The tyrosine kinase inhibitor lenvatinib is oxidized by rat cytochromes P450 and affects their expression in rat liver.

IF 2.1 4区医学 Q3 PHARMACOLOGY & PHARMACY Acta Pharmaceutica Pub Date : 2024-09-14 Print Date: 2024-09-01 DOI:10.2478/acph-2024-0027

Radek Indra, Sandra Jelínková, Katarína Kollárová, Petra Zahumenská, Josef Dvořák, Šárka Dušková, Helena Dračínská

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Abstract

Lenvatinib is an orally effective tyrosine kinase inhibitor used to treat several types of tumors, including progressive, radioiodine-refractory differentiated thyroid cancer and advanced renal cell carcinoma. Although this drug is increasingly used in therapy, its metabolism and effects on the organism are still not described in detail. Using the rat as an experimental animal model, this study aimed to investigate the metabolism of lenvatinib by rat microsomal enzymes and cytochrome P450 (CYPs) enzymes recombinantly expressed in Supersomes^TM in vitro and to assess the effect of lenvatinib on rat CYP expression in vivo. Two metabolites, O-desmethyl lenvatinib, and lenvatinib N-oxide, were produced by rat CYPs in vitro. CYP2A1 and 2C12 were found to be the most effective in forming O-desmethyl lenvatinib, while CYP3A2 was found to primarily form lenvatinib N-oxide. The administration of lenvatinib to rats caused changes in the expression of mRNA and protein, as well as the activity of various CYPs, particularly in an increase in CYP1A1. Thus, the administration of lenvatinib to rats has an impact on the level of CYPs.

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酪氨酸激酶抑制剂来伐替尼被大鼠细胞色素P450氧化，并影响它们在大鼠肝脏中的表达。

伦伐替尼是一种口服有效的酪氨酸激酶抑制剂，用于治疗多种类型的肿瘤，包括进展期、放射性碘难治性分化型甲状腺癌和晚期肾细胞癌。虽然这种药物越来越多地被用于治疗，但其代谢和对机体的影响仍未得到详细描述。本研究以大鼠为实验动物模型，旨在研究重组在SupersomesTM中的大鼠微粒体酶和细胞色素P450（CYPs）酶对来伐替尼的体外代谢，并评估来伐替尼对大鼠体内CYP表达的影响。大鼠CYPs在体外产生了两种代谢物--O-去甲基来伐替尼和来伐替尼N-氧化物。研究发现，CYP2A1和2C12能最有效地形成O-去甲基来伐替尼，而CYP3A2则主要形成来伐替尼N-氧化物。给大鼠服用来伐替尼可导致mRNA和蛋白质的表达以及各种CYPs的活性发生变化，尤其是CYP1A1的活性增加。因此，大鼠服用来伐替尼会影响CYPs的水平。

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来源期刊

Acta Pharmaceutica PHARMACOLOGY & PHARMACY-

CiteScore

5.20

自引率

3.60%

发文量

审稿时长

>12 weeks

期刊介绍： AP is an international, multidisciplinary journal devoted to pharmaceutical and allied sciences and contains articles predominantly on core biomedical and health subjects. The aim of AP is to increase the impact of pharmaceutical research in academia, industry and laboratories. With strong emphasis on quality and originality, AP publishes reports from the discovery of a drug up to clinical practice. Topics covered are: analytics, biochemistry, biopharmaceutics, biotechnology, cell biology, cell cultures, clinical pharmacy, drug design, drug delivery, drug disposition, drug stability, gene technology, medicine (including diagnostics and therapy), medicinal chemistry, metabolism, molecular modeling, pharmacology (clinical and animal), peptide and protein chemistry, pharmacognosy, pharmacoepidemiology, pharmacoeconomics, pharmacodynamics and pharmacokinetics, protein design, radiopharmaceuticals, and toxicology.