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 of hepatic impairment on the absolute transnasal bioavailability and pharmacokinetics of butorphanol.


METHODS
Twelve (eight men and four women) healthy subjects and 12 (eight men and four women) patients with hepatic impairment received a 1 mg dose of butorphanol by intravenous or transnasal administration on two separate occasions. Hepatic function was assessed by antipyrine and indocyanine green clearance tests. Serial blood and urine samples were collected after each dose. Plasma samples were analyzed for butorphanol, and urine samples were analyzed for butorphanol and its metabolites.


RESULTS
No statistical difference in maximum plasma concentration (Cmax) for butorphanol was observed between the two groups of volunteers after transnasal administration. However, total plasma clearance (CL), steady-state volume of distribution, area under the concentration-time curve [AUC(0-infinity)], and elimination half-life of butorphanol in patients with hepatic impairment were significantly altered (approximately twofold to threefold). The absolute transnasal bioavailability of butorphanol was significantly higher (approximately 20%) in patients with hepatic impairment. A greater fraction of the administered dose was recovered from the 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 of indocyanine green and antipyrine in hepatically impaired patients. The percentage of reduction in butorphanol CL was highly correlated to the estimated degree of portosystemic shunts in the patients with hepatic impairment.


CONCLUSIONS
Based on the comparable Cmax but the increased AUC in patients with liver dysfunction, the initial dose of butorphanol nasal spray may not need to be adjusted. However, the subsequent dosing intervals for butorphanol should be prolonged.
Vachharajani
N N
NN
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA.
Shyu
W C
WC
Garnett
W R
WR
Morgenthien
E A
EA
Barbhaiya
R H
RH
D000281:Administration, Intranasal; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000983:Antipyrine; D019540:Area Under Curve; D001682:Biological Availability; D002077:Butorphanol / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004396:Coloring Agents; D005260:Female; D006801:Humans; D007208:Indocyanine Green; D007275:Injections, Intravenous; D008102:Liver Circulation; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008297:Male; D008875:Middle Aged; D012016:Reference Values
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004396:Coloring Agents; D007208:Indocyanine Green; D002077:Butorphanol; D000983:Antipyrine