Disposition of intravenous pyrimethamine in healthy volunteers

A proportion of patients with AIDS and toxoplasmic encephalitis (TE) sustai n low plasma pyrimethamine concentrations during oral treatment, possibly b ecause of incomplete and variable bioavailability, We wanted to develop a s afe, practicable intravenous (i.v.) formulation of pyrimethamine and charac terize its disposition in healthy volunteers, A neutral, aqueous, sterile s olution of pyrimethamine was produced and presented in sealed glass ampoule s, 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. Pyrimetha mine levels in plasma were measured by highperformance liquid chromatograph y. 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; t hereafter, concentrations declined in a log-linear manner, with a half-life of 140 +/- 31 h.