THE ABSOLUTE BIOAVAILABILITY AND PHARMACOKINETICS OF BUTORPHANOL NASAL SPRAY IN PATIENTS WITH HEPATIC IMPAIRMENT

Objective: The objective of the study was to investigate the effects o f hepatic impairment on the absolute transnasal bioavailability and ph armacokinetics of butorphanol, Study Design: Twelve (eight men and fou r women) healthy subjects and 12 (eight men and four women) patients w ith hepatic impairment received a 1 mg dose of butorphanol by intraven ous or transnasal administration on two separate occasions, Hepatic fu nction was assessed by antipyrine and indocyanine green clearance test s, Serial blood and urine samples were collected after each dose, Plas ma samples were analyzed for butorphanol, and urine samples were analy zed for butorphanol and its metabolites, Results: No statistical diffe rence in maximum plasma concentration (C-max) for butorphanol was obse rved between the two groups of volunteers after transnasal administrat ion, However, total plasma clearance (CL), steady-state volume of dist ribution, area under the concentration-time curve [AUC(0-infinity)], a nd elimination half-life of butorphanol in patients with hepatic impai rment were significantly altered (similar to two-fold to threefold), T he absolute transnasal bioavailability of butorphanol was significantl y higher (similar to 20%) in patients with hepatic impairment, A great er fraction of the administered dose was recovered from tile urine in hepatically impaired patients compared to that in healthy subjects (23 % to 31% versus 10% to 11%), There was a significant reduction in CL o f indocyanine green and antipyrine in hepatically impaired patients. T he percentage of reduction in butorphanol CL was highly correlated to the estimated degree of portosystemic shunts in the patients with hepa tic impairment, Conclusion: Based on the comparable C-max but the incr eased AUC in patients with liver dysfunction, tile initial dose of but orphanol nasal spray may not need to be adjusted, However, the subsequ ent dosing intervals for butorphanol should be prolonged.