title: Paracetamol and simvastatin: a potential interaction resulting in hepatotoxicity.
abstract: The safety profile of paracetamol and simvastatin is sufficiently well known, although no interactions between these two medicinal products have been described in the scientific literature so far. A 66-year-old female patient who experienced myocardial infarction and underwent coronary artery bypass grafting 9 years ago was taking simvastatin at a daily dose of 10 mg. Liver enzyme tests were carried out regularly, and their results were always normal. Later on, the patient took 6 tablets of fixed combination medicinal product Gripex(TM) (paracetamol, pseudoephedrine, and dextromethorphan) per day due to a fever. The daily dose of paracetamol taken by the patient totaled 1.95 g. The patient developed severe jaundice, nausea, vomiting; blood bilirubin levels increased more than 3 times; alanine transaminase, more than 10 times; and asparagine transaminase, more than 5 times. Paracetamol is metabolized by CYP enzymes (CYP2E1, 1A2, 2A6, 3A4) to a reactive metabolite, N-acetyl-p-benzoquinone-imine (NAPQI). Under conditions of excessive NAPQI formation or reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of cellular proteins, forming NAPQI-protein adducts. Simvastatin is a substrate of CYP3A4 enzyme. Clinical and pharmacological data, available in the published literature, allow the assumption that simvastatin may induce CYP3A4 and result in increased hepatoxicity of paracetamol.
authors.affiliation: Institute of Physiology and Pharmacology, Medical Academy, Lithuanian University of Health Sciences, A. Mickevičiaus 9, 44307 Kaunas, Lithuania.
authors.forename: Gintautas
authors.initials: G
authors.lastname: Gumbrevičius
authors.forename: Audrius
authors.initials: A
authors.lastname: Sveikata
authors.forename: Renata
authors.initials: R
authors.lastname: Sveikatienė
authors.forename: Edgaras
authors.initials: E
authors.lastname: Stankevičius
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000009:adverse effects*; D001026:Coronary Artery Bypass; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D007565:Jaundice / Q000139:chemically induced; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D009203:Myocardial Infarction / Q000517:prevention & control / Q000601:surgery; D009325:Nausea / Q000139:chemically induced; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects*; D014839:Vomiting / Q000139:chemically induced
chemical_list: D018712:Analgesics, Non-Narcotic; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000082:Acetaminophen; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human