PURPOSE: 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.
PURPOSE: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: M M Malingré; J H Schellens; O Van Tellingen; M Ouwehand; H A Bardelmeijer; H Rosing; F J Koopman; M E Schot; W W Ten Bokkel Huinink; J H Beijnen Journal: Br J Cancer Date: 2001-11-16 Impact factor: 7.640