Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (2000) 67, 275–282; doi: 10.1067/mcp.2000.104736
Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation*
Peter T. Manyike PhD1, Evan D. Kharasch MD, PhD1, Thomas F. Kalhorn BS1 and John T. Slattery PhD1
1Departments of Pharmaceutics, Anesthesiology, and Medicinal Chemistry, University of Washington. Seattle, Wash
Correspondence: John T. Slattery, PhD, Department of Pharmaceutics, University of Washington, Box 357610 H272 Health Sciences Building, Seattle, WA 98195-7610. E-mail: jts@u.washington.edu
*Supported in part by grants GM 32165 and GM 48712 from the National Institutes of Health (Bethesda, Md)
Received 3 September 1999; Accepted 29 November 1999.
Abstract
Background: CYP2E1, 1A2, and 3A4 have all been implicated in the formation of N-acetyl-p-benzoquinone imine (NAPQI), the reactive intermediate of acetaminophen (INN, paracetamol), in studies in human liver microsomes and complementary deoxyribonucleic acid–expressed enzymes. However, recent pharmacokinetic evidence in humans has shown that the involvement of CYP1A2 is negligible in vivo. The purpose of this study was to evaluate the respective roles of CYP2E1 and 3A4 in vivo.
Methods: The involvement of CYP2E1 was assessed through pretreatment of adult human volunteers with disulfiram to inhibit the enzyme and the role of CYP3A4 through its induction in a second cohort of adults with rifampin (INN, rifampicin). Each of the respective studies was an open-label, balancedrandomized crossover design. Blood samples were obtained serially for 12 hours and urine was collected for 24 hours after acetaminophen administration. Acetaminophen was assayed in plasma, and acetaminophen and metabolites were assayed in urine.
Results: The recovery of the thiol metabolites formed by conjugation of NAPQI with glutathione was decreased by 69%, and the formation clearance of NAPQI was decreased by 74% (both P < .01) by pretreatment with disulfiram. Rifampin pretreatment had no effect on the formation of NAPQI or the recovery of thiol metabolites formed by conjugation of NAPQI with glutathione.
Conclusions: CYP2E1 accounts for the formation of NAPQI in intact humans; the contribution of other isozymes of cytochrome P450 appears to be negligible. Under some conditions, disulfiram may be useful in diminishing the formation of NAPQI after acetaminophen overdose. (Clin Pharmacol Ther 2000;67:275-82.)
