Rhabdomyolysis caused by the moderate CYP3A4 inhibitor fluconazole in a patient on stable atorvastatin therapy: a case report and literature review

Hsiao, Shu Hwa; Chang, Hui-Wen; Hsieh, Tung-Han; Kao, Shu Min; Yeh, Pin-Hsi; Wu, Ta Jen

doi:10.1111/jcpt.12425

Cited by 18 publications

(10 citation statements)

References 21 publications

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“…Non-traumatic rhabdomyolysis has been reported as a severe adverse effect of azole antifungals, which have been used alone or concomitantly with statins [5][6][7]10]. Despite the fact that muscle damage occurred in this case, however, severe consequences such as rhabdomyolysis were successfully prevented due to our awareness of the muscle toxicity of azole antifungals and the timely discontinuation of voriconazole.…”

Section: Discussionmentioning

confidence: 79%

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Muscle toxicity induced by intravenous voriconazole in a cryptogenic organizing pneumonia patient misdiagnosed as suspected pulmonary fungal infection

Wang

Zhou

et al. 2020

Preprint

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Background Although voriconazole is a widely used azole antifungal agent in clinical practice, its side effect of muscle toxicity is extremely rare. The present study demonstrates an adverse effect of progressive myotoxicity induced by intravenous voriconazole in a cryptogenic organizing pneumonia patient misdiagnosed as suspected pulmonary fungal infection.Case presentation A 78-year-old male was admitted to our hospital due to recurrent cough and expectoration for four months. His previous chest CT scan indicated alveolar opacities and multiple cavitary nodules in the right lower lobe. Pulmonary fungal infection was considered due to weakly positive results of serum galactomannan and 1,3 β-D-glucan test,with no evidence of malignant tumor, tuberculosis, or Wegener's granulomatosis. The patient experienced diffuse myalgia with significantly elevated muscle enzymes after voriconazole administration for 13 days, and recovered uneventfully due to immediate voriconazole cessation and enhanced intravenous fluid infusion. Furthermore, the pulmonary cavitary nodules were consistent with the pathological findings of cryptogenic organizing pneumonia.Conclusions Voriconazole-associated myotoxicity should be considered when a patient presents with evidence of muscle injury during voriconazole administration. Morever, although invasive pulmonary fungal infection can often show multiple nodules with cavities in CT scan, the initiation of anti-fungal agents should be cautious before the pathological features of multiple cavitary nodules are identified, in order to avoid potential serious adverse events.

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Section: Discussionmentioning

confidence: 79%

“…Azole antifungal agent-induced myotoxicity has been previously reported, and most cases are associated with concomitant statin use because of the supression of drug metabolism [5][6][7]. However, as a member of azole antifungal agent, voriconazole has been rarely reported to have independent myotoxic effects [2,3].…”

Section: Discussionmentioning

confidence: 99%

Muscle toxicity induced by intravenous voriconazole in a cryptogenic organizing pneumonia patient misdiagnosed as suspected pulmonary fungal infection

Wang

Zhou

et al. 2020

Preprint

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“…This serious side effect of ibrutinib was potentially attributable to interaction with the CYP3A4 inhibitor verapamil (Lambert Kuhn, Levêque, Lioure, Gourieux, & Bilbault, ). In addition, a case reported that rhabdomyolysis was caused by the moderate CYP3A4 inhibitor fluconazole in a patient on stable atorvastatin therapy (Hsiao et al, ). Repaglinide and gemfibrozil are the substrate and inhibitor for CYP2C8, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…The K i represents the absolute affinity of an inhibitor for its target enzyme and lower K i value means stronger inhibitory effect of inhibitor against the target enzyme (Darras & Pang, 2017 Gourieux, & Bilbault, 2016). In addition, a case reported that rhabdomyolysis was caused by the moderate CYP3A4 inhibitor fluconazole in a patient on stable atorvastatin therapy (Hsiao et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Identification of cytochrome P450 isoforms involved in the metabolism of artocarpin and assessment of its drug–drug interaction

Liu

2018

Biomedical Chromatography

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Artocarpin isolated from an agricultural plant Artocarpus communis has shows anti-inflammation and anticancer activities. In this study, we utilized recombinant human UDP-glucuronosyltransferasesupersomes (UGTs) and human liver microsomes to explore its inhibitory effect on UGTs and cytochrome p450 enzymes (CYPs). Chemical inhibition studies and screening assays with recombinant human CYPs were used to identify if CYP isoform is involved in artocarpin metabolism. Artocarpin showed strong inhibition against UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, CYP2C8 and CYP3A4. In particular, artocarpin exhibited competitive inhibition against CYP3A4 and noncompetitive inhibition against UGT1A3 and UGT1A7. The half inhibition concentration values for CYP3A4, UGT1A3 and UGT1A7 were 4.67, 3.82 and 4.82 μm, and the inhibition kinetic parameters for them were 0.78, 2.67 and 3.14 μm, respectively. After artocarpin was incubated in human liver microsomes and determined by HPLC, we observed its main metabolites (M1 and M2). In addition, we proved that CYP2D6 played the key role in the biotransformation of artocarpin in human liver microsomes. The result of molecular docking further confirmed that artocarpin interacted with CYP2D6, CYP2C8 and CYP3A4 through hydrogen bonds. This study provided preliminary results for further research on artocarpin or artocarpin-containing herbs.

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“…Most of the statins, except pravastatin, are metabolized by the cytochrome P450 (CYP) enzymes (Wei and Zhang 2015 ; Hsiao et al. 2016 ). Interactions involving CYP are therefore possible.…”

Section: Introductionmentioning

confidence: 99%

Effects of Danshen tablets on pharmacokinetics of atorvastatin calcium in rats and its potential mechanism

Sun

Wang

Fan

et al. 2018

Pharmaceutical Biology

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Context: Danshen tablets (DST), an effective traditional Chinese multi-herbal formula, are often combined with atorvastatin calcium (AC) for treating coronary heart disease in the clinic.Objective: This study investigated the effects of DST on the pharmacokinetics of AC and the potential mechanism.Materials and methods: The pharmacokinetics of AC (1 mg/kg) with or without pretreatment of DST (100 mg/kg) were investigated using LC-MS/MS. The effects of DST (50 μg/mL) on the metabolic stability of AC were also investigated using rat liver microsome incubation systems.Results: The results indicated that Cmax (23.87 ± 4.27 vs. 38.94 ± 5.32 ng/mL), AUC(0–t) (41.01 ± 11.32 vs. 77.28 ± 12.92 ng h/mL), and t1/2 (1.91 ± 0.18 vs. 2.74 ± 0.23 h) decreased significantly (p < 0.05) when DST and AC were co-administered, which suggested that DST might influence the pharmacokinetic behavior of AC when they are co-administered. The metabolic stability (t1/2) of AC was also decreased (25.7 ± 5.2 vs. 42.5 ± 6.1) with the pretreatment of DST.Discussion and conclusions: This study indicated that the main components in DST could accelerate the metabolism of AC in rat liver microsomes and change the pharmacokinetic behaviors of AC. So these results showed that the herb-drug interaction between DST and AC might occur when they were co-administered. Therefore, the clinical dose of AC should be adjusted when DST and AC are co-administered.

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Rhabdomyolysis caused by the moderate CYP3A4 inhibitor fluconazole in a patient on stable atorvastatin therapy: a case report and literature review

Abstract: Our case demonstrates that in some subjects even a moderate CYP3A4 inhibitor such as fluconazole may lead to rhabdomyolysis in subjects receiving a statin.

Cited by 18 publications

References 21 publications

Muscle toxicity induced by intravenous voriconazole in a cryptogenic organizing pneumonia patient misdiagnosed as suspected pulmonary fungal infection

Muscle toxicity induced by intravenous voriconazole in a cryptogenic organizing pneumonia patient misdiagnosed as suspected pulmonary fungal infection

Identification of cytochrome P450 isoforms involved in the metabolism of artocarpin and assessment of its drug–drug interaction

Effects of Danshen tablets on pharmacokinetics of atorvastatin calcium in rats and its potential mechanism

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