK, Peters GR. Lack of a pharmacokinetic/pharmacodynamic interactionbetween nimodipine and tirilazad mesylate in healthy volunteers. J Clin Pharmacol (1994) 34, 837–41.
Fleishaker JC,Pearson LK, Peters GR. Gender does not affect the degree of induction of tirilazad clearance by phenobarbital. Eur J Clin Pharmacol (1996) 50, 139–45.
Fleishaker JC,Hulst LK, Peters GR. The effect of phenytoin on the pharmacokinetics of tirilazad mesylate in healthy male volunteers. Clin Pharmacol Ther (1994) 56, 389–97.
Fleishaker JC,Pearson LK, Peters GR. Induction of tirilazad clearance by phenytoin. Biopharm Drug Dispos (1998) 19, 91–6.
Fleishaker JC,Pearson LK, Peters GR. Effect of gender on the degree of induction of tirilazadclearance by phenytoin. Clin Pharmacol Ther (1996) 59, 168.