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Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Another concern is that there is evidence that ingestion of significant quantities of quercetin may cause interactions with certain medications. For example, there is some evidence that quercetin binds to the bacterial DNA gyrase enzyme and may interact with the fluoroquinolone antibiotics that target this enzyme. Quercetin has also been reported to inhibit the metabolic enzyme CYP2C8 and may potentially interfere with the pharmacokinetics of a wide range of drugs, including the anticancer agents taxol and paclitaxel. This is a potential problem, as some cancer patients prescribed taxol or paclitaxel may take a quercetin-containing supplement in the belief that it may be beneficial for their disease. However, as these anticancer agents are metabolized primarily by CYP2C8, their bioavailability may be increased unpredictably, potentially leading to harmful side effects.
Role of Genetic Variability in Breast Cancer Treatment Outcomes
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Kandace L. Amend, Ji-Yeob Choi, Christine B. Ambrosone
The taxanes paclitaxel and docetaxel interfere with microtubular disassembly, ultimately resulting in DNA fragmentation and features of apoptosis (71). The contributions of genetic variability to paclitaxel metabolism and breast cancer outcomes is still unclear. CYP2C8 is thought to be the main CYP-metabolizing enzyme of paclitaxel, while CYP3A4 and CYP3A5 play more minor roles in drug metabolism (19). At least three known variants in CYP2C8 exist, and the CYP2C8*3 variant allele has been associated with decreased paclitaxel 6-αhydroxylase activity in human cell lines and human liver microsomes (72). In a recent study of paclitaxel metabolism in breast cancer, however, CYP2C8 genotypes (CYP2C8*3 and CYP2C8*4) were not significantly associated with paclitaxel clearance (73). Ethnic variation exists in the distribution of CYC2C8 alleles, with the CYP2C8*2 allele more common in African-Americans than Caucasians (18% vs. 0%, respectively) and the CYP2C*3 allele more common in whites (13%) than African-Americans (2%). The CYPC2*5 allele is found in 9% of Asians (74).
Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
CYP2C8 is responsible for the oxidation metabolism of many clinical drugs including thiazolidinediones, meglitinides, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, chemotherapeutic agents (e.g., paclitaxel), anti-malarials, antiarrhythmics, and retinoid derivatives (Lai et al. 2009; Totah and Rettie 2005; Xiaoping et al. 2013). The enzyme also plays an intermediate or minor role in metabolism of other agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, diclofenac, and tenoxicam), fluvastatin, simvastatin acid, carbamazepine, cyclophosphamide, dapsone, diltiazem, ifosfamide, loperamide, methadone, morphine, torsemide, loratadine, anastrozole, fenretinide, verapamil, and zopiclone (Illingworth et al. 2011; Kamdem et al. 2010; Totah and Rettie 2005). The antihistamine drug loratadine is converted to desloratadine through dealkylation, 3-hydroxydesloratadine, 5-hydroxydesloratadine, and 6-hydroxydesloratadine by CYP2C8 with major contribution from 3A4 (Kazmi et al. 2015; Yumibe et al. 1996).
Evaluation of the inhibitory effect of quercetin on the pharmacokinetics of tucatinib in rats by a novel UPLC–MS/MS assay
Published in Pharmaceutical Biology, 2022
Ying Zhang, Ya-nan Liu, Saili Xie, Xuegu Xu, Ren-ai Xu
Following oral administration after a high-fat meal, area under the plasma concentration–time curve from time zero extrapolated to infinite (AUC0→∞) of tucatinib increases 1.5-fold and the time to peak concentration (Tmax) is delayed from 1.5 h to 4 h (Kunte et al. 2020). Given that cancer patients often take multiple drugs, whether the combination of tucatinib and other drugs would cause drug–drug interactions (DDIs) must be explored. CYP2C8 was proved to be the major metabolic enzyme in vitro, in addition to CYP3A to a lesser extent (Lee 2020). It was reported that gemfibrozil (a strong CYP2C8 inhibitor) increased the exposure of tucatinib when they were given with concomitant administration (Lee 2020). Thus, it is essential to establish a quantitative method for tucatinib in biological fluids to investigate its pharmacokinetic characteristics and potential DDIs. To the best of our knowledge, there is no published analytical and bioanalytical method available for tucatinib determination in biological fluids.
Current and future pharmacotherapy options for drug-resistant epilepsy
Published in Expert Opinion on Pharmacotherapy, 2022
Cenobamate has good oral bioavailability and a long half-life allowing for once-daily dosing. Given its promise in focal epilepsy, cenobamate is being further investigated in ongoing trials for use as an adjunctive therapy in patients with generalized epilepsies and generalized tonic-clonic seizures. It has numerous effects on the CYP enzyme system including inhibition of CYP2B6, CYP2C19 and CYP3A as well as inducing CYP2B6, CYP2C8 and CYP3A4. Cenobamate has several important interactions with other ASMs because it inhibits CYP2C19 and, therefore, can increase blood levels of phenytoin, phenobarbital, and the active metabolite of clobazam N-desmethylclobazam. Cenobamate has also been shown to reduce blood levels of lamotrigine and carbamazepine as well as the oral contraceptive.
A comprehensive analysis of six forms of cytochrome P450 2C (CYP2C) in pigs
Published in Xenobiotica, 2022
Yasuhiro Uno, Saho Morikuni, Mitsuya Shiraishi, Atsushi Asano, Hiroaki Kawaguchi, Norie Murayama, Hiroshi Yamazaki
The cytochrome P450 (P450 or CYP) family contains enzymes that metabolise various endogenous and exogenous substrates. In humans, the P450 family consists of 57 functional genes and 58 pseudogenes (Nelson et al. 2004). The human CYP2C subfamily contains CYP2C8, CYP2C9, CYP2C18, and CYP2C19, and these drug-metabolising enzymes metabolise 20% or more of prescribed drugs such as diclofenac, warfarin, and omeprazole (Goldstein 2001; Zanger and Schwab 2013). Human CYP2C proteins make up ∼16% and ∼25% of the total P450 content in liver and small intestine (Shimada et al. 1994; Paine et al. 2006), making the CYP2C enzymes important for drug metabolism. The drug-metabolising capability of human CYP2Cs differs among individuals and populations, partially as a result of genetic polymorphisms. For example, impaired CYP2C9*2 and CYP2C9*3 alleles partly account for poor-metaboliser phenotypes that are more common in Caucasians than in African or Asian populations (Ingelman-Sundberg et al. 2007; Zanger and Schwab 2013).