Dose-dependent fluconazole hepatotoxicity proven on biopsy and rechallenge

Wells, Claire E.; Lever, Andrew M. L.

doi:10.1016/0163-4453(92)91346-d

Cited by 43 publications

(21 citation statements)

References 3 publications

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“…The inhibition of P450 enzymes may increase liver exposure of the parent drug, which has the potential to cause DILI. For example, clinically dose-dependent hepatotoxicity of fluconazole, which is a potent inhibitor of CYP2C19 and a moderate inhibitor of CYP2C9 and CYP3A, was observed (Wells and Lever, 1992). Phenytoin (300 mg/d) is an inhibitor of CYP2C9 with a narrow therapeutic index.…”

Section: Discussionmentioning

confidence: 99%

High Daily Dose and Being a Substrate of Cytochrome P450 Enzymes Are Two Important Predictors of Drug-Induced Liver Injury

et al. 2014

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Drug-induced liver injury (DILI) is complicated and difficult to predict. It has been observed that drugs with extensive hepatic metabolism have a higher likelihood of causing DILI. Cytochrome P450 (P450) enzymes are primarily involved in hepatic metabolism. Identifying the associations of DILI with drugs that are P450 substrates, inhibitors, or inducers will be extremely helpful to clinicians during the decision-making process of caring for a patient suspected of having DILI. We collected metabolism data on P450 enzymes for 254 orally administered drugs in the Liver Toxicity Knowledge Base Benchmark Dataset with a known daily dose, and applied logistic regression to identify these associations. We revealed that drugs that are substrates of P450 enzymes have a higher likelihood of causing DILI [odds ratio (OR), 3.99; 95% confidence interval (95% CI), 2.07-7.67; P < 0.0001], which is dose-independent, and drugs that are P450 inhibitors have a higher likelihood of generating DILI only when they are administered at high daily doses (OR, 6.03; 95% CI, 1.32-27.5; P = 0.0098). However, drugs that are P450 inducers are not observed to be associated with DILI (OR, 1.55; 95% CI, 0.65-3.68; P = 0.3246). Our findings will be useful in identifying the suspected medication as a cause of liver injury in clinical settings.

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Section: Discussionmentioning

confidence: 99%

High Daily Dose and Being a Substrate of Cytochrome P450 Enzymes Are Two Important Predictors of Drug-Induced Liver Injury

et al. 2014

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“…jaundice and abnormal liver function tests were seen in some patients treated with fluconazole in HIV-related oral candidal infection (Franklin et al, 1990). It is also reported that a patient with AIDS-related oropharyngeal candidosis treated with fluconazole developed a dose-related liver dysfunction (Wells and Lever, 1992). Since animal studies have demonstrated embryotoxicity, it is prudent for fluconazole to be avoided in pregnancy (Aleck and Bartley, 1997;Laurence et al, 1997).…”

Section: (F) Median Rhomboid Glossitismentioning

confidence: 99%

Oral Candidal Infections and Antimycotics

Ellepola

Samaranayake

2000

Critical Reviews in Oral Biology & Medicine

208

236

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The advent of the human immunodeficiency virus infection and the increasing prevalence of compromised individuals in the community due to modern therapeutic advances have resulted in a resurgence of opportunistic infections, including oral candidoses. One form of the latter presents classically as a white lesion of "thrush" and is usually easily diagnosed and cured. Nonetheless, a minority of these lesions appears in new guises such as erythematous candidosis, thereby confounding the unwary clinician and complicating its management. Despite the availability of several effective antimycotics for the treatment of oral candidoses, failure of therapy is not uncommon due to the unique environment of the oral cavity, where the flushing effect of saliva and the cleansing action of the oral musculature tend to reduce the drug concentration to sub-therapeutic levels. This problem has been partly circumvented by the introduction of the triazole agents, which initially appeared to be highly effective. However, an alarming increase of organisms resistant to the triazoles has been reported recently. In this review, an overview of clinical manifestations of oral candidoses and recent advances in antimycotic therapy is given, together with newer concepts, such as the post-antifungal effect (PAFE) and its possible therapeutic implications.

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“…He was afebrile and had no symptoms of dependent effect. Another case of dose-dependent fluconazole hepatotoxicity has been reported [6]. Fluconazole-induced liver inrespiratory or cardiac distress.…”

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confidence: 99%