Voriconazole-Induced Hepatitis via Simvastatin- and Lansoprazole-Mediated Drug Interactions: A Case Report and Review of the Literature.
Therapeutic voriconazole concentrations have a narrow window of effectiveness before causing cholestatic hepatitis. After undergoing 1 year of voriconazole therapy for pulmonary aspergillosis, a 44-year-old man began treatment with 30 mg lansoprazole for gastroesophageal reflux symptoms. Within 5 days of starting treatment with lansoprazole, the patient presented with fatigue, jaundice, and cholestatic hepatitis. The hepatitis promptly resolved after stopping lansoprazole treatment. Sixteen months later, the patient was given simvastatin therapy, as recommended by the American Diabetes Association to prevent cardiovascular disease for patients with diabetes who are aged >40 years and have one additional risk factor. Within 2 weeks of taking simvastatin, a 3-hydroxy-3-methylglutaryl CoA reductase (statin) therapy, the patient redeveloped fatigue, jaundice, and cholestatic hepatitis. He described both episodes of fatigue and jaundice similarly in terms of onset and intensity. Voriconazole is metabolized by both CYP2C19 and CYP3A4 isoenzymes. Lansoprazole is an inhibitor of the CYP2C19 isoenzyme. Competition between voriconazole and lansoprazole likely led to increased voriconazole serum concentration and acute cholestatic hepatitis in this patient. Simvastatin inhibits the CYP3A4 isoenzyme. After the patient took 10 mg simvastatin daily for 2 weeks, cholestatic hepatitis occurred. The voriconazole concentration remained elevated (4.1 μg/ml) when measured 15 days after stopping simvastatin. The patient's Naranjo Adverse Drug Reaction Probability Scale score of 7 revealed that the cholestatic hepatitis was probably precipitated by lansoprazole. Likewise, the patient's Naranjo score of 9 also revealed that cholestatic hepatitis was attributable to a definite adverse drug reaction precipitated by the addition of simvastatin to the stable baseline regimen of voriconazole. In a single patient, two different inhibitors of the cytochrome P450 pathway stimulated voriconazole-induced cholestatic hepatitis. Although the major cytochrome P450 pathways for the metabolism and clearance of lansoprazole and simvastatin are different, they both likely contributed to the reduced hepatic clearance of voriconazole in this patient.
Private Neurology Practice, Walnut Creek, CA (J.L.L.); and Department of Internal Medicine, David Geffen School of Medicine, Harbor-UCLA Medical Center, Los Angeles, California (J.A.T.).
Jose Luis
JL
Lopez
Private Neurology Practice, Walnut Creek, CA (J.L.L.); and Department of Internal Medicine, David Geffen School of Medicine, Harbor-UCLA Medical Center, Los Angeles, California (J.A.T.) jtayek@dhs.lacounty.gov.
John A
JA
Tayek
D000328:Adult; D000935:Antifungal Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000209:etiology*; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism; D065689:Cytochrome P-450 CYP2C19 Inhibitors / Q000009:adverse effects; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000009:adverse effects; D004347:Drug Interactions; D050171:Dyslipidemias / Q000175:diagnosis / Q000188:drug therapy*; D005764:Gastroesophageal Reflux / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D041781:Jaundice, Obstructive / Q000139:chemically induced; D064747:Lansoprazole / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D019338:Polypharmacy; D054328:Proton Pump Inhibitors / Q000009:adverse effects*; D055732:Pulmonary Aspergillosis / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D019821:Simvastatin / Q000009:adverse effects*; D065819:Voriconazole / Q000009:adverse effects* / Q000493:pharmacokinetics
D000935:Antifungal Agents; D065689:Cytochrome P-450 CYP2C19 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D019821:Simvastatin; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D065819:Voriconazole