EFFECT OF ERYTHROMYCIN AND ITRACONAZOLE ON THE PHARMACOKINETICS OF INTRAVENOUS LIGNOCAINE

Objective: We have studied the possible interaction of erythromycin an d itraconazole, both inhibitors of cytochrome P450 3A4 isoenzyme (CYP3 A4), with intravenous lignocaine in nine healthy volunteers using a ra ndomized cross-over study design. Methods: The subjects were given ora l placebo, erythromycin (500 mg three times a day) or itraconazole (20 0 mg once a day) for 4 days. Intravenous lignocaine 1.5 mg.kg(-1) was given with an infusion for 60 min on the fourth day of pretreatment wi th placebo, erythromycin or itraconazole. Timed plasma samples were co llected until 11 h. The concentrations of lignocaine and its metabolit e monoethylglycinexylidide (MEGX) were measured by gas chromatography. Results: The area under the lignocaine concentration-time curve was s imilar during all three phases but erythromycin significantly increase d the elimination half-life of lignocaine from 2.5 to 2.9 (0.7) h comp ared with placebo. Following itraconazole administration, t(1/2) was 2 .6 h. The values for plasma clearance and volume of distribution at st eady state were similar during all the phases. Compared with placebo a nd itraconazole, erythromycin significantly increased MEGX peak concen trations by approximately 40% and AUC((0-11 h)) by 45-60%. Conclusion: The plasma decay of lignocaine administered intravenously is virtuall y unaffected by the concomitant administration of erythromycin and itr aconazole. However, erythromycin increases the concentrations of MEGX, which indicates that erythromycin either increases the relative amoun t of lignocaine metabolized via N-de-ethylation or decreases the furth er metabolism of MEGX. Further studies are necessary to elucidate the clinical significance of the erythromycin-induced elevated concentrati ons of MEGX during prolonged intravenous infusions of lignocaine.