Nitrofurantoin-induced liver failure

Luk, Trevor; Edwards, Brett; Bates, Duane; Evernden, Christopher; Edwards, Jenny

doi:10.46747/cfp.6705342

Cited by 11 publications

(1 citation statement)

References 24 publications

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“…It is used in the short term to treat acute urinary tract infections and in the long term as prophylaxis against recurrent infections. Unfortunately, it is also associated with drug-induced liver injury (DILI), which is the most common adverse effect of NFT exposure [ 1 , 2 , 3 , 4 , 5 , 6 ]. Severe fatalities due to hepatic toxicity have been reported [ 7 , 8 ], and autoimmune-like hepatitis has been identified as the most common cause [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Development of a Physiologically Based Pharmacokinetic Model for Nitrofurantoin in Rabbits, Rats, and Humans

Sharma,

Burgers,

Beltman

2023

Pharmaceutics

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Nitrofurantoin (NFT) is a commonly used antibiotic for the treatment of urinary tract infections that can cause liver toxicity. Despite reports of hepatic adverse events associated with NFT exposure, there is still limited understanding of the interplay between NFT exposure, its disposition, and the risk of developing liver toxicity. In this study, we aim to develop a physiologically based pharmacokinetic (PBPK) model for NFT in three different species (rabbits, rats, and humans) that can be used as a standard tool for predicting drug-induced liver injury (DILI). We created several versions of the PBPK model using previously published kinetics data from rabbits, and integrated enterohepatic recirculation (EHR) using rat data. Our model showed that active tubular secretion and reabsorption in the kidney are critical in explaining the non-linear renal clearance and urine kinetics of NFT. We subsequently extrapolated the PBPK model to humans. Adapting the physiology to humans led to predictions consistent with human kinetics data, considering a low amount of NFT to be excreted into bile. Model simulations predicted that the liver of individuals with a moderate-to-severe glomerular filtration rate (GFR) is exposed to two-to-three-fold higher concentrations of NFT than individuals with a normal GFR, which coincided with a substantial reduction in the NFT urinary concentration. In conclusion, people with renal insufficiency may be at a higher risk of developing DILI due to NFT exposure, while at the same time having a suboptimal therapeutic effect with a high risk of drug resistance. Our PBPK model can in the future be used to predict NFT kinetics in individual patients on the basis of characteristics like age and GFR.

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Section: Introductionmentioning

confidence: 99%

Development of a Physiologically Based Pharmacokinetic Model for Nitrofurantoin in Rabbits, Rats, and Humans

Sharma,

Burgers,

Beltman

2023

Pharmaceutics

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Nitrofurantoin

2021

Reactions Weekly

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Fatal drug-induced liver injury: case reportA 53-year-old woman developed fatal drug-induced liver injury during treatment with nitrofurantoin for cystitis and prophylaxis for recurrent cystitis.The woman presented to the hospital with dark coloured urine and jaundice. She also had scleral icterus at the time of presentation, but other physical tests were noncontributory, and she had no fever, and her vital signs were normal. She had a history of chronic obstructive pulmonary disease, multiple sclerosis, recurrent urinary tract infections, and a distant cholecystectomy. She was an ex-smoker who had not drink alcohol or used any illegal drugs. Her home medications including zopiclone, clonazepam, paroxetine, and umeclidinium. Additionally, she had received nitrofurantoin 100 mg twice a day for cystitis and continued to receive for the past 12 months for prophylaxis for recurrent cystitis. No change in her medications were made since then [route not stated]. She had refused to use any herbal products and over-the-counter medications.The woman's treatment with nitrofurantoin was stopped. Clonazepam was switched to lorazepam as it won't depends upon hepatic metabolism, and all other drugs continued to be used. Blood tests included ALT, AST, ALP, γ-glutamyltransferase, total bilirubin, direct bilirubin, lactate dehydrogenase, ferritin, and international normalised ratio results were all elevated, however, albumin level was reduced and glucose and creatinine were normal. Seven years before admission, her liver test results were normal and there was no interval blood test. Laboratory investigation including HIV, anti-smooth muscle antibody, antimitochondrial antibody, hepatitis A, B, and C viruses and autoimmune Liver Disease panel were all negative. Also, ceruloplasmin, and α1-Antitrypsin were normal. Her immunoglobulin A levels were mildly elevated, IgG levels were normal, and she had positive antinuclear antibody results. Her abdominal computed tomography and ultrasound revealed patent portal-hepatic vasculature and hepatic nodularity indicative of cirrhosis. Hepatology was consulted due to the low possibility of infection, ischemic, autoimmune, or metabolic causes of her jaundice. On the day 4 of hospitalisation, her liver biopsy showed acute hepatitis, accompanied by obvious parenchymal necrosis and collapse, and cholestasis, but no obvious bridging fibrosis, consistent with nitrofurantoininduced liver injury. Over the following 7 days, she had been rapidly deteriorated and developed ascites with acquiring refractory hepatic encephalopathy. After consulting with hepatology about her announced nursing goals and wheelchair usage status, she was found to be unsuitable for transplantation. Due to the poor prognosis, and after discussing the goals of care with her family, she was transferred to a comfortable level of care. She passed away 24 days after her first visit. Her Naranjo score was 6 out of 13, which was indicated probable relation between nitrofurantoin and adverse drug reaction.

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