Pharmacokinetics and pharmacodynamics of the acetylcholinesterase inhibitor metrifonate in patients with renal impairment

The aim of this study was to assess the influence of renal function on the pharmacokinetics, pharmacodynamics, safety, and tolerability of the acetylc holinesterase inhibitor metrifonate. Four groups of six age- and gender-mat ched subjects with varying degrees of renal function (creatinine clearances more than 90, 60-90, 30-60, and less than 30 mL/min/1.73 m(2), respectivel y) were administered a single 50-mg oral dose of metrifonate. Blood and uri ne samples were collected for 24 hours and concentrations of metrifonate an d its metabolites dichlorvos, dichloroacetic acid, and M3 were determined. Inhibition of acetylcholinesterase activity in erythrocytes and butyrylchol inesterase in plasma were also measured. Metrifonate was well tolerated in all treatment groups. The urinary excretion of metrifonate and dichlorvos d ecreased with decreasing renal function but accounted for less than 2% of t he elimination. There were no statistically significant differences in prim ary pharmacokinetic parameters-C-max, t(max), area under the concentration- time curve (AUC), and t(1/2)-of metrifonate and dichlorvos among the differ ent groups. The excretion of dichloroacetic acid and M3 was not influenced by renal impairment. Acetylcholinesterase was not inhibited, whereas butyry lcholinesterase was inhibited markedly but independently of renal function. No metrifonate dose adjustments are needed when treating subjects with ren al impairment.