Inhibitory effects of Thai herbal extracts on the cytochrome P450 3A-mediated the metabolism of gefitinib, lapatinib and sorafenib

Chumaphorn Rodseeda; Paveena Yamanont; Darawan Pinthong; Porntipa Korprasertthaworn

doi:10.1016/j.toxrep.2022.10.004

Inhibitory effects of Thai herbal extracts on the cytochrome P450 3A-mediated the metabolism of gefitinib, lapatinib and sorafenib

Toxicol Rep. 2022 Oct 4:9:1846-1852. doi: 10.1016/j.toxrep.2022.10.004. eCollection 2022.

Authors

Chumaphorn Rodseeda^{1

2

3}, Paveena Yamanont⁴, Darawan Pinthong⁴, Porntipa Korprasertthaworn^{1

3

4}

Affiliations

¹ Graduate Program in Toxicology, Faculty of Science, Mahidol University, Bangkok, Thailand.
² Department of Occupational Health and Safety, School of Public Health, University of Phayao, Phayao, Thailand.
³ Center of Excellence on Environmental Health and Toxicology (EHT), OPS, MHESI, Thailand.
⁴ Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.

Abstract

Herbal products are widely used in cancer patients via co-administration with chemotherapy. Previous studies have demonstrated that pharmacokinetic interactions between herbs and anticancer drugs exist due to inhibition of drug-metabolizing enzymes, particularly cytochrome P450s (CYPs). The aim of this study was to determine the inhibitory effects of Andrographis paniculata, Curcuma zedoaria, Ganoderma lucidum, Murdannia loriformis and Ventilago denticulata extracts on the metabolism of gefitinib, lapatinib and sorafenib. The activities of CYP3A in human liver microsome on the metabolism of gefitinib, lapatinib and sorafenib in the absence and presence of Thai herbal extracts were assayed using high-performance liquid chromatography analysis. Curcuma zedoaria extract potently inhibited CYP3A-mediated lapatinib and sorafenib metabolism with IC₅₀ values of 4.18 ± 3.20 and 7.59 ± 1.23 μg/mL, respectively, while the metabolism of gefitinib was strongly inhibited by Murdannia loriformis and Ventilago denticulata extracts with IC₅₀ values of 7.53 ± 2.87 and 7.06 ± 1.23 μg/mL, respectively. Andrographis paniculata and Ganoderma lucidum extracts had less effect on the metabolism of the tested anticancers (IC₅₀ values >10 μg/mL). In addition, kinetic analysis of the ability of Curcuma zedoaria extract to inhibit CYP3A-mediated metabolism of anticancer drugs was best described by the noncompetitive and competitive inhibition models with K_i values of 20.08 and 11.55 μg/mL for the metabolism of gefitinib and sorafenib, respectively. The present study demonstrated that there were potential pharmacokinetic interactions between tyrosine kinase inhibitors and herbal extracts.

Keywords: ATP, adenosine 5′ triphosphate; CYP, cytochrome P450; Cytochrome P450 3A; DMSO, dimethyl sulfoxide; Drug−herb interaction; EGFR, epidermal growth factor receptor; FDA, Food and Drug Administration; GEF, gefitinib; G−6−P, glucose−6−phosphate; G−6−PD, G−6−P dehydrogenase; HER2, human epidermal growth factor receptor 2; HLM, human liver microsome; HPLC, high-performance liquid chromatography; Herbal extract; IC50, half maximal inhibitory concentration; Ki, inhibition constant; LC/MS, liquid mass spectrometry; NADP, nicotinamide adenine dinucleotide phosphate; PDGFR, platelet−derived growth factor receptor; RAF, Rapidly Accelerated Fibrosarcoma; SOR, sorafenib; TKI, tyrosine kinase inhibitor; Tyrosine kinase inhibitor; UGT, UDP-glucuronosyltransferase; UV, ultraviolet; VEGFR, vascular endothelial growth factor receptor.