Disposition of intravenous pyrimethamine in healthy volunteers

A proportion of patients with AIDS and toxoplasmic encephalitis (TE) sustain low plasma pyrimethamine concentrations during oral treatment, possibly because of incomplete and variable bioavailability, We wanted to develop a safe, practicable intravenous (i.v.) formulation of pyrimethamine and characterize its disposition in healthy volunteers, A neutral, aqueous, sterile solution of pyrimethamine was produced and presented in sealed glass ampoules, Pyrimethamine (1 mg/kg) was given to eight healthy male volunteers by i.v. infusion over 2 h, and blood was sampled over a 2 week period. Pyrimethamine levels in plasma were measured by highperformance liquid chromatography. The drug was well tolerated by all volunteers, and there mere no changes in vital signs, electrocardiogram, hematology, or biochemical parameters. The maximum pyrimethamine concentration of 2,089 +/- 565 ng ml(-1) (mean +/- standard deviation) was achieved shortly after the end of the infusion; thereafter, concentrations declined in a log-linear manner, with a half-life of 140 +/- 31 h.