title: Tipranavir/ritonavir induction of buprenorphine glucuronide metabolism in HIV-negative subjects chronically receiving buprenorphine/naloxone.
abstract: 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 C(max) 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 AUC(0?24?h) (p?=?.0216) and C(max) (p?=?.0088) were significantly decreased in the presence of steady-state TPV/r.
  
  
  CONCLUSIONS
  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.
authors: AIDS Program, Yale University School of Medicine, New Haven, CT, USA. Robert.bruce@yale.edu
authors: R Douglas
authors: RD
authors: Bruce
authors: David E
authors: DE
authors: Moody
authors: Wenfang B
authors: WB
authors: Fang
authors: Diane
authors: D
authors: Chodkowski
authors: Laurie
authors: L
authors: Andrews
authors: Gerald H
authors: GH
authors: Friedland
mesh_terms: D000328:Adult; D002047:Buprenorphine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000069479:Buprenorphine, Naloxone Drug Combination; D004347:Drug Interactions; D005260:Female; D018023:HIV Seronegativity; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D008875:Middle Aged; D009270:Naloxone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009293:Opioid-Related Disorders / Q000097:blood / Q000188:drug therapy; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011753:Pyrones / Q000008:administration & dosage / Q000494:pharmacology*; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides
chemical_list: D000069479:Buprenorphine, Naloxone Drug Combination; D009292:Narcotic Antagonists; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D009270:Naloxone; D002047:Buprenorphine; D019438:Ritonavir; C107201:tipranavir