COMPARISON OF THE PHARMACOKINETICS OF TIRILAZAD MESYLATE IN HEALTHY-VOLUNTEERS AND STABLE SUBJECTS WITH MILD LIVER-CIRRHOSIS

Objective: The pharmacokinetics of tirilazad mesylate and an active re duced metabolite, U89678, were studied in 7 volunteers with mild cirrh osis of the liver and seven age, sex, weight and smoking status matche d healthy normal volunteers. Subjects received a single intravenous in fusion of 2.0 mg . kg(-1) tirilazad mesylate over 10 min. Results: Mea n tirilazad AUC(0-infinity) was 8.83 mu mol h . l(-1) and 18.6 mu mol h . l(-1) in healthy volunteers and cirrhotic subjects, respectively. Mean tirilazad clearance in cirrhotics (12.7 l . h(-1)) was approximat ely 2.1 fold lower than in healthy volunteers (27.8 l . h(-1). The dif ferences were statistically significant. Mean U-89678 AUC(0-infinity) in cirrhotic subjects (3.88 mu mol h . l(-1)) was 2.5 fold higher than in healthy controls (1.53 mu mol h . l(-1)), but the difference was m arginally significant. Conclusion: These results indicate that clearan ce of both tirilazad mesylate and U89678 is decreased in subjects with hepatic impairment. This observation may be attributed either to decr eases in liver blood flow and/or intrinsic clearance. The results of t his study thus suggest that increased monitoring and or a reduction in tirilazad dosing may be necessary in patients with hepatic impairment .