Pharmacokinetic and relative bioavailability studies of cimoxatone in humans

The pharmacokinetics of the reversible MAO-A inhibitor, cimoxatone, and its O-demethyl metabolite MD 770222 were investigated in eight healthy adult volunteers following single doses of 20- and 40-mg tablets, and 40-mg aqueous suspension. Cimoxatone plasma conc./time curves were fitted using a one-compartment open model, with absorption and elimination half-lives of about 0.5 and 12.0 h, respectively. Visual fittings, parameter estimates, and statistical analysis (Akaike information criterion) showed that data were better fitted by first-order than by zero-order absorption rate. A lag time of 20-25 min was observed for both formulations. MD 770222, which is also a selective and reversible inhibitor of MAO A although less potent than cimoxatone, is the major plasma metabolite and its plasma elimination half-life is about three times longer than cimoxatone. Although cimoxatone solubility in water is only 5 ppm, the drug appears to be well absorbed as indicated by the tight conformity of the pharmacokinetic parameters. Cmax and AUC values doubled from the 20- to the 40-mg dose. A statistical analysis showed that the systemic availability of cimoxatone from the 40-mg tablet is higher than from the suspension (p less than 0.05), and this difference is even more pronounced on analysis of the metabolite data (p less than 0.01). Particle size analysis of cimoxatone pronounced on analysis of the metabolite data (p less than 0.01). Particle size analysis of cimoxatone powder showed the formation of agglomerates for the suspension which, by reduction of surface area, could decrease the availability of the drug.