Effect of Erythromycin and Itraconazole on the Pharmacokinetics of Oral Lignocaine

Abstract

Absiruct: Lignocaine is metabolized by cytochrome P450 3A4 enzyme (CYP3A4), and has a moderate to high extraction ratio resulting in oral bioavailability of 30%. We have studied the possible effect of two inhibitors of CYP3A4, erythromycin and itraconazole, on the pharmacokinetics of oral lignocaine in nine volunteers using a cross-over study design. The subjects were given erythromycin orally (500 mg three times a day), itraconazole (200 mg once a day) or placebo for four days. On day 4, each subject ingested a single dose of 1 mg/kg of oral lignocaine. Plasma samples were collected until 10 hr and concentrations of lignocaine and its major metabolite, monoethylglycinexylidide were measured by gas chromatography. Both erythromycin and itraconazole increased the area under the lignocaine plasma concentration-time curve [AUC(O-m)] and lignocaine peak concentrations by 40-70% (P<0.05). Compared to placebo and itraconazole, erythromycin increased monoethylglycinexylidide peak concentrations by approximately 40% (P<O.Ol) and AUC(0-m) by 60% (PCO.01). The clinical implication of this study is that erythromycin and itraconazole may significantly increase the plasma concentrations and toxicity of oral lignocaine. The extent of the interaction of lignocaine with these CYP3A4 inhibitors was, however, less than that of, e.g. midazolam or buspirone, and it did not correlate with the CYP3A4 inhibiting potency of erythromycin and itraconazole.Lignocaine is the most widely used local anaesthetic in the world. It is administered by injection or by local application to mucous membranes. It is also a popular antiarrhythmic agent used in the treatment of ventricular arrhytmias.Lignocaine is eliminated mainly by metabolism and only negligible amounts are excreted unchanged in urine (Tucker & Mather 1979). Studies in vitro have shown that cytochrome P450 3A4 isoenzyme (CYP3A4) is important in the metabolism of lignocaine (Bargetzi et al. 1989;Imaoka et al. 1990). We have shown that two potent inhibitors of CYP3A4, erythromycin and itraconazole, have an insignificant effect on the pharmacokinetics of intravenous lignocaine (Isohanni et al. 1998). However, lignocaine is also used in painful conditions of the mouth and throat. For instance, for pharyngeal pain, lignocaine solution is gargled and swallowed if necessary. Lignocaine solution may also be swallowed before endoscopic procedures. If lignocaine is swallowed, it is subjected to first-pass metabolism which reduces the bioavailability to some 30% (Tucker & Mather 1979).We have shown that the area under the drug concentration-time curve of some orally administered CYP3A4 substrates, midazolam, triazolam and buspirone is greatly increased (from 4 to 25 times) by concomitant use of itraconazole or erythromycin (Olkkola et al. 1993(Olkkola et al. & 1996Kivisto et al. 1997;Varhe et al. 1994). If the extensive first-pass metabolism of oral lignocaine would be inhibited to the Author for correspondence: Klaus T. Olkkola. Department of Anaesthesia, University of Helsinki, PO. Box 260 ...

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

“…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]. A subsequent study concluded that ERY increased the lidocaine AUC by 40–70% and the MEGX AUC by 40% [161]. …”

Effect of Fluvoxamine and Erythromycin on the Pharmacokinetics of Oral Lidocaine

“…CYP1A2 is the major enzyme catalyzing the formation of both MEGX and 3‐OH‐lidocaine at therapeutically relevant plasma lidocaine concentrations (Wang et al 2000). We have previously shown that in man the inhibition of CYP3A4 alone, either by erythromycin or itraconazole increases the exposure to oral lidocaine (Isohanni et al 1999). Accordingly, the effect of erythromycin alone on oral lidocaine was not studied in the present cross‐over design.…”

“…After oral ingestion, lidocaine has extensive first pass metabolism resulting in bioavailibity of about 30% (Tucker & Mather 1979). The CYP 3A4 inhibitors erythromycin and itraconazole have increased the exposure to oral lidocaine by 40–70% (Isohanni et al 1999). However, there is no information on the effect of CYP 1A2 inhibitors on the pharmacokinetics of oral lidocaine.…”

Liposuction: contemporary issues for the anesthesiologist

“…Regarding pharmacokinetics, lidocaine is cleared from the body by deethylation in the liver by the cytochrome P450 system [20]. The P450 system is a large group of proteins embedded in the lipid bilayer of the endoplasmic reticulum.…”