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 high-performance liquid chromatography. The drug was well tolerated by all volunteers, and there were 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.
Almond
D S
DS
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, United Kingdom.
Szwandt
I S
IS
Edwards
G
G
Lee
M G
MG
Winstanley
P A
PA
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004660:Encephalitis / Q000188:drug therapy; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D011739:Pyrimethamine / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D000962:Antimalarials; D011739:Pyrimethamine