Acute Kidney Injury from Excessive Potentiation of Calcium-channel Blocker via Synergistic CYP3A4 Inhibition by Clarithromycin Plus Voriconazole

Mishima, Eikan; Maruyama, Kouichi; Nakazawa, Toru; Abe, Takaaki; Ito, Sadayoshi

doi:10.2169/internalmedicine.56.8313

Cited by 14 publications

(19 citation statements)

References 14 publications

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“…Voriconazole, a commonly used antifungal triazole, has potent inhibitory effects on CYP3A4 [ 5 ]. In the presence of CYP3A4-inhibitors, drugs that are metabolized by CYP3A4, such as nifedipine, will accumulate leading to toxicity [ 6 , 10 ]. Hypotension from co-prescribing voriconazole together with nifedipine has been reported [ 6 , 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…In the presence of CYP3A4-inhibitors, drugs that are metabolized by CYP3A4, such as nifedipine, will accumulate leading to toxicity [ 6 , 10 ]. Hypotension from co-prescribing voriconazole together with nifedipine has been reported [ 6 , 10 ]. Hypotension induced by concomitant use of CCB and macrolide antibiotics, particularly erythromycin and clarithromycin, are more frequently reported [ 7 – 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…CCB and voriconazole may therefore be co-administrated occasionally. CYP3A4-inhibitors can raise the concentration of CCB and cause hypotension and even acute kidney injury (AKI) [ 6 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Severe secondary hyperkalemia and arrhythmia from drug interactions between calcium‐channel blocker and voriconazole: a case presentation

Zhao

Zhu

et al. 2021

BMC Nephrol

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Background Patients with kidney disease may have concurrent hypertension and infection. Dihydropyridine calcium-channel blockers (CCB) are the most popular class of antihypertensive drugs used in clinical settings and can be metabolized by cytochrome P450 isoenzyme 3A4 (CYP3A4). Voriconazole is a commonly used antifungal treatment and a CYP3A4-inhibitor. Insufficient attention to drug interactions from the concomitant use of CCB and voriconazole may result in serious adverse reactions. Case presentation Here, we report a patient with acute kidney injury on stable anti-neutrophil cytoplasm antibody associated vasculitis who developed hyperkalemia resulting in sinus arrest with junctional escape rhythm attributed to drug interactions of CCB with voriconazole. This is a very rarely reported case and may be an under-recognized complication. After continuous renal replacement therapy and changing the anti-hypertensive drugs, symptoms, and laboratory abnormalities of the patient fully recovered. Conclusions This case warns us of severe consequences of drug interactions. Co-prescription of CYP3A4-inhibitors with calcium-channel blockers increases the risk of hypotension and acute kidney injury, which may further induce hyperkalemia and arrhythmia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Severe secondary hyperkalemia and arrhythmia from drug interactions between calcium‐channel blocker and voriconazole: a case presentation

Zhao

Zhu

et al. 2021

BMC Nephrol

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“…This antibiotic is also a P-gp substrate and a strong competitive inhibitor. Therefore, its concentration and the resulting CYP3A4 inhibitory activity may be higher when it is simultaneously applied with lapatinib, which is also a P-gp inhibitor (18)(19)(20)(21)(22). It is very likely that clarithromycin will be applied to oncological patients treated with lapatinib.…”

Section: Pharmacokinetic Interaction After Oral Coadministration Of Cmentioning

confidence: 99%

“…One group (n = 6) received first clarithromycin and next lapatinib (I Lap+Clar ), second group (n = 6) received placebo (0.9% NaCl) and lapatinib (II Lap ). Clarithromycin was administrated at a dose of 25 mg per kg of body weight to the I Lap+Clar group (19,20). Lapatinib (100 mg/kg) was dissolved in 1 mL DMSO (dimethyl sulfoxide) and administered directly into the animal stomach using a gastric probe.…”

Section: Animalsmentioning

confidence: 99%

Pharmacokinetic Interaction After Oral Coadministration of Clarithromycin and the Tyrosine Kinase Inhibitor Lapatinib in Rats

Karbownik¹,

Porażka²,

Łuczak³

et al. 2019

Acta Poloniae Pharmaceutica - Drug Research

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Lapatinib is a tyrosine kinase inhibitor used to treat patients with locally advanced or metastatic breast cancer exhibiting overexpression of the human epidermal growth factor receptor 2 (HER2 receptor, ErbB2). Preclinical and clinical studies suggest that lapatinib is mainly metabolized by CYP3A4, therefore the study in an animal model was designed to investigate the pharmacokinetic interaction of lapatinib and clarithromycin, a well-known CYP3A4 inhibitor. The rats were subjected to one of the two study groups: lapatinib + clarithromycin (I Lap+Clar ; n = 6), and lapatinib + placebo (II Lap ; n = 6). The animals were treated with lapatinib in the oral single dose of 100 mg/kg. The antibiotic was administered orally at a dose of 25 mg/kg. Blood sampling was performed until 30 hours after dosing for pharmacokinetic assays. Plasma concentrations of lapatinib were measured by liquid chromatography-mass spectrometry. The comparison of lapatinib maximum concentration and area under the concentration-time curve in the I Lap+Clar with the control group II Lap gave the ratios of 1.38 (90% confidence interval (CI)) (1.14; 1.68) and 1.16 (0.75; 1.79), respectively. A statistically significant difference between analyzed groups was revealed only for maximum concentration (p = 0.0107). Single oral administration of clarithromycin significantly increased the concentration of lapatinib in rats, therefore caution should be taken during concomitant treatment with this macrolide and the tyrosine kinase inhibitor in patients.

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Cytochrome P450 Inhibition by Antimicrobials and Their Mixtures in Rainbow Trout Liver Microsomes In Vitro

Pihlaja

Niemissalo

Sikanen

2021

Enviro Toxic and Chemistry

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Antimicrobials are ubiquitous in the environment and can bioaccumulate in fish. In the present study, we determined the half-maximal inhibitory concentrations (IC50) of 7 environmentally abundant antimicrobials (ciprofloxacin, clarithromycin, clotrimazole, erythromycin, ketoconazole, miconazole, and sulfamethoxazole) on the cytochrome P450 (CYP) system in rainbow trout (Oncorhynchus mykiss) liver microsomes, using 7-ethoxyresorufin O-deethylation (EROD, CYP1A) and 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylation (BFCOD, CYP3A) as model reactions. Apart from ciprofloxacin and sulfamethoxazole, all antimicrobials inhibited either EROD or BFCOD activities or both at concentrations <500 µM. Erythromycin was the only selective and time-dependent inhibitor of BFCOD. Compared with environmental concentrations, the IC50s of individual compounds were generally high (greater than milligrams per liter); but as mixtures, the antimicrobials resulted in strong, indicatively synergistic inhibitions of both EROD and BFCOD at submicromolar (~micrograms per liter) mixture concentrations. The cumulative inhibition of the BFCOD activity was detectable even at picomolar (~nanograms per liter) mixture concentrations and potentiated over time, likely because of the strong inhibition of CYP3A by ketoconazole (IC50 = 1.7 ± 0.3 µM) and clotrimazole (IC50 = 1.2 ± 0.2 µM). The results suggest that if taken up by fish, the mixtures of these antimicrobials may result in broad CYP inactivation and increase the bioaccumulation risk of any other xenobiotic normally cleared by the hepatic CYPs even at biologically relevant concentrations.

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Acute Kidney Injury from Excessive Potentiation of Calcium-channel Blocker via Synergistic CYP3A4 Inhibition by Clarithromycin Plus Voriconazole

Cited by 14 publications

References 14 publications

Severe secondary hyperkalemia and arrhythmia from drug interactions between calcium‐channel blocker and voriconazole: a case presentation

Severe secondary hyperkalemia and arrhythmia from drug interactions between calcium‐channel blocker and voriconazole: a case presentation

Pharmacokinetic Interaction After Oral Coadministration of Clarithromycin and the Tyrosine Kinase Inhibitor Lapatinib in Rats

Cytochrome P450 Inhibition by Antimicrobials and Their Mixtures in Rainbow Trout Liver Microsomes In Vitro

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