Pre-clinical drug-drug interaction (DDI) of gefitinib or erlotinib with Cytochrome P450 (CYP) inhibiting drugs, fluoxetine and/or losartan.

Autor: Luong TT; Walter Reed National Military Medical Center, Biomedical Laboratory, Department of Research, 8901 Rockville Pike, Bethesda, MD 20889, United States., McAnulty MJ; Walter Reed National Military Medical Center, Biomedical Laboratory, Department of Research, 8901 Rockville Pike, Bethesda, MD 20889, United States., Evers DL; Walter Reed National Military Medical Center, Biomedical Laboratory, Department of Research, 8901 Rockville Pike, Bethesda, MD 20889, United States., Reinhardt BJ; Walter Reed National Military Medical Center, Biomedical Laboratory, Department of Research, 8901 Rockville Pike, Bethesda, MD 20889, United States., Weina PJ; Walter Reed National Military Medical Center, Biomedical Laboratory, Department of Research, 8901 Rockville Pike, Bethesda, MD 20889, United States.; Defense Health Headquarters, 7700 Arlington Blvd, Falls Church, VA 22042, United States.
Jazyk: angličtina
Zdroj: Current research in toxicology [Curr Res Toxicol] 2021 Jun 04; Vol. 2, pp. 217-224. Date of Electronic Publication: 2021 Jun 04 (Print Publication: 2021).
DOI: 10.1016/j.crtox.2021.05.006
Abstrakt: Objective: To evaluate drug-drug interactions (DDIs) between gefitinib or erlotinib with fluoxetine, and/or losartan.
Methods: Human pooled microsomes, supersomes, and cryopreserved human hepatocytes were used to monitor DDIs in vitro . RED (Rapid Equilibrium Dialysis) protein binding was employed to investigate other pharmacokinetics.
Results: Gefitinib is significantly metabolized by Cytochrome P450 (CYP) 2D6 and CYP3A4, with less than 80% of the drug remaining. Erlotinib is significantly metabolized by CYP3A4, CYP2D6, and CYP1A2. Although gefitinib and erlotinib were metabolized by the same CYP isoenzymes, the metabolites formed from degradation of the two drugs were different.Fluoxetine inhibited CYP2D6 and CYP3A4 metabolism of gefitinib with an IC 50 of 65.12 ± 1.88 µM and 4.11 ± 2.26 µM, respectively. Fluoxetine also inhibited CYP2D6 and CYP3A4 metabolism of erlotinib with an IC 50 of 7.06 ± 1.54 µM and 4.57 ± 1.22 µM, respectively.For hepatocytes, fluoxetine affected the metabolism of gefitinib or erlotinib, while losartan had no effect. Gefitinib and erlotinib inhibited the metabolism of fluoxetine and losartan. Two-drug combinations involving gefitinib or erlotinib with fluoxetine or losartan yielded insignificant (p-value ≥ 0.05) differences in metabolism. However, combinations involving three drugs yielded significant degrees of inhibition (p-value ≤ 0.05). Three drug combinations involving fluoxetine and losartan with gefitinib or erlotinib yielded significant degrees of inhibition of the metabolism of gefitinib, but not for that of erlotinib.
Conclusion: As could be predicted by previous studies involving the inhibitory effect of fluoxetine on CYP3A4 and CYP2D6, and studies involving CYP metabolism of gefitinib and erlotinib, the tests performed here confirmed that fluoxetine has an inhibitory effect on metabolism of gefitinib or erlotinib by the main CYP isoenzymes involved. This study suggests a variable inhibitory effect of fluoxetine particularly on CYP2D6 activity towards gefitinib or erlotinib; erlotinib metabolism is less affected. Likewise, the combination of fluoxetine and losartan does not significantly affect hepatocyte metabolism of erlotinib, but does for that of gefitinib. The results presented in this study thus indicate a need for DDI assays to involve multiple drugs to properly study multidrug regimens.
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Databáze: MEDLINE
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