Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function
2004; Wiley; Volume: 75; Issue: 1 Linguagem: Inglês
10.1016/j.clpt.2003.09.007
ISSN1532-6535
Autores Tópico(s)Hormonal Regulation and Hypertension
ResumoClinical Pharmacology & TherapeuticsVolume 75, Issue 1 p. 80-88 Pharmacokinetics and Drug Disposition Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: Effects of liver function Rocco Orlando MD, Rocco Orlando MD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, ItalySearch for more papers by this authorPierpaolo Piccoli PhD, Pierpaolo Piccoli PhD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, ItalySearch for more papers by this authorSara De Martin PhD, Sara De Martin PhD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, ItalySearch for more papers by this authorRoberto Padrini MD, Roberto Padrini MD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, ItalySearch for more papers by this authorMaura Floreani PhD, Maura Floreani PhD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, ItalySearch for more papers by this authorPietro Palatini PhD, Corresponding Author Pietro Palatini PhD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, Italy Dipartimento di Farmacologia ed Anestesiologia, Università di Padova, Largo E Meneghetti 2, 35131 Padova, Italy. E-mail: [email protected]Search for more papers by this author Rocco Orlando MD, Rocco Orlando MD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, ItalySearch for more papers by this authorPierpaolo Piccoli PhD, Pierpaolo Piccoli PhD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, ItalySearch for more papers by this authorSara De Martin PhD, Sara De Martin PhD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, ItalySearch for more papers by this authorRoberto Padrini MD, Roberto Padrini MD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, ItalySearch for more papers by this authorMaura Floreani PhD, Maura Floreani PhD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, ItalySearch for more papers by this authorPietro Palatini PhD, Corresponding Author Pietro Palatini PhD Department of Medical and Surgical Sciences and Pharmacology and Anesthesiology, University of Padova, Padova, Italy Dipartimento di Farmacologia ed Anestesiologia, Università di Padova, Largo E Meneghetti 2, 35131 Padova, Italy. E-mail: [email protected]Search for more papers by this author First published: 22 January 2004 https://doi.org/10.1016/j.clpt.2003.09.007Citations: 14Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Objectives This study was designed (1) to evaluate the effect of a cytochrome P450 (CYP) 1A2 inhibitor, fluvoxamine, on the pharmacokinetics of intravenous lidocaine and its 2 pharmacologically active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), to confirm recent in vitro results indicating that CYP1A2 is the main isoform responsible for lidocaine biotransformation and (2) to assess whether liver function has any influence on the fluvoxamine-lidocaine interaction. Methods The study was carried out in 10 healthy volunteers and 20 patients with cirrhosis, 10 with mild (Child grade A) and 10 with severe (Child grade C) liver dysfunction, according to a randomized, double-blind, 2-phase, crossover design. In one phase all participants received placebo for 6 days; in the other phase they received 50 mg fluvoxamine for 2 days and 100 mg fluvoxamine for the next 4 days. On day 6, a 1-mg/kg lidocaine dose was administered intravenously 2 hours after the last dose of fluvoxamine or placebo. Plasma concentrations of lidocaine, MEGX, GX, and fluvoxamine were measured up to 12 hours after lidocaine injection. Results The effects of fluvoxamine coadministration were dependent on liver function. Lidocaine clearance was decreased on average by 60% (from 12.1 mL/min · kg to 4.85 mL/min · kg, P < .001) in healthy subjects and by 44% (from 9.83 mL/min · kg to 5.06 mL/min · kg, P < .001) in patients with mild liver dysfunction, with proportional increases in terminal half-lives, whereas virtually no effect was produced in patients with severe liver dysfunction (4.21 mL/min · kg versus 3.65 mL/min · kg, P > .05). Analogous effects were observed on MEGX and GX formation kinetics, which were drastically impaired in healthy subjects and patients with mild liver cirrhosis but virtually unaffected in patients with severe cirrhosis. Conclusion CYP1A2 is the enzyme principally responsible for the metabolic disposition of lidocaine in subjects with normal liver function. The extent of fluvoxamine-lidocaine interaction decreases as liver function worsens, most likely because of the concomitant decrease in the hepatic level of CYP1A2. These observations indicate that results obtained in healthy subjects cannot be extended a priori to patients with liver dysfunction, but the clinical consequences of inhibition of drug metabolism must also be assessed in such patients. Clinical Pharmacology & Therapeutics (2004) 75, 80–88; doi: 10.1016/j.clpt.2003.09.007 References 1Pieper, J. A. and Lima, H. (1992). Lidocaine. Chap. 21. In: WE Evans, JJ Schentag, WJ Jusko, editors. Applied pharmacokinetics. Principles of therapeutic drug monitoring. 3rd ed. Vancouver (WA): Applied Therapeutics. 6– 9. 22Bargetzi, M. J., Aoyama, T., Gonzales, F. J. and Meyer, U. A. (1989). 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