The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib

Vavrová, Katarína; Indra, Radek; Pompach, Petr; Heger, Zbyněk; Hodek, Petr

doi:10.1016/j.biopha.2021.112391

Cited by 14 publications

(12 citation statements)

References 53 publications

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“… 2012 ; Vavrova et al. 2022 ), the induction of CYP1A1 by toddalolactone will decrease the concentration of substrate and further reduce the clinical effects. Thus, further research focussed on CYP1A1-mediated DDIs is needed.…”

Section: Discussionmentioning

confidence: 99%

In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression

Shan¹,

Shi²,

Hu³

et al. 2022

Pharmaceutical Biology

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Context Toddalolactone, the main component of Toddalia asiatica (L.) Lam. (Rutaceae), has anticancer, antihypertension, anti-inflammatory, and antifungal activities. Objective This study investigated the metabolic characteristics of toddalolactone. Materials and methods Toddalolactone metabolic stabilities were investigated by incubating toddalolactone (20 μM) with liver microsomes from humans, rabbits, mice, rats, dogs, minipigs, and monkeys for 0, 30, 60, and 90 min. The CYP isoforms involved in toddalolactone metabolism were characterized based on chemical inhibition studies and screening assays. The effects of toddalolactone (0, 10, and 50 µM) on CYP1A1 and CYP3A5 protein expression were investigated by immunoblotting. After injecting toddalolactone (10 mg/kg), in vivo pharmacokinetic profiles using six Sprague–Dawley rats were investigated by taking 9-time points, including 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 h. Results Monkeys showed the greatest metabolic capacity in CYP-mediated and UGT-mediated reaction systems with short half-lives ( T 1/2 ) of 245 and 66 min, respectively, while T 1/2 of humans in two reaction systems were 673 and 83 min, respectively. CYP1A1 and CYP3A5 were the major CYP isoforms involved in toddalolactone biotransformation. Induction of CYP1A1 protein expression by 50 μM toddalolactone was approximately 50% greater than that of the control (0 μM). Peak plasma concentration ( C max ) for toddalolactone was 0.42 μg/mL, and T max occurred at 0.25 h post-dosing. The elimination t 1/2 was 1.05 h, and the AUC 0–t was 0.46 μg/mL/h. Conclusions These findings demonstrated the significant species differences of toddalolactone metabolic profiles, which will promote appropriate species selection in further toddalolactone studies.

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Section: Discussionmentioning

confidence: 99%

In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression

Shan¹,

Shi²,

Hu³

et al. 2022

Pharmaceutical Biology

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“…Several in vitro studies evaluated the pharmacokinetics of MKIs that are mainly metabolized in the liver by cytochrome P450 (CYP). These studies showed that CYP3A4, stimulated by cytochrome b5, is mainly involved in MKI metabolism and oxidation, but other cytochromes (i.e., CYP1A1, CYP1B1, CYP3A5, CYP2D6) also seem to be involved in this process [ 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Pilot Study on the Impact of Polymorphisms Linked to Multi-Kinase Inhibitor Metabolism on Lenvatinib Side Effects in Patients with Advanced Thyroid Cancer

Cantara

Dalmiglio

Marzocchi

et al. 2023

IJMS

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Multi-kinase inhibitors (MKIs) represent the best therapeutic option in advanced thyroid cancer patients. The therapeutic efficacy and toxicity of MKIs are very heterogeneous and are difficult to predict before starting treatment. Moreover, due to the development of severe adverse events, it is necessary to interrupt the therapy some patients. Using a pharmacogenetic approach, we evaluated polymorphisms in genes coding for proteins involved with the absorption and elimination of the drug in 18 advanced thyroid cancer patients treated with lenvatinib, and correlated the genetic background with (1) diarrhea, nausea, vomiting and epigastric pain; (2) oral mucositis and xerostomia; (3) hypertension and proteinuria; (4) asthenia; (5) anorexia and weight loss; (6) hand foot syndrome. Analyzed variants belong to cytochrome P450 (CYP3A4 rs2242480 and rs2687116 and CYP3A5 rs776746) genes and to ATP-binding cassette transporters (ABCB1 rs1045642, rs2032582 and rs2235048 and ABCG2 rs2231142). Our results suggest that the GG genotype for rs2242480 in CYP3A4 and CC genotype in rs776746 for CYP3A5 were both associated with the presence of hypertension. Being heterozygous for SNPs in the ABCB1 gene (rs1045642 and 2235048) implicated a higher grade of weight loss. The ABCG2 rs2231142 statistically correlated with a higher extent of mucositis and xerostomia (CC genotype). Heterozygous and rare homozygous genotypes for rs2242480 in CYP3A4 and for rs776746 for CYP3A5 were found to be statistically linked to a worse outcome. Evaluating the genetic profile before starting lenvatinib treatment may help to predict the occurrence and grade of some side effects, and may contribute to improving patient management.

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“…Following hepatic metabolism, lenvatinib is primarily eliminated through feces via bile, with a smaller portion excreted in urine. Previous studies have demonstrated that lenvatinib undergoes biotransformation through various pathways including oxidation, hydroxylation, dealkylation, and glucuronidation 2 . Methylation has been identified as the major pathway of lenvatinib biotransformation, resulting in the formation of O‐desmethyl lenvatinib (M2), N‐decyclopropyl lenvatinib (M1), and lenvatinib N‐oxide (M3) as the major metabolites.…”

Section: Introductionmentioning

confidence: 99%

“…The metabolism of lenvatinib is anticipated to be mainly facilitated by CYP3A4 and CYP1A1 enzymes, along with cytochrome b5. 2 In a study investigating the coadministration of rifampicin and lenvatinib, it was observed that rifampicin, a P-glycoprotein (P-gp) inhibitor, resulted in an increase in the area under the plasma concentration-time curve (AUC (0À∞) ) and maximum plasma concentration (C max ) of lenvatinib when administered as a single dose. 9 However, when rifampicin was administered multiple times, the AUC (0À∞) and C max of lenvatinib decreased.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the inhibitory effect of azoles on pharmacokinetics of lenvatinib in rats both in vivo and in vitro by UPLC‐MS/MS

Xia,

Song,

et al. 2023

Thoracic Cancer

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BackgroundLenvatinib is a multitargeted tyrosine kinase inhibitor used in the treatment of a variety of solid tumors. This study aims to investigate the potential pharmacokinetic interactions between lenvatinib and various azoles (ketoconazole, voriconazole, isavuconazole and posaconazole) when orally administered to rats.MethodsA total of 30 Sprague–Dawley rats were randomly allocated into five groups and administered 20 mg/kg of ketoconazole, voriconazole, isavuconazole and 30 mg/kg of posaconazole and 0.5% CMC‐Na, through gavage for a duration of 7 days prior to the commencement of the experiment. On the final day, the rats were given 10 mg/kg of lenvatinib. The blood concentration of lenvatinib was determined using UPLC‐MS–MS. In vitro lenvatinib were incubated with azoles and rat liver microsomes (RLMs) or human liver microsomes (HLMs). Molecular docking was lastly used to examine the binding strength of the enzymes and ligands with Autodock Vina.ResultsAUC and Cmax of lenvatinib significantly increased with each of the azoles (p < 0.05), whereas CLz/F decreased 0.83‐flod, 0.41‐fold (p < 0.05) and 0.72‐fold (p < 0.01) in voriconazole, isavuconazole and ketoconazole in rats. The IC50 of lenvatinib with the azoles were 0.237, 1.300, 0.355 and 2.403 μM in RLMs and 0.160, 1.933, 3.622 and 1.831 μM in HLMs. Molecular docking analysis suggested that azoles exhibited a strong binding ability towards the target enzymes.ConclusionIt is imperative to acknowledge the potential drug–drug interactions mediated by CYP3A4 between azoles and lenvatinib, as these interactions hold significant implications for their clinical utilization.

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The impact of individual human cytochrome P450 enzymes on oxidative metabolism of anticancer drug lenvatinib

Cited by 14 publications

References 53 publications

In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression

In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression

Pilot Study on the Impact of Polymorphisms Linked to Multi-Kinase Inhibitor Metabolism on Lenvatinib Side Effects in Patients with Advanced Thyroid Cancer

Evaluation of the inhibitory effect of azoles on pharmacokinetics of lenvatinib in rats both in vivo and in vitro by UPLC‐MS/MS

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