Effect of erythromycin and itraconazole on the pharmacokinetics of oral lignocaine

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, erythrom ycin and itraconazole, on the pharmacokinetics of oral lignocaine in nine v olunteers using a cross-over study design. The subjects were given erythrom ycin 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 con centrations of lignocaine and its major metabolite, monoethylglycinexylidid e were measured by gas chromatography Both erythromycin and itraconazole in creased the area under the lignocaine plasma concentration-time curve [AUC( 0-infinity)] and lignocaine peak concentrations by 40-70% (P<0.05). Compare d to placebo and itraconazole, erythromycin increased monoethylglycinexylid ide peak concentrations by approximately 40% (P<0.01) and AUC(0-infinity) b y 60% (P<0.01). 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 wi th these CYP3A4 inhibitors was, however, less than that of, e.g. midazolam or buspirone, and it did not correlate with the CYP3A4 inhibiting potency o f erythromycin and itraconazole.