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Pharmacokinetics of Dasatinib in Rats: a Potential Food–Drug Interaction with Naringenin

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Abstract

Background and Objectives

The novel tyrosine kinase inhibitor (TKI) dasatinib, a multitarget inhibitor of Bcr-Abl and Src family kinases, has been licensed for the treatment of Ph+ acute lymphoblastic leukemia and chronic myeloid leukemia. Many citrus-based foods include the flavonoid naringenin, which is commonly available. Dasatinib is a Cyp3a4, P-gp, and Bcrp1 substrate, which makes it sensitive to potential food–drug interactions. The concurrent use of naringenin may change the pharmacokinetics of dasatinib, which could result in adverse effects and toxicity. The present investigation examined the impact of naringenin on the pharmacokinetics interactions of DAS and proposes a possible interaction mechanism in Wistar rats.

Methods

Rats were provided with a single oral dose of dasatinib (25 mg/kg) with or without naringenin pretreatment (150 mg/kg p.o. daily for 7 days, n = 6 in each group). Dasatinib was quantified in plasma by UHPLC MS/MS assay. Noncompartmental analysis was used to compute the pharmacokinetic parameters, and immunoblot was used to assess the protein expression in the hepatic and intestinal tissues.

Results

Following 7 days of naringenin pretreatment, the plasma mean concentration of dasatinib was enhanced compared with without pretreatment. In rats that were pretreated with naringenin, the pharmacokinetics of the orally administered dasatinib (25 mg/kg) was shown to be significantly different from that of dasatinib given without pretreatment (p < 0.05). There was a significant enhancement in pharmacokinetic parameters elimination half-life (T1/2), time to maximum concentration ( Tmax), maximum concentration )Cmax), area under the concentration–time curve (AUC0–t), area under the moment curve (AUMC0–∞), and mean residence time (MRT) by 28.41%, 50%, 103.54%, 72.64%, 115.08%, and 15.19%, respectively (p < 0.05) and suppression in elimination rate constant (Kel), volume of distribution (Vd), and clearance (CL) by 21.09%, 31.13%, and 46.25%, respectively, in comparison with dasatinib alone group (p < 0.05). The enhancement in dasatinib bioavailability and systemic exposure resulted from the significant inhibition of Cyp3a2, Mdr1/P-gp, and Bcrp1 expression and suppression of the dasatinib hepatic and intestinal metabolism, which enhanced the rate of dasatinib absorption and decreased its elimination.

Conclusion

Concurrent use of naringenin-containing supplements, herbs, or foods with dasatinib may cause serious and potentially life-threatening drug interactions. Further studies are necessary to determine the clinical significance of these findings.

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Acknowledgements

The authors are grateful to the Researchers Supporting Project Number (RSPD2024R541) at King Saud University, Riyadh, Saudi Arabia for funding this project.

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Authors and Affiliations

  1. Department of Pharmaceutics, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia

    Mohammad Raish, Badr Abdul Karim, Yousef A. Bin Jardan, Abdul Ahad & Fahad I. Al-Jenoobi

  2. Department of Clinical Pharmacy, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia

    Ajaz Ahmad & Khalid M. Alkharfy

  3. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia

    Muzaffar Iqbal

  4. Experimental Animal Care Facility, College of Pharmacy, King Saud University, 11451, Riyadh, Saudi Arabia

    Omer Mansour Mohammed

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  1. Mohammad Raish
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Correspondence to Mohammad Raish.

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Institutional Review Board Statement

The research was approved by the Research Ethics Committee of King Saud University College of Pharmacy Riyadh, Saudi Arabia (KSU-SE-21-58).

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Author Contributions

MR and AA: conceptualization, formal analysis, and writing and reviewing original draft. BAK: experimental work. YABJ: methodology and supervision. AA, MI: formal analysis. KMA: writing and reviewing original draft. FIA-J: conceptualization, supervision, funding acquisition, writing–review and editing.

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Raish, M., Ahmad, A., Karim, B.A. et al. Pharmacokinetics of Dasatinib in Rats: a Potential Food–Drug Interaction with Naringenin. Eur J Drug Metab Pharmacokinet 49, 239–247 (2024). https://doi.org/10.1007/s13318-024-00881-9

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