The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects

Lignocaine clearance declines during continuous intravenous infustion in man and in vitrostudies suggest that this may partly be due to inhibition by MEGX, a metabolite of lignocaine, MEGX is pharmacologically active in animals, but this is not yet proven in man. This study examined the pharmacokinetics and pharmacodynamics of lignocaine and MEGX in eight healthy male volunteers given lignocaine HCl 120mg, MEGX HCl 120 mg, lignocaine HCl 120 mg+MEGX HCl 120 mg, and placebo, administered according to a randomized double-blind protocol. One-, two-, or three-compartment models were fitted to drug and metabolite blood concentration-time profiles and clearance, volume (V_ss), andhalf-life values were calculated and compared by paired t-test. Systolic time intervals and QTinterval were recorded and compared by repeated measures ANOVA. When administered in combination with MEGX, lignocaine clearance was significantly reduced from 58±18 to 48±13 L hr(su–1) (p <0.02). The V(inss) was unchanged and there was a trend toward an increase in terminal half-life. Lignocaine, MEGX, and the combination significantly reduced QTinterval up to 30 min after injection and this was maintained to 2 hr with the lignocaine and the combination. Transient side effects were experienced with all active treatments, but were most pronounced with the combination. Thus, lignocaine clearance was inhibited by MEGX, which was pharmacologically active in man.