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

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.

KEY WORDS

bioavailability excipient nalbuphine pharmacodynamic pharmacokinetic 

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

Notes

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.

References

  1. 1.
    Kalasz H, Antal I. Drug excipients. Curr Med Chem. 2006;13:2535–63.PubMedCrossRefGoogle Scholar
  2. 2.
    Chen ML. Lipid excipients and delivery systems for pharmaceutical development: a regulatory perspective. Adv Drug Deliv Rev. 2008;60(6):768–77.PubMedCrossRefGoogle Scholar
  3. 3.
    Buggins TR, Dickinson PA, Taylor G. The effects of pharmaceutical excipients on drug disposition. Adv Drug Deliv Rev. 2007;59(15):1482–503.PubMedCrossRefGoogle Scholar
  4. 4.
    Wandel C, Kim RB, Stein CM. “Inactive” excipients such as Cremophor can affect in vivo drug disposition. Clin Pharmacol Ther. 2003;73(5):394–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Bravo González RC, Huwyler J, Boess F, Walter I, Bittner B. In vitro investigation on the impact of the surface-active excipients Cremophor EL, Tween 80 and Solutol HS 15 on the metabolism of midazolam. Biopharm Drug Dispos. 2004;25(1):37–49.PubMedCrossRefGoogle Scholar
  6. 6.
    Tayrouz Y, Ding R, Burhenne J, Riedel KD, Weiss J, Hoppe-Tichy T, et al. Pharmacokinetic and pharmaceutic interaction between digoxin and Cremophor RH40. Clin Pharmacol Ther. 2003;73(5):397–405.PubMedCrossRefGoogle Scholar
  7. 7.
    Bittner B, González RC, Walter I, Kapps M, Huwyler J. Impact of Solutol HS 15 on the pharmacokinetic behaviour of colchicine upon intravenous administration to male Wistar rats. Biopharm Drug Dispos. 2003;24(4):173–81.PubMedCrossRefGoogle Scholar
  8. 8.
    Mountfield RJ, Senepin S, Schleimer M, Walter I, Bittner B. Potential inhibitory effects of formulation ingredients on intestinal cytochrome P450. Int J Pharm. 2000;211(1–2):89–92.PubMedCrossRefGoogle Scholar
  9. 9.
    Cornaire G, Woodley J, Hermann P, Cloarec A, Arellano C, Houin G. Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int J Pharm. 2004;278:119–31.PubMedCrossRefGoogle Scholar
  10. 10.
    Ren X, Mao X, Cao L, Xue K, Si L, Qiu J, et al. Nonionic surfactants are strong inhibitors of cytochrome p4503A biotransformation activity in vitro and in vivo. Eur J Pharm Sci. 2009;36:401–11.PubMedCrossRefGoogle Scholar
  11. 11.
    Melnikova I. Pain market. Nat Rev Drug Discov. 2010;9:589–90.PubMedCrossRefGoogle Scholar
  12. 12.
    Snidvongs S, Mehta V. Recent advances in opioid prescription for chronic non-cancer pain. Postgrad Med J. 2012;88:66–72.PubMedCrossRefGoogle Scholar
  13. 13.
    Amabile CM, Bowman BJ. Overview of oral modified-release opioid products for the management of chronic pain. Ann Pharmacother. 2006;40:1327–35.PubMedCrossRefGoogle Scholar
  14. 14.
    Beaver WT, Feise GA, Robb D. Analgesic effect of intramuscular and oral nalbuphine in postoperative pain. Clin Pharmacol Ther. 1981;29(2):174–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 3: opioids, NSAIDs, steroids, and post-discharge medications. Headache. 2012;52(3):467–82.PubMedCrossRefGoogle Scholar
  16. 16.
    Pugh CC, Drummond RA. A dose-response study with nalbuphine hydrochloride for pain in patients after upper abdominal surgery. Br J Anaesth. 1987;59(11):1356–64.PubMedCrossRefGoogle Scholar
  17. 17.
    Jang S, Kim H, Kim D, Jeong MW, Ma T, Kim S, et al. Attenuation of morphine tolerance and withdrawal syndrome by coadministration of nalbuphine. Arch Pharm Res. 2006;29:677–84.PubMedCrossRefGoogle Scholar
  18. 18.
    Schmidt WK, Tam SW, Shotzberger GS, Smith Jr DH, Clark R, Vernier VG. Nalbuphine. Drug Alcohol Depen. 1985;14(3–4):339–62.CrossRefGoogle Scholar
  19. 19.
    Aitkenhead AR, Lin ES, Achola KJ. The pharmacokinetics of oral and intravenous nalbuphine in healthy volunteers. Br J Clin Pharmacol. 1988;25(2):264–8.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Lo MW, Schary WL, Whitney Jr CC. The disposition and bioavailability of intravenous and oral nalbuphine in healthy volunteers. J Clin Pharmacol. 1987;27(11):866–73.PubMedCrossRefGoogle Scholar
  21. 21.
    Wang HJ, Hsiong CH, Pao LH, Chang WL, Zhang LJ, Lin MJ, et al. New finding of nalbuphine metabolites in men: NMR spectroscopy and UPLC–MS/MS spectrometry assays in a pilot human study. Metabolomics. 2013. doi:10.1007/s11306-013-0605-y.PubMedCentralPubMedGoogle Scholar
  22. 22.
    King CD, Rios GR, Green MD, Tephly TR. UDP-glucuronosyltransferases. Curr Drug Metab. 2000;1(2):143–61.PubMedCrossRefGoogle Scholar
  23. 23.
    Kay B, Lindsay RG, Mason CJ, Healy TE. Oral nalbuphine for the treatment of pain after dental extractions. Br J Anaesth. 1988;61(3):313–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Okun R. Analgesic effects of oral nalbuphine and codeine in patients with postoperative pain. Clin Pharmacol Ther. 1982;32(4):517–24.PubMedCrossRefGoogle Scholar
  25. 25.
    Hanks GW. The clinical usefulness of agonist-antagonistic opioid analgesics in chronic pain. Drug Alcohol Depend. 1987;20:339–46.PubMedCrossRefGoogle Scholar
  26. 26.
    Pao LH, Hu OYP, Fan HY, Lin CC, Liu LC, Huang PW. Herb-drug interaction of 50 Chinese herbal medicines on CYP3A4 activity in vitro and in vivo. Am J Chin Med. 2012;40(1):57–73.PubMedCrossRefGoogle Scholar
  27. 27.
    Coffman BL, Rios GR, King CD, Tephly TR. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos. 1997;25:1–4.PubMedGoogle Scholar
  28. 28.
    Wahlstrom A, Lenhammar L, Ask B, Rane A. Tricyclic antidepressants inhibit opioid receptor binding in human brain and hepatic morphine glucuronidation. Pharmacol Toxicol. 1994;75(1):23–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Wang JJ, Ho ST, Hu OYP, Chu KM. An innovative cold tail-flick test: the cold ethanol tail-flick test. Anesth Analg. 1995;80:102–7.PubMedGoogle Scholar
  30. 30.
    Tang HS, Hu OYP. Assessment of liver function using a novel galactose single point method. Digestion. 1992;52:222–31.PubMedCrossRefGoogle Scholar
  31. 31.
    Panakanti R, Narang AS. Impact of excipient interactions on drug bioavailability from solid dosage forms. Pharm Res. 2012;29:2639–59.PubMedCrossRefGoogle Scholar
  32. 32.
  33. 33.
  34. 34.
    Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol. 2000;40:581–616.PubMedCrossRefGoogle Scholar
  35. 35.
    Rege BD, Kao JPY, Polli JE. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur J Pharm Sci. 2002;16(4–5):237–46.PubMedCrossRefGoogle Scholar
  36. 36.
    da Silva MEF, Meirelles NC. Interaction of non-ionic surfactants with hepatic CYP in Prochilodus scrofa. Toxicol in Vitro. 2004;18(6):859–67.PubMedCrossRefGoogle Scholar
  37. 37.
    Hussain MA, Aungst BJ, Shefter E. Buccal and oral bioavailability of nalbuphine in rats. J Pharm Sci. 1986;75:218–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Malingre MM, Schellens JH, Van Tellingen O, Ouwehand M, Bardelmeijer HA, Rosing H, et al. The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients. Br J Cancer. 2001;85(10):1472–7.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Zhu S, Huang R, Hong M, Jiang Y, Hu Z, Liu C, et al. Effects of polyoxyethylene (40) stearate on the activity of P-glycoprotein and cytochrome P450. Eur J Pharm Sci. 2009;37:573–80.PubMedCrossRefGoogle Scholar

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

Personalised recommendations