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 reduced metabolite, U89678, were studied in 7 volunteers with mild cirrhosis of the liver, and seven age, sex, weight and smoking status matched healthy normal volunteers. Subjects received a single intravenous infusion of 2.0 mg.kg-1 tirilazad mesylate over 10 min.


RESULTS
Mean tirilazad AUCzero-infinity was 8.83 mumol h.l-1 and 18.6 mumol h.l-1 in healthy volunteers and cirrhotic subjects, respectively. Mean tirilazad clearance in cirrhotics (12.7 l.h-1) was approximately 2.1 fold lower than in healthy volunteers (27.8 l.h-1). The differences were statistically significant. Mean U-89678 AUCzero-infinity in cirrhotic subjects (3.88 mumol h.l-1) was 2.5 fold higher than in healthy controls (1.53 mumol h.l-1), but the difference was marginally significant.


CONCLUSIONS
These results indicate that clearance of both tirilazad mesylate and U89678 is decreased in subjects with hepatic impairment. This observation may be attributed either to decreases in liver blood flow and/or intrinsic clearance. The results of this study thus suggest that increased monitoring and or a reduction in tirilazad dosing may be necessary in patients with hepatic impairment.
Pearson
L K
LK
Upjohn Company, Kalamazoo, MI 49007, USA.
Fleishaker
J C
JC
Peters
G R
GR
D000975:Antioxidants / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011281:Pregnatrienes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
D000975:Antioxidants; D011281:Pregnatrienes; C087053:U 89678; C053355:tirilazad