Pharmacokinetics of lidocaine and its deethylated metabolite: dose and time dependency studies in man.

Abstract

The concentrations of lidocaine and of its deethylated metabolite, MEGX, were measured in blood following the intravenous administration of 50 and 100 mg lidocaine hydrochloride, the oral administration of 100, 300, and 500 mg lidocaine hydrochloride monohydrate, and the oral administration of 300 mg lidocaine hydrochloride monohydrate every 8 h for seven doses, to three healthy volunteers. The range of values for the parameters defining the disposition kinetics of lidocaine were: terminal half-life, 50-231 min; total clearance, 13-17 ml/min/kg; initial dilution space, 0.13-2.5 liters/kg; and volume of distribution at steady state, 0.6-4.5 liters/kg. Lidocaine absorption from solution was rapid, but due to presystemic hepatic metabolism, the availability was low, the range of average values lying between 0.19 and 0.38. No dose or time dependency in lidocaine and monoethylglycinexylidide pharmacokinetics following the single dose studies of lidocaine were noted. Effective hepatic blood flow, based on total clearance and availability measurements, was estimated to be 18-27 ml/min/kg. The concentrations of MEGX were approximately one-third of those of lidocaine following intravenous lidocaine and were comparable following oral lidocaine, but as predicted, the dose normalized area under the MEGX concentration-time curve was constant and independent of the route of administration of lidocaine. In two subjects, the blood concentrations of lidocaine and MEGX following multiple doses of oral lidocaine were those predicted from the single dose studies. In the third subject, the degree of accumulation of lidocaine was greater than predicted. The reasons and mechanism for this difference between subjects on multiple dosing remains unclear.