Tipranavir Ritonavir Induction of Buprenorphine Glucuronide Metabolism in HIV-Negative Subjects Chronically Receiving Buprenorphine Naloxone

• Published in: The American journal of drug and alcohol abuse Vol. 37; no. 4; pp. 224 - 228
• Main Authors: Bruce, R. Douglas, Moody, David E., Fang, Wenfang B., Chodkowski, Diane, Andrews, Laurie, Friedland, Gerald H.
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare 01.07.2011; Taylor & Francis; Taylor & Francis Ltd
• Subjects: Acquired Immune Deficiency Syndrome; Adult; Antiretroviral drugs; Buprenorphine; Buprenorphine - administration & dosage; Buprenorphine - pharmacokinetics; Buprenorphine - therapeutic use; Buprenorphine, Naloxone Drug Combination; Chronically; Drug Interactions; Female; glucuronide pharmacokinetics; HIV; HIV Seronegativity; HIV/AIDS; Human immunodeficiency virus; Humans; Inactivation, Metabolic; Induction; Inhibition; Male; Medicine; Metabolism; Middle Aged; Naloxone; Naloxone - administration & dosage; Naloxone - pharmacokinetics; Naloxone - therapeutic use; Narcotic Antagonists - administration & dosage; Narcotic Antagonists - pharmacokinetics; opioid dependence; Opioid-Related Disorders - blood; Opioid-Related Disorders - drug therapy; Pharmacology; Pyridines - administration & dosage; Pyridines - pharmacology; Pyrones - administration & dosage; Pyrones - pharmacology; ritonavir; Ritonavir - administration & dosage; Ritonavir - pharmacology; tipranavir; Treatment
• ISSN: 0095-2990; 1097-9891; 1097-9891
• DOI: 10.3109/00952990.2011.568081

Background: Previous reports on the pharmacokinetic of tipranavir (TPV) and buprenorphine (BUP)/ naloxone found that coadministration resulted in an 80% reduction in the area under the curve AUC of the primary BUP metabolite, norBUP, without any pharmacodynamic consequences. This study was conducted to characterize how tipranivir/ritonavir effects the glucuronide metabolites of BUP and may explain the reduction in the norBUP. Methods: HIV-seronegative subjects stabilized on at least 3 weeks of BUP/naloxone sequentially underwent baseline and steady-state pharmacokinetic evaluation of twice daily TPV 500 mg coadministered with ritonavir 200 mg (TPV/r). Results: Twelve subjects were enrolled and ten completed the study. The steady-state pharmacokinetics for BUP-3-glucuronide (BUP-3G) and norBUP-3-glucuronide (norBUP-3G) in the presence and absence of steady-state TPV/r were analyzed. The Cmax of BUP-3G was 8.78 ± 5.23 ng/mL without TPV/r and increased to 12.7 ± 11.7 after steady state of TPV/r was achieved. The AUC of BUP-3G was 31.1 ± 19.4 (ng/mL) (h) without TPV/r and increased to 58. 6 ± 49.5 after steady state of TPV/r was achieved (p = .0966). In contrast, steady-state norBUP-3G AUC0-24 h (p = .0216) and Cmax (p = .0088) were significantly decreased in the presence of steady-state TPV/r. Conclusions and Scientific Significance: This study further elucidates the effects of TPV/r on glucuronidation. The current evaluation of glucuronide metabolites of BUP and norBUP are suggestive of combined inhibition of Uridine diphosphate (UDP)-glucuronosyltransferase of the 1A family and cytochrome P450 3A4 that spares UGT2B7 leading to a shunting of BUP away from production of norBUP and toward BUP-3G as seen by a statistically significant increase in the AUC of BUP-3G.