Effect of erythromycin and itraconazole on the pharmacokinetics of intravenous lignocaine.
OBJECTIVE
We have studied the possible interaction of erythromycin and itraconazole, both inhibitors of cytochrome P450 3A4 isoenzyme (CYP3A4), with intravenous lignocaine in nine healthy volunteers using a randomized cross-over study design.


METHODS
The subjects were given oral placebo, erythromycin (500 mg three times a day) or itraconazole (200 mg once a day) for 4 days. Intravenous lignocaine 1.5 mg x kg(-1) was given with an infusion for 60 min on the fourth day of pretreatment with placebo, erythromycin or itraconazole. Timed plasma samples were collected until 11 h. The concentrations of lignocaine and its metabolite monoethylglycinexylidide (MEGX) were measured by gas chromatography.


RESULTS
The area under the lignocaine concentration-time curve was similar during all three phases but erythromycin significantly increased the elimination half-life of lignocaine from 2.5 to 2.9 (0.7) h compared with placebo. Following itraconazole administration, t1/2 was 2.6 h. The values for plasma clearance and volume of distribution at steady state were similar during all the phases. Compared with placebo and itraconazole, erythromycin significantly increased MEGX peak concentrations by approximately 40% and AUC(0-11 h) by 45-60%.


CONCLUSIONS
The plasma decay of lignocaine administered intravenously is virtually unaffected by the concomitant administration of erythromycin and itraconazole. However, erythromycin increases the concentrations of MEGX, which indicates that erythromycin either increases the relative amount of lignocaine metabolized via N-de-ethylation or decreases the further metabolism of MEGX. Further studies are necessary to elucidate the clinical significance of the erythromycin-induced elevated concentrations of MEGX during prolonged intravenous infusions of lignocaine.
Isohanni
M H
MH
Department of Anaesthesia, University of Helsinki, HYKS, Finland.
Neuvonen
P J
PJ
Palkama
V J
VJ
Olkkola
K T
KT
D000328:Adult; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004917:Erythromycin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D017964:Itraconazole / Q000494:pharmacology*; D008012:Lidocaine / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors
D000900:Anti-Bacterial Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017964:Itraconazole; D004917:Erythromycin; D008012:Lidocaine; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human