Fluoropyrimidines such as 5-fluorouracil (5-FU) are well known to have drug-drug interactions with anticoagulant medications such as warfarin. This study investigated the mRNA expression of pharmacokinetic (PK)-related genes in response to 5-FU using the hepatocarcinoma cell lines after examining relevant gene expression via RNA sequencing. We used HepaRG cells for 5-FU treatment analysis because these cells displayed PK-related gene expression. 5-FU exposure significantly reduced cytochrome P450 3A4 (CYP3A4) mRNA expression. Additionally, the mRNA expression of nuclear receptor subfamily 1 group I member 2 (also known as pregnane X receptor), a nuclear receptor transcription factor that promotes the expression of many CYP genes, was also decreased in HepaRG cells following 5-FU treatment. The mRNA expressions of the CYP2B6 and ATP-binding cassette transporter genes were decreased after 5-FU treatment. This study revealed that 5-FU treatment reduced PK-related gene expression in HepaRG cells. These findings should be useful for further drug-drug interaction research.
Drug-drug interactions (DDIs) between warfarin (WF) and fluoropyrimidines are well known. Coadministration of WF and 5-fluorouracil (5-FU) leads to elevations in prothrombin time international normalised ratio (PT-INR). The inhibition of drug metabolism through suppression of CYP activity is a possible cause of prolonged PT-INR elevations. 5-FU and its metabolites are suspected to inhibit CYPs, but the precise mechanisms of action remain unknown. This study aimed to investigate the possible DDI effects of the co-administration of 5-FU with WF using PT-INR and PT-INR/dose ratio as pharmacodynamic parameters. Retrospective case series data were collected from patients who received parenteral 5-FU chemotherapy from April 2009 to December 2019 at the University of the Ryukyus Hospital. Seven patients who received 5-FU in combination with WF were analysed. There was a significant increase in PT-INR and PT-INR/dose during the co-administration of WF and 5-FU ( p 0.0018 and p 0.0187, respectively; paired t-test). The findings demonstrated significant DDI between 5-FU and WF evident as elevated PT-INR and PT-INR/dose ratio.
Amiodarone and tramadol are known to have drug-drug interactions that potentiate the effects of the anticoagulant warfarin. Herein we report a case which suggests increasing prothrombin time-international normalized ratio (PT-INR) and PT-INR/dose ratio due to the concomitant administration of warfarin, amiodarone (a cytochrome P450 2C9 inhibitor) and tramadol (an enhancer of anticoagulant effects of warfarin). A 72-yearold woman underwent emergency surgery following a suspected non-obstructive mesenteric ischemia, and diagnosis was confirmed. After surgery, the patient was given 2 mg/day of WF, and tramadol/acetaminophen, followed by amiodarone. After the concomitant dose of the triple combination, the PT-INR increased to over 7.02 (above the upper limit of the laboratory). The physician consulted the pharmacist for dose adjustment, and the pharmacist recommended a reduction in the dose to 0.5 mg. After restarting warfarin, PT-INR was controlled to 1.66-2.02. However, the PT-INR/dose ratio increased from 1.22 to 3.32-4.04 compared to the initial dose. The results suggest that these enhanced anticoagulant effects may be due to the inhibition of WF metabolism. Although the patient underwent resection of the small intestine, the effects of oral vitamin K1 were observed one day after administration. In conclusion, frequent PT-INR monitoring, and pharmacist intervention such as the assessment and dose adjustment in this report should be beneficial during anticoagulation therapy when multiple concomitant medications with suspected drug-drug interactions are present.
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