Pharmaceutical Research

, Volume 31, Issue 7, pp 1676–1688 | Cite as

Commonly Used Excipients Modulate UDP-Glucuronosyltransferase 2B7 Activity to Improve Nalbuphine Oral Bioavailability in Humans

  • Hong-Jaan Wang
  • Cheng-Huei Hsiong
  • Shung-Tai Ho
  • Min-Jen Lin
  • Tung-Yuan Shih
  • Pei-Wei Huang
  • Oliver Yoa-Pu Hu
Research Paper



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.


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.


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.


Tween-PEG successfully improved oral NAL bioavailability and could formulate a useful oral dosage form for patient’s convenience.


bioavailability excipient nalbuphine pharmacodynamic pharmacokinetic 



Cold ethanol tail-flick


Electrospray ionization


Food and Drug Administration


Generally recognized as safe


Galactose single point


Human liver microsome


Inactive ingredient guide






Polyethylene glycol


Polyvinyl pyrrolidone


Rat liver microsome


The combination with equal dose of Tween 20 and PEG 400


Uridinyl diphosphate glucuronosyltransferase


Ultra-high performance liquid chromatography tandem mass


World Health Organization



This study was funded by The Department of Health, Executive Yuan of Taiwan (No. DOH97-TD-I-111-DD002). No conflict of interest to be declared by authors.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Hong-Jaan Wang
    • 1
  • Cheng-Huei Hsiong
    • 2
  • Shung-Tai Ho
    • 3
    • 4
  • Min-Jen Lin
    • 2
  • Tung-Yuan Shih
    • 1
  • Pei-Wei Huang
    • 2
  • Oliver Yoa-Pu Hu
    • 1
    • 2
  1. 1.Graduate Institute of Life SciencesNational Defense Medical CenterTaipeiTaiwan
  2. 2.School of PharmacyNational Defense Medical CenterTaipeiRepublic of China
  3. 3.Department of Anesthesiology, Taipei Veterans General HospitalNational Yang-Ming UniversityTaipeiTaiwan
  4. 4.Department of AnesthesiologyNational Defense Medical CenterTaipeiTaiwan

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