Advertisement

Effect of Naltrexone Hydrochloride on Cytochrome P450 1A2, 2C9, 2D6, and 3A4 Activity in Human Liver Microsomes

  • Haitham AlRabiah
  • Abdul Ahad
  • Gamal A. E. Mostafa
  • Fahad I. Al-Jenoobi
Original Research Article
  • 75 Downloads

Abstract

Background and Objective

Cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4 are the most important phase I drug-metabolizing enzymes in the liver, but there is a dearth of literature available on the effects of naltrexone hydrochloride on these major enzymes present in the human liver. Thus, in the present study, the effect of naltrexone hydrochloride on the activity of CYP1A2, 2C9, 2D6, and 3A4 using human liver microsomes (HLM) was investigated.

Methods

A selective probe for CYP1A2, 2C9, 2D6, and 3A4 was incubated with HLM with or without naltrexone hydrochloride. Phenacetin O-deethylation, tolbutamide 4-hydroxylation, dextromethorphan O-demethylation, and testosterone 6β-hydroxylation reactions were monitored for enzyme activity.

Results

The activity of all the studied CYP enzymes except 1A2 was significantly inhibited by naltrexone hydrochloride 1 µM. Furthermore, 1 µM naltrexone hydrochloride inhibited CYP3A4 enzyme activity, the most by 37.9% followed by CYP2C9 (36.5%) and CYP2D6 (31.8%). The CYP2C9 and CYP2D6 metabolic activities were greatly affected by naltrexone hydrochloride, which even at the lowest concentration of naltrexone hydrochloride (0.01 µM) significantly decreased the metabolic activity by 34.9 and 16.0%, respectively. The half maximal inhibition concentration (IC50) values for CYP2C9 and CYP2D6 inhibition were 3.40 ± 1.78 and 5.92 ± 1.58 µM, respectively.

Conclusion

These outcomes advocate that there is a great possibility of drug interactions resulting from the concurrent administration of naltrexone hydrochloride with actives that are metabolized by these CYP enzymes, particularly CYP2C9 and CYP2D6. Nevertheless, further clarification is needed through detailed in vivo pharmacokinetic studies.

Notes

Acknowledgement

The authors thank the Deanship of Scientific Research and RSSU at King Saud University for their technical support.

Compliance with Ethical Standards

Funding

The authors extend their appreciation to the deanship of scientific research and the research center, college of Pharmacy, King Saud University for funding this research.

Conflict of interest

H. AlRabiah, A. Ahad, G. A. E. Mostafa, and F. I. Al-Jenoobi have no conflicts of interest to declare.

References

  1. 1.
    Raknes G, Smabrekke L. Low-dose naltrexone and opioid consumption: a drug utilization cohort study based on data from the Norwegian prescription database. Pharmacoepidemiol Drug Saf. 2017;26(6):685–93.CrossRefGoogle Scholar
  2. 2.
    Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Med Hypotheses. 2009;72(3):333–7.CrossRefGoogle Scholar
  3. 3.
    Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014;33(4):451–9.CrossRefGoogle Scholar
  4. 4.
    Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009;10(4):663–72.CrossRefGoogle Scholar
  5. 5.
    Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013;65(2):529–38.CrossRefGoogle Scholar
  6. 6.
    Campisi G, Giannola LI, Florena AM, De Caro V, Schumacher A, Gottsche T, et al. Bioavailability in vivo of naltrexone following transbuccal administration by an electronically-controlled intraoral device: a trial on pigs. J Control Releas. 2010;145(3):214–20.CrossRefGoogle Scholar
  7. 7.
    Liu JC, Ma JD, Morello CM, Atayee RS, Best BM. Naltrexone metabolism and concomitant drug concentrations in chronic pain patients. J Anal Toxicol. 2014;38(4):212–7.CrossRefGoogle Scholar
  8. 8.
    McLaughlin PJ, Zagon IS. Duration of opioid receptor blockade determines biotherapeutic response. Biochem Pharmacol. 2015;97(3):236–46.CrossRefGoogle Scholar
  9. 9.
    Raknes G, Smabrekke L. A sudden and unprecedented increase in low dose naltrexone (LDN) prescribing in Norway. Patient and prescriber characteristics, and dispense patterns. A drug utilization cohort study. Pharmacoepidemiol Drug Saf. 2017;26(2):136–42.CrossRefGoogle Scholar
  10. 10.
    Kobayashi K, Nakajima M, Chiba K, Yamamoto T, Tani M, Ishizaki T, et al. Inhibitory effects of antiarrhythmic drugs on phenacetin O-deethylation catalysed by human CYP1A2. Br J Clin Pharmacol. 1998;45(4):361–8.CrossRefGoogle Scholar
  11. 11.
    Eagling VA, Tjia JF, Back DJ. Differential selectivity of cytochrome P450 inhibitors against probe substrates in human and rat liver microsomes. Br J Clin Pharmacol. 1998;45(2):107–14.CrossRefGoogle Scholar
  12. 12.
    Al-Jenoobi FI. Effects of some commonly used Saudi folk herbal medications on the metabolic activity of CYP2C9 in human liver microsomes. Saudi Pharm J. 2010;18(3):167–71.CrossRefGoogle Scholar
  13. 13.
    Korashy HM, Al-Jenoobi FI, Raish M, Ahad A, Al-Mohizea AM, Alam MA, et al. Impact of herbal medicines like Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida, on cytochrome P450 2C11 gene expression in rat liver. Drug Res (Stuttg). 2015;65(7):366–72.Google Scholar
  14. 14.
    Al-Jenoobi FI, Korashy HM, Ahad A, Raish M, Al-Mohizea AM, Alam MA, et al. Potential inhibitory effect of herbal medicines on rat hepatic cytochrome P450 2D gene expression and metabolic activity. Pharmazie. 2014;69(11):799–803.PubMedGoogle Scholar
  15. 15.
    Al-Jenoobi FI, Al-Thukair AA, Abbas FA, Ansari MJ, Alkharfy KM, Al-Mohizea AM, et al. Effect of black seed on dextromethorphan O- and N-demethylation in human liver microsomes and healthy human subjects. Drug Metab Lett. 2010;4(1):51–5.CrossRefGoogle Scholar
  16. 16.
    Bendriss EK, Markoglou N, Wainer IW. High-performance liquid chromatography assay for simultaneous determination of dextromethorphan and its main metabolites in urine and in microsomal preparations. J Chromatogr B Biomed Sci Appl. 2001;754(1):209–15.CrossRefGoogle Scholar
  17. 17.
    Wang X, Yeung JH. Effects of Salvia miltiorrhiza extract on the liver CYP3A activity in humans and rats. Phytother Res. 2011;25(11):1653–9.CrossRefGoogle Scholar
  18. 18.
    Baati T, Horcajada P, Gref R, Couvreur P, Serre C. In vitro determination of the CYP 3A4 activity in rat hepatic microsomes by liquid-phase extraction and HPLC-photodiode array detection. J Pharmacol Toxicol Methods. 2012;66(1):29–34.CrossRefGoogle Scholar
  19. 19.
    Borek-Dohalska L, Hodek P, Hudecek J, Stiborova M. Experimental approaches to evaluate activities of cytochromes P450 3A. Interdiscip Toxicol. 2008;1(2):155–9.CrossRefGoogle Scholar
  20. 20.
    Pan Y, Mak JW, Ong CE. Development and validation of HPLC methods for the determination of CYP2D6 and CYP3A4 activities. Curr Pharm Anal. 2012;8(3):219–24.CrossRefGoogle Scholar
  21. 21.
    Lee SY, Jang H, Lee JY, Kwon KI, Oh SJ, Kim SK. Inhibition of cytochrome P450 by ethambutol in human liver microsomes. Toxicol Lett. 2014;229(1):33–40.CrossRefGoogle Scholar
  22. 22.
    Iwata H, Tezuka Y, Kadota S, Hiratsuka A, Watabe T. Mechanism-based inactivation of human liver microsomal CYP3A4 by rutaecarpine and limonin from Evodia fruit extract. Drug Metab Pharmacokinet. 2005;20(1):34–45.CrossRefGoogle Scholar
  23. 23.
    Volpicelli JR, Rhines KC, Rhines JS, Volpicelli LA, Alterman AI, O’Brien CP. Naltrexone and alcohol dependence. Role of subject compliance. Arch Gen Psychiatry. 1997;54(8):737–42.CrossRefGoogle Scholar
  24. 24.
    Resnick RB, Schuyten-Resnick E, Washton AM. Assessment of narcotic antagonists in the treatment of opioid dependence. Annu Rev Pharmacol Toxicol. 1980;20:463–74.CrossRefGoogle Scholar
  25. 25.
    Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Human cytochromes P450 mediating phenacetin O-deethylation in vitro: validation of the high affinity component as an index of CYP1A2 activity. J Pharm Sci. 1998;87(12):1502–7.CrossRefGoogle Scholar
  26. 26.
    von Moltke LL, Greenblatt DJ, Duan SX, Schmider J, Kudchadker L, Fogelman SM, et al. Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes, SSRI antidepressants, nefazodone and venlafaxine. Psychopharmacology. 1996;128(4):398–407.CrossRefGoogle Scholar
  27. 27.
    Tassaneeyakul W, Birkett DJ, Veronese ME, McManus ME, Tukey RH, Quattrochi LC, et al. Specificity of substrate and inhibitor probes for human cytochromes P450 1A1 and 1A2. J Pharmacol Exp Ther. 1993;265(1):401–7.PubMedGoogle Scholar
  28. 28.
    Edwards RJ, Adams DA, Watts PS, Davies DS, Boobis AR. Development of a comprehensive panel of antibodies against the major xenobiotic metabolising forms of cytochrome P450 in humans. Biochem Pharmacol. 1998;56(3):377–87.CrossRefGoogle Scholar
  29. 29.
    Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin Pharmacokinet. 2009;48(11):689–723.CrossRefGoogle Scholar
  30. 30.
    Gopisankar MG. CYP2D6 pharmacogenomics. Egypt J Med Hum Genet. 2017;18(4):309–13.CrossRefGoogle Scholar
  31. 31.
    Zhou SF. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab. 2008;9(4):310–22.CrossRefGoogle Scholar
  32. 32.
    Mason BJ, Goodman AM, Dixon RM, Hameed MH, Hulot T, Wesnes K, et al. A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Neuropsychopharmacology. 2002;27(4):596–606.CrossRefGoogle Scholar
  33. 33.
    Swift R, Davidson D, Rosen S, Fitz E, Camara P. Naltrexone effects on diazepam intoxication and pharmacokinetics in humans. Psychopharmacology. 1998;135(3):256–62.CrossRefGoogle Scholar
  34. 34.
    Maany I, O’Brien CP, Woody G. Interaction between thioridazine and naltrexone. Am J Psychiatry. 1987;144(7):966.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Haitham AlRabiah
    • 1
  • Abdul Ahad
    • 2
  • Gamal A. E. Mostafa
    • 1
  • Fahad I. Al-Jenoobi
    • 2
  1. 1.Department of Pharmaceutical Chemistry, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia
  2. 2.Department of Pharmaceutics, College of PharmacyKing Saud UniversityRiyadhSaudi Arabia

Personalised recommendations