Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function.
OBJECTIVE
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.


CONCLUSIONS
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.
Orlando
Rocco
R
Department of Medical and Sugical Sciences, University of Padua, Italy.
Piccoli
Pierpaolo
P
De Martin
Sara
S
Padrini
Roberto
R
Floreani
Maura
M
Palatini
Pietro
P
D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004311:Double-Blind Method; D016666:Fluvoxamine / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D007262:Infusions, Intravenous; D008012:Lidocaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D012720:Severity of Illness Index
D000889:Anti-Arrhythmia Agents; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D016666:Fluvoxamine; D008012:Lidocaine; D017367:Selective Serotonin Reuptake Inhibitors; C001306:glycinexylidide; C001173:monoethylglycinexylidide