Cimetidine-carbaryl interaction in humans: evidence for an active metabolite of carbaryl.

The influence of cimetidine on the pharmacokinetic and pharmacodynamic response to the insecticide carbaryl has been investigated in isolated human erythrocytes (red blood cells; RBC) and after oral administration of 1 mg/kg carbaryl to four normal subjects in the absence or presence of cimetidine (300 mg, 8/hr for 3 days). Carbaryl induced a concentration-dependent reduction of isolated RBC acetylcholinesterase activity requiring 1 microgram/ml to achieve 20% inhibition. Cimetidine also induced a dose-dependent inhibition of RBC acetylcholinesterase activity, but at 40-fold higher concentrations. At high concentrations, cimetidine was additive to carbaryl-induced inhibition of RBC acetylcholinesterase, but exhibited no effect at the therapeutically relevant concentrations (10 micrograms/ml). After oral carbaryl administration to normal subjects, plasma concentrations rapidly rose to a peak, then declined with a half-life of 0.79 +/- 0.47 hr. Oral carbaryl clearance was 5.4 +/- 2.0 l/min. Peak plasma carbaryl concentrations were associated with 27% inhibition of RBC acetylcholinesterase activity, and the concentration associated with a reduction of RBC acetylcholinesterase activity of 20% was 0.02 microgram/ml. The terminal half-life for the dynamic response was 2.6 +/- 1.5 hr. After pretreatment with cimetidine, peak plasma carbaryl concentrations doubled and clearance was reduced (to 2.5 +/- 1.5 l/min) (P less than .05). However, half-life remained unchanged. Despite increased carbaryl levels, the maximum inhibition of RBC acetylcholinesterase activity was significantly reduced, and the concentration of carbaryl required to achieve 20% inhibition of RBC acetylcholinesterase activity was increased to approximately 0.5 microgram/ml. These results are consistent with the hypothesis that carbaryl is metabolized by drug-metabolizing enzymes that can be inhibited by cimetidine.(ABSTRACT TRUNCATED AT 250 WORDS)