The Effect of Erythromycin and Fluvoxamine on the Pharmacokinetics of Intravenous Lidocaine

Abstract

Inhibitors of CYP3A4 (cytochrome P450 3A4) have a minor effect on lidocaine pharmacokinetics. We studied the effect of coadministration of the antidepressant fluvoxamine (CYP1A2 inhibitor) and antimicrobial drug erythromycin (CYP3A4 inhibitor) on lidocaine pharmacokinetics in a double-blind, randomized, three-way crossover study. Nine volunteers ingested daily 100 mg fluvoxamine and placebo, 100 mg fluvoxamine and 1500 mg erythromycin, or their corresponding placebos for 5 days. On day 6, 1.5 mg/kg lidocaine was administered IV over 60 min. Concentrations of lidocaine and its major metabolite monoethylglycinexylidide were measured for 10 h. Fluvoxamine alone decreased the clearance of lidocaine by 41% (P < 0.001) and prolonged its elimination half-life from 2.6 to 3.5 h (P < 0.01). During the combination of fluvoxamine and erythromycin, lidocaine clearance was 53% smaller than during placebo (P < 0.001) and 21% smaller than during fluvoxamine alone (P < 0.05). During the combination phase the half-life of lidocaine (4.3 h) was longer than during the placebo (2.6 h; P < 0.001) or fluvoxamine (3.5 h; P < 0.01). We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces elimination of lidocaine and may increase the risk of lidocaine toxicity. Concomitant use of both fluvoxamine and a CYP3A4 inhibitor such as erythromycin can further increase plasma lidocaine concentrations by decreasing its clearance.

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

“…Ropivacaine co-administration, studied in a double-blinded 3-way cross-over study in 8 healthy subjects, showed no changes in parent drug PK but a slight decrease in metabolite PK [159]. Administrating ERY with the local anesthetic lidocaine (lignocaine) has also been studied [160–162]. One study concluded that ERY either increases lidocaine metabolism to monoethylglycinexylidide (MEGX) or reduces further metabolism of MEGX, based on a 45–60% increase of MEGX AUC [162].…”

Estimated Maximal Safe Dosages of Tumescent Lidocaine

“…Multiple large surveys involving thousands of procedures have found no evidence of tumescent lidocaine toxicity at recommended dosages. [50][51][52] However, 55 mg/kg may be too risky if lidocaine absorption is too rapid (failure to add epinephrine to the solution of tumescent lidocaine) or if lidocaine metabolism is too slow (diabetes, 53 adverse interactions with drugs that inhibit the hepatic microsomal isoenzymes cytochrome P450 3A4 and 1A2 such as erythromycin, 54 sertraline, fluconazole or ciprofloxacin, propofol, 55 or general anesthesia 56 ) or if patients have very low serum protein concentrations or if surgery is cancelled before liposuction can be completed. Based on the present data and considerable worldwide experience, we believe that 45 mg/kg is a safe and prudent maximum dosage of tumescent lidocaine for liposuction.…”

Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro-In Vivo Extrapolation of Drug Clearance

“…Mean values of CL int, liver for LID N-deethylation calculated from kinetic parameters generated in the absence and presence of BSA were 28 and 75 l/h, respectively, whereas predicted values of CL H were 9.1 and 21 l/h, respectively. CL int, in vivo and in vivo CL H were calculated from data reported for healthy volunteers administered intravenous LID (1-1.5 mg/kg) in four recent kinetic studies (Orlando et al, 2003(Orlando et al, , 2004Olkkola et al, 2005;De Martin et al, 2006). Mean values of CL int, in vivo and in vivo CL H from the four studies ranged from 142 to 198 and from 32 to 40 l/h, respectively.…”