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


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.


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.


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.


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.



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

Compliance with Ethical Standards


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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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

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