title: Commonly used excipients modulate UDP-glucuronosyltransferase 2b7 activity to improve nalbuphine oral bioavailability in humans.
abstract: OBJECTIVE
  Nalbuphine (NAL) is a potent opioid analgesic, but can only be administered by injection. The major aim of this study was to develop an oral NAL formulation employing known excipients as UDP-glucuronosyltransferase 2B7 (UGT2B7) inhibitors to improve its oral bioavailability.
  
  
  METHODS
  Twenty commonly used pharmaceutical excipients were screened in vitro by using liver microsomes to identify inhibitors of UGT2B7, the major NAL metabolic enzyme. Tween 20 and PEG 400 were potent UGT2B7 inhibitors and both were co-administered (Tween-PEG) with NAL to rats and humans for pharmacokinetic and/or pharmacodynamic analyses.
  
  
  RESULTS
  In animal studies, oral Tween-PEG (4 mg/kg of each) significantly increased the area under the plasma NAL concentration-time curve (AUC) and the maximal plasma concentration (Cmax) by 4- and 5-fold, respectively. The results of the pharmacodynamic analysis were in agreement with those of the pharmacokinetic analysis, and showed that Tween-PEG significantly enhanced the analgesic effects of orally administered NAL. In humans, oral Tween-PEG (240 mg of each) also increased NAL Cmax 2.5-fold, and AUC by 1.6-fold.
  
  
  CONCLUSIONS
  Tween-PEG successfully improved oral NAL bioavailability and could formulate a useful oral dosage form for patient's convenience.
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors: Hong-Jaan
authors: HJ
authors: Wang
authors: Cheng-Huei
authors: CH
authors: Hsiong
authors: Shung-Tai
authors: ST
authors: Ho
authors: Min-Jen
authors: MJ
authors: Lin
authors: Tung-Yuan
authors: TY
authors: Shih
authors: Pei-Wei
authors: PW
authors: Huang
authors: Oliver Yoa-Pu
authors: OY
authors: Hu
mesh_terms: D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D005079:Excipients / Q000008:administration & dosage / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009266:Nalbuphine / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D011136:Polysorbates / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000701:Analgesics, Opioid; D005079:Excipients; D011136:Polysorbates; D011092:Polyethylene Glycols; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D009266:Nalbuphine