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

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Abstract

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.

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Abbreviations

CET:

Cold ethanol tail-flick

ESI:

Electrospray ionization

FDA:

Food and Drug Administration

GRAS:

Generally recognized as safe

GSP:

Galactose single point

HLM:

Human liver microsome

IIG:

Inactive ingredient guide

M3G:

Morphine-3-glucuronide

NAL:

Nalbuphine

PEG:

Polyethylene glycol

PVP:

Polyvinyl pyrrolidone

RLM:

Rat liver microsome

Tween-PEG:

The combination with equal dose of Tween 20 and PEG 400

UGT:

Uridinyl diphosphate glucuronosyltransferase

UPLC–MS/MS:

Ultra-high performance liquid chromatography tandem mass

WHO:

World Health Organization

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ACKNOWLEDGMENTS AND DISCLOSURES

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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Authors and Affiliations

  1. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan

    Hong-Jaan Wang, Tung-Yuan Shih & Oliver Yoa-Pu Hu

  2. School of Pharmacy, National Defense Medical Center, 161 Minchuan East Road, Sec. 6, Taipei, 114, Taiwan, Republic of China

    Cheng-Huei Hsiong, Min-Jen Lin, Pei-Wei Huang & Oliver Yoa-Pu Hu

  3. Department of Anesthesiology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan

    Shung-Tai Ho

  4. Department of Anesthesiology, National Defense Medical Center, Taipei, Taiwan

    Shung-Tai Ho

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  1. Hong-Jaan Wang
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Correspondence to Oliver Yoa-Pu Hu.

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Wang, HJ., Hsiong, CH., Ho, ST. et al. Commonly Used Excipients Modulate UDP-Glucuronosyltransferase 2B7 Activity to Improve Nalbuphine Oral Bioavailability in Humans. Pharm Res 31, 1676–1688 (2014). https://doi.org/10.1007/s11095-013-1272-4

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  • DOI: https://doi.org/10.1007/s11095-013-1272-4

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