Abstract
In this study, the effects of 17 CYP3A4 variants and drug-drug interactions (DDI) with its mechanism on alectinib metabolism were investigated. In vitro incubation systems of rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4 variants were established. The formers were used to screen potential drugs that inhibited alectinib metabolism and study the underlying mechanism, and the latter was used to determine the dynamic characteristics of CYP3A4 variants. Alectinib and its main metabolite M4 were quantitatively determined by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results showed that compared with CYP3A4.1, only CYP3A4.29 showed higher catalytic activity, while the catalytic activity of CYP3A4.4, .7, .8, .12, .14, .16, .17, .18, .19, .20, .23, and .24 decreased significantly. Among them, the catalytic activity of CYP3A4.20 is the lowest, only 2.63% of that of CYP3A4.1. Based on the RLM incubation system in vitro, 81 drugs that may be combined with alectinib were screened, among which 18 drugs had an inhibition rate higher than 80%. In addition, nicardipine had an inhibition rate of 95.09% with a half-maximum inhibitory concentration (IC50) value of 3.54 ± 0.96 μM in RLM and 1.52 ± 0.038 μM in HLM, respectively. There was a mixture of non-competitive and anti-competitive inhibition of alectinib metabolism in both RLM and HLM. In vivo experiments of Sprague–Dawley (SD) rats, compared with the control group (30 mg/kg alectinib alone), the AUC(0–t), AUC(0–∞), Tmax and Cmax of alectinib administered in combination with 6 mg/kg nicardipine were significantly increased in the experimental group. In conclusion, the metabolism of alectinib was affected by polymorphisms of the CYP3A4 gene and nicardipine. This study provides reference data for clinical individualized administration of alectinib in the future.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
References
Androutsopoulos VP, Ruparelia K, Arroo RR, Tsatsakis AM, Spandidos DA (2009a) CYP1-mediated antiproliferative activity of dietary flavonoids in MDA-MB-468 breast cancer cells. Toxicology 264(3):162–170. https://doi.org/10.1016/j.tox.2009.07.023
Androutsopoulos VP, Tsatsakis AM, Spandidos DA (2009b) Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention. BMC Cancer 9:187. https://doi.org/10.1186/1471-2407-9-187
Androutsopoulos VP, Papakyriakou A, Vourloumis D, Tsatsakis AM, Spandidos DA (2010) Dietary flavonoids in cancer therapy and prevention: substrates and inhibitors of cytochrome P450 CYP1 enzymes. Pharmacol Ther 126(1):9–20. https://doi.org/10.1016/j.pharmthera.2010.01.009
Calvo E, Lee J-S, Kim S-W et al (2019) Modulation of fexofenadine pharmacokinetics by osimertinib in patients with advanced EGFR-mutated non-small cell lung cancer. J Clin Pharmacol 59(8):1099–1109. https://doi.org/10.1002/jcph.1403
Cleary Y, Gertz M, Morcos PN et al (2018) Model-based assessments of CYP-mediated drug-drug interaction risk of alectinib: physiologically based pharmacokinetic modeling supported clinical development. Clin Pharmacol Ther 104(3):505–514. https://doi.org/10.1002/cpt.956
Duma N, Santana-Davila R, Molina JR (2019) Non-small cell lung cancer: epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc 94(8):1623–1640. https://doi.org/10.1016/j.mayocp.2019.01.013
Duruisseaux M, Besse B, Cadranel J et al (2017) Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer (IFCT-1302 CLINALK): a French nationwide cohort retrospective study. Oncotarget 8(13):21903–21917. https://doi.org/10.18632/oncotarget.15746
Howlader N, Forjaz G, Mooradian MJ et al (2020) The effect of advances in lung-cancer treatment on population mortality. N Engl J Med 383(7):640–649. https://doi.org/10.1056/NEJMoa1916623
Imyanitov EN, Iyevleva AG, Levchenko EV (2021) Molecular testing and targeted therapy for non-small cell lung cancer: current status and perspectives. Crit Rev Oncol Hematol 157:103194. https://doi.org/10.1016/j.critrevonc.2020.103194
Kodama T, Tsukaguchi T, Yoshida M, Kondoh O, Sakamoto H (2014) Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. Cancer Lett 351(2):215–221. https://doi.org/10.1016/j.canlet.2014.05.020
Kwak EL, Bang Y-J, Camidge DR et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703. https://doi.org/10.1056/NEJMoa1006448
Libiad Y, Boutayeb S, Chaibi A (2022) Drug-drug interactions of tyrosine kinase inhibitors in treatment of non-small-cell lung carcinoma. Bull Cancer 109(3):358–381. https://doi.org/10.1016/j.bulcan.2021.11.019
Morcos PN, Yu L, Nieforth KA et al (2016) Absorption, distribution, metabolism, and excretion (Adme) of the alk inhibitor alectinib: results from an absolute bioavailability/mass balance study in healthy subjects. Clin Pharmacol Ther 99:S62–S62
Morcos PN, Cleary Y, Guerini E et al (2017a) Clinical drug-drug interactions through cytochrome P450 3A (CYP3A) for the selective ALK inhibitor alectinib. Clin Pharmacol Drug Dev 6(3):280–291. https://doi.org/10.1002/cpdd.298
Morcos PN, Yu L, Bogman K et al (2017b) Absorption, distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects. Xenobiotica 47(3):217–229. https://doi.org/10.1080/00498254.2016.1179821
Morcos PN, Guerini E, Parrott N et al (2017c) Effect of food and esomeprazole on the pharmacokinetics of alectinib, a highly selective ALK inhibitor, in healthy subjects. Clin Pharmacol Drug Dev 6(4):388–397. https://doi.org/10.1002/cpdd.296
Nakagawa T, Fowler S, Takanashi K et al (2018) In vitro metabolism of alectinib, a novel potent ALK inhibitor, in human: contribution of CYP3A enzymes. Xenobiotica 48(6):546–554. https://doi.org/10.1080/00498254.2017.1344910
Nakamura K, Ariyoshi N, Iwatsubo T et al (2005) Inhibitory effects of nicardipine to cytochrome P450 (CYP) in human liver microsomes. Biol Pharm Bull 28(5):882–885
Nishino M, Soejima K, Mitsudomi T (2019) Brain metastases in oncogene-driven non-small cell lung cancer. Transl Lung Cancer R 8:S298–S307. https://doi.org/10.21037/tlcr.2019.05.15
Sakamoto H, Tsukaguchi T, Hiroshima S et al (2011) CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 19(5):679–690. https://doi.org/10.1016/j.ccr.2011.04.004
Sato-Nakai M, Kawashima K, Nakagawa T et al (2017) Metabolites of alectinib in human: their identification and pharmacological activity. Heliyon 3(7):e00354. https://doi.org/10.1016/j.heliyon.2017.e00354
Sekiguchi N, Nagao S, Takanashi K et al (2017) Preclinical evaluation of the potential for cytochrome P450 inhibition and induction of the selective ALK inhibitor, alectinib. Xenobiotica 47(12):1042–1051. https://doi.org/10.1080/00498254.2016.1261308
Seto T, Kiura K, Nishio M et al (2013) CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1–2 study. Lancet Oncol 14(7):590–598. https://doi.org/10.1016/S1470-2045(13)70142-6
Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660
Tomasini P, Egea J, Souquet-Bressand M, Greillier L, Barlesi F (2019) Alectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: clinical trial evidence and experience with a focus on brain metastases. Ther Adv Respir Dis. https://doi.org/10.1177/1753466619831906
Tsatsakis AM (2021) Toxicological risk assessment and multi-system health impacts from exposure. Academic Press, London
Wallin JD (1990) Intravenous nicardipine hydrochloride: treatment of patients with severe hypertension. Am Heart J 119(2 Pt 2):434–437
Werk AN, Cascorbi I (2014) Functional gene variants of CYP3A4. Clin Pharmacol Ther 96(3):340–348. https://doi.org/10.1038/clpt.2014.129
Yeung KS, Gubili J, Mao JJ (2018) Herb-Drug Interactions in Cancer Care Oncology (williston Park) 32(10):516–520
Zhao D, Chen J, Chu M, Long X, Wang J (2020) Pharmacokinetic-based drug-drug interactions with anaplastic lymphoma kinase inhibitors: a review. Drug Des Devel Ther 14:1663–1681. https://doi.org/10.2147/DDDT.S249098
Zhou S, Chan E, Lim LY et al (2004) Therapeutic drugs that behave as mechanism-based inhibitors of cytochrome P450 3A4. Curr Drug Metab 5(5):415–442
Zhou S, Yung Chan S, Cher Goh B et al (2005) Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin Pharmacokinet 44(3):279–304
Zhou Q, Yu X, Shu C et al (2011) Analysis of CYP3A4 genetic polymorphisms in Han Chinese. J Hum Genet 56(6):415–422. https://doi.org/10.1038/jhg.2011.30
Zhou X-Y, Hu X-X, Wang C-C et al (2019) Enzymatic activities of CYP3A4 allelic variants on quinine 3-hydroxylation in vitro. Front Pharmacol 10:591. https://doi.org/10.3389/fphar.2019.00591
Acknowledgements
This work was supported by the National Key Research and Development Program of China (2020YFC2008301), and the National Natural Science Foundation of China (82104297).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Liu, Yn., Chen, J., Wang, J. et al. Effects of drug-drug interactions and CYP3A4 variants on alectinib metabolism. Arch Toxicol 97, 2133–2142 (2023). https://doi.org/10.1007/s00204-023-03524-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-023-03524-1