Inhibitory Effect of 5‐Fluorouracil on Cytochrome P450 2C9 Activity in Cancer Patients

Abstract

Drug interactions have been reported between 5-fluorouracil and cytochrome P450 2C9 (CYP2C9) substrates, S-warfarin and phenytoin. This study was performed to determine the influence of 5-fluorouracil on cytochrome P450 2C9 (CYP2C9) activity in colorectal cancer patients (nΩ17) receiving 5-fluorouracil. Losartan was used as a marker to assess CYP2C9 activity. Losartan and its CYP2C9 dependent metabolite, E-3174, were determined in urine. The ratios of urinary losartan/E-3174 before and after the 5-fluorouracil treatment were compared for each patient. Genotyping was performed to detect the CYP2C9*2 and CYP2C9*3. At the end of the first cycle of 5-fluorouracil, losartan/E-3174 ratio was increased by 28.0% compared to the pre-treatment values (PΩ0.15). In five patients recruited for phenotyping after three 5-fluorouracil cycles, the metabolic ratio was increased significantly by 5.3 times (PΩ0.03). The results suggest that in most patients 5-fluorouracil inhibited CYP2C9 activity. This inhibition was more pronounced when the total administered dose increased. This finding may help explain the mechanism of interaction between 5-fluorouracil and CYP2C9 substrates.5-Fluorouracil is a fluorinated pyrimidine analogue used in the treatment of a variety of solid tumours including gastrointestinal, breast, head and neck cancer (Rich et al. 2004). The cytotoxicity of 5-fluorouracil is mainly due to the formation of fluoro-deoxyuridine-monophosphate metabolite, which inhibits thymidylate synthetase and incorporates into ribonucleic acid (Rich et al. 2004). 5-Fluorouracil has a rather short elimination half-life in plasma and is mostly eliminated by dihydropyrimidine dehydrogenase (Gonzalez & Fernandez-Salguero 1995). Due to many complications during chemotherapy, many other drugs are co-administrated during treatment with 5-fluorouracil. Increasing number of drug-drug interactions between warfarin and 5-fluorouracil-based chemotherapies have been reported. These interactions result in bleeding complications due to the prolongation of prothrombin time (Brown 1997(Brown & 1999Kolesar et al. 1999). 5-Fluorouracil has also been reported to interact with phenytoin, resulting in elevated phenytoin plasma concentrations and neurotoxic side effects (Gilbar & Brodribb 2001;Konishi et al. 2002;Rosemergy & Findlay 2002;Brickell et al. 2003). Both S-warfarin and phenytoin are established CYP2C9 substrates (Lee et al. 2002). The mechanism of these interactions is unclear. Available evidence from case reports and in vitro studies in liver microAuthor for correspondence: Umit Yasar, Hacettepe University, Faculty of Medicine, Department of Pharmacology, 06100 Sihhiye, Ankara, Turkey (fax π90 312 3105312, e-mail uyasar/hacettepe.edu. tr).somes suggests that the interaction is not due to a competitive inhibition of CYP2C9 (Brown 1999;Park & Kim 2003). The effect of 5-fluorouracil on in vivo CYP2C9 activity in man has not been studied. Prospective clinical studies are needed to clarify the mechanism of the interaction between the su...

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

“…Capecitabine coadministration led to increased exposure to celecoxib without major changes in exposure to its major metabolites. Based on (1) our pharmacokinetic findings; (2) reports of increases in drug exposure to the CYP2C9 substrates warfarin, phenytoin, and losartan in the presence of fluoropyrimidines; (3) numerous case reports describing bleeding and/or alteration in coagulation parameters upon coadministration of warfarin and fluoropyrimidines; and (4) the absence of direct CYP2C9 inhibition by 5‐FU, our findings suggest downregulation of CYP2C9 by fluoropyrimidines. Given the widespread use of chemotherapy regimens including a fluoropyrimidine and the fact that several common drugs are CYP2C9 substrates, our work highlights the importance of conducting DDI studies to investigate potential changes in transcriptional regulation along with underlying mechanisms and the potential time course of the interaction for appropriate drug monitoring.…”

“…These findings are in agreement with our results, as the increases in celecoxib exposure we observed during and after capecitabine treatment suggest that CYP2C9 activity is affected and its recovery rate is slow, a finding explained by the turnover half‐life for CYP2C9 activity of 9 days estimated in the aforementioned study. Another study investigated the effect of 5‐FU on losartan oxidation, a marker for CYP2C9 activity . Losartan was administered as a single oral dose (25 mg) at least 2 days before the first 5‐FU administration (425 mg/m 2 5‐FU with 20 mg/m 2 folinic acid, 1‐hour infusion), and immediately after the last 5‐FU dose of a 21‐day cycle.…”

Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome P450 2C9 and variants

“…At this time, we don’t have an explanation for this phenomenon; moreover, this occurrence has not been found with other substrates evaluated for the hydroxylation by this variant [22–24]. On the other hand, we have observed a similar phenomenon for UGT1A10 variants involved in glucuronidation reactions of phenols and several derivatives of estrogens [25,26].…”

Impact of capecitabine and S-1 on anticoagulant activity of warfarin in patients with gastrointestinal cancer

“…In addition, Afsar et al [29] reported that a single administration of FU suppressed CYP3A and CYP2C11 catalytic activity. In humans, a study by Gunes et al [30] reported inhibition of CYP2C9 activity by FU in patients receiving losartan, Gray area represents periods during which chemotherapy was administered which is metabolized to E-3174 by CYP2C9. By contrast, capecitabine and its metabolites (5′-DFUR, 5′-DFCR, 5-FU, and FBAL) had no inhibitory effects on substrates of cytochrome P450 for major isoenzymes, such as 1A2, 2A6, 3A4, 2C9, 2C19, 2D6, and 2E1, in an in vitro study with human liver microsomes [31].…”