Introduction: Adverse drug reactions (ADRs) are a major health concern worldwide. There are multiple causes of ADRs, some of which are preventable. Pharmacogenomics accounts for ≈80% variab...

The role of pharmacogenomics in adverse drug reactions

Severe hepatotoxicity from combination chemotherapy with cisplatin and 5-fluorouracil is a rare adverse effect. In this case report, we present a case with severe hepatotoxicity immediately following chemotherapy with cisplatin and 5-fluorouracil. This female patient had previously been treated with this combination with no hepatotoxicity. The elevated liver enzymes quickly normalized after chemotherapy was stopped. There were no specific changes in liver imaging. As hepatotoxicity occurred after repeated administration of cisplatin, we suggest that this hepatotoxicity might represent a case of allergic hepatitis caused by cisplatin. Severe hepatotoxicity should be watched for with repeated administration of cisplatin.

A case of severe hepatotoxicity induced by cisplatin and 5-fluorouracil

The manifestation of acute hepatotoxicity caused by 5-fluorouracil could be characterized by asymptomatic elevations of liver enzymes, hepatic steatosis and fuminant hepatitis. Natural antioxidants have potential as excellent treatment strategy against diseases and drug-induced toxicities. This study assessed the potential of resveratrol (RSV) to abrogate the hepatotoxic effect of 5-FU in rats. Forty adult male albino rats (240g± 20g) were randomized and orally supplemented with RSV (10, 20 and 40 mg/kg/day) prior to the administration of 5-FU (20mg/kg/day) intraperitoneally for 5 days. On day 6, after weighing, the rats were anesthetized, blood samples were collected and centrifuged and sera obtianed. Liver tissues were harvested and weighed. Sera and liver samples were evaluated for biochemical parameters. Liver tissues were assessed for histology. Body weight was significantly (p <0.05) decreased where as liver weight was significantly (p <0.01) increased in 5-FU administered rats in relation to control. Serum and liver lactate dehydrogenase, aminotransferases (AST), alkaline phosphatase, gamma-glutamyl transferase, total bilirubin, conjugated bilirubin and malondialdehyde levels were significantly (p <0.001) increased in 5FU-administered rats in relation to control. Liver glutathione peroxidase, catalase, glutathione and superoxide dismutase levels were significantly (p <0.001) decreased in 5-FU administered rats in relation to control. The liver of 5-FU administered rats showed necrosis and steatosis. The hepatotoxic effect of 5-FU was abrogated in a dose-related fashion in RSV 10 mg/kg (p <0.05), 20mg/kg (p <0.01), and RSV 40mg/kg (p <0.001) supplemented rats in relation to 5-FU. RVS may be clinically effective against 5-FU-induced hepatotoxicity.

https://tips.sums.ac.ir/article_47251_7d188cfa203978a9d510db6fb450362f.pdf

Resveratrol abrogates 5-flourouracil -induced hepatotoxicity: A preclinical study

Chemotherapy is associated with different patterns of histopathological changes of the non-tumor-bearing liver. Hepatic infarction represents a relatively rare condition; the prevalence in several series of consecutive autopsies is 1.1%. To the best of our knowledge, no cases of liver infarction secondary to chemotherapy have been reported to date. We report a case of segmental hepatic infarction following the adjuvant chemotherapy with Oxaliplatin and Capecitabine in a patient who had undergone total gastrectomy and distal esophagectomy for gastric cancer. Liver infarction is usually managed by conservative therapy; interventional procedures such as percutaneous imaging-guided drainage or surgical evacuation should be reserved in cases where septic complications occur, with development of a hepatic abscess from the necrotic area. It is important to avoid misdiagnoses with liver metastases in order to define the most appropriate clinical management strategy. KEY WORDS: Adjuvant chemotherapy, Gastric cancer, Liver infarction, Hepatic necrosis.

A case of segmental hepatic necrosis complicating oxaliplatin and capecitabine chemotherapy A case report and review of the literature.

Abstract In 2015, the United States Food and Drug Administration (FDA) approved uridine triacetate to treat overdose and severe toxicity of the fluoropyrimidine chemotherapy agents 5‐fluorouracil (5‐FU) and its oral prodrug capecitabine. Uridine triacetate is as an oral prodrug of uridine that competes with cytotoxic fluoropyrimidine metabolites for incorporation into nucleotides. Two million people worldwide start fluoropyrimidine chemotherapy each year, with 20‐30% developing severe or life‐threatening adverse effects, often attributable to a genetic predisposition such as dihydropyrimidine dehydrogenase deficiency. Whilst genetic prescreening is recommended prior to starting fluoropyrimidine agents, this only prevents 20‐30% of early‐onset life‐threatening toxicity and so does not obviate the need for an antidote. Initial in‐human studies established that uridine triacetate more than doubles the maximum tolerated weekly 5‐FU bolus dose. A lack of clinical equipoise meant a placebo‐controlled phase III trial was not ethical and so the phase III trials used historical controls. These found that uridine triacetate improved survival in those with fluoropyrimidine overdose and severe toxicity from 16% to 94%, with 34% able to resume chemotherapy within 30 days. Five case reports of delayed fluoropyrimidine toxicity demonstrate improvement following uridine triacetate treatment 120‐504 h after last fluoropyrimidine administration, suggesting efficacy beyond the FDA licencing indications. Mechanistically uridine triacetate would be expected to be effective for overdose and severe toxicity of tegafur (a 5‐FU prodrug), but there are no published case reports describing this. Uridine triacetate is available internationally through an expanded access scheme and has been available in the UK since 2019 on a named patient basis. 

Review of the fluoropyrimidine antidote uridine triacetate

Some articles have reported severe toxicities induced by cisplatin/5-fluorouracil regimens, nevertheless, severe and lethal liver toxicity has not been previously reported. In this article, we report the case of a 72-year-old woman, who developed fulminant hepatitis, hypoglycemia and hypotension with atrial fibrillation not responding to treatment. After ruling out all other possible causes of hepatitis, the toxicity was more likely attributed to 5-fluorouracil. Genotyping was performed and the patient was found to be a homozygote carrier of the T variant of the MTHFR gene. The patient died two days later. Several factors, including genetic factors, could explain this severe toxicity. The present case discusses the importance of personalized medicine in oncology based on pharmacogenetic analysis of polymorphisms.

Lethal hepatotoxicity following 5-fluorouracil/cisplatin chemotherapy: a relevant case report

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Lethal hepatotoxicity following 5-fluorouracil/cisplatin chemotherapy: a relevant case report