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

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

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.

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Acknowledgement

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

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia

    Haitham AlRabiah & Gamal A. E. Mostafa

  2. Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia

    Abdul Ahad & Fahad I. Al-Jenoobi

Authors
  1. Haitham AlRabiah
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  2. Abdul Ahad
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  3. Gamal A. E. Mostafa
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  4. Fahad I. Al-Jenoobi
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Corresponding author

Correspondence to Abdul Ahad.

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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.

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AlRabiah, H., Ahad, A., Mostafa, G.A.E. et al. Effect of Naltrexone Hydrochloride on Cytochrome P450 1A2, 2C9, 2D6, and 3A4 Activity in Human Liver Microsomes. Eur J Drug Metab Pharmacokinet 43, 707–713 (2018). https://doi.org/10.1007/s13318-018-0482-x

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