Chemical formula: C₁₂H₁₃ClN₄ Molecular mass: 248.711 g/mol PubChem compound: 4993
Pyrimethamine is an antiparasitic agent. The antiparasitic action of pyrimethamine is due to its specific activity on folic acid metabolism in the Plasmodium and Toxoplasma parasites. In this respect it competitively inhibits the dihydrofolate reductase enzyme with an affinity far greater for the protozoal than for the human enzyme.
Pyrimethamine is almost completely absorbed from the gastrointestinal tract. Peak plasma concentrations generally occur 2 to 4 hours after a dose and can vary widely between individuals; concentrations ranging from 260 to 1411 ng/ml after daily oral doses of 25 mg.
The volume of distribution for pyrimethamine is approximately 2L/kg. In patients with HIV infection, population pharmacokinetic analysis has indicated that the mean volume of distribution (corrected for bioavailability) is 246+/-64L.
About 80 to 90% of the pyrimethamine is bound to plasma proteins.
Pyrimethamine is mainly concentrated in the kidneys, lungs, liver, and spleen. In AIDS patients given daily dose of pyrimethamine, concentrations of about one-fifth of those in the serum occur in cerebrospinal fluid.
Pyrimethamine crosses the placenta. It is distributed into breast milk
Pyrimethamine is predominantly metabolised by the liver. The mean elimination half-life is 85 hours. Pyrimethamine is slowly excreted in urine. In AIDS patients, the total clearance is 1.28+/-0.41L/h resulting in an elimination half life of 139+/-34h. Data are lacking on the nature of the metabolites of pyrimethamine, their route/rate of formation and elimination in man and any pharmacological activity, particularly after prolonged daily dosing.
Multiple dose studies indicate that steady state is achieved in 12 to 20 days with daily dosing. It is theoretically possible that metabolic pathways might be saturable, leading to excessive accumulation of the drug in some patients. However, it has been demonstrated that plasma levels are approximately proportional to dose at steady state so this appears unlikely. Genetic variation in the exposure to pyrimethamine has been reported but these data are unsubstantiated.
Some studies in patients with AIDS have indicated shorter half lives than those noted above: these are very likely to be a consequence of inappropriate sampling and analytical techniques. However, if there are patients in whom the half-life is particularly short, steady state therapeutic levels might be inadequate.
In microbial tests, pyrimethamine was found to be non-mutagenic in the Ames Salmonella assay whereas DNA damage was seen in the Escherichia coli repair assay. Further in vitro data indicate that pyrimethamine induces mutagenic activity in mouse lymphoma cells in the absence, but not in the presence of metabolic activation.
Pyrimethamine also showed clastogenic activity in mammalian lymphocytes in the absence of metabolic activation.
Following intraperitoneal administration, pyrimethamine has been shown to induce chromosomal damage in male rodent germ cells although studies in somatic cells (micronucleus tests) are either negative or inconclusive. Studies following oral administration of pyrimethamine in rodents showed negative results in female germ cells and in male and female bone marrow/peripheral blood cells.
A study in mice (dosed with either 500 or 1000 ppm pyrimethamine in the diet for 5 days per week, for 78 weeks) showed no evidence of carcinogenicity in females. Survival in the male mice did not allow for an assessment of carcinogenicity in this sex.
A similar study in rats dosed at 200 or 400 ppm pyrimethamine showed no evidence of carcinogenicity.
No changes in early development were seen in embryos from 15 mice given a single intra-gastric dose of pyrimethamine (50 mg/kg bodyweight) on the first day of gestation. However development of mouse and rat embryos in culture was severely hindered by pyrimethamine in a dose-dependent manner.
Pyrimethamine was teratogenic in rodents and in the Gottingen minipig in a dose-dependent manner.
Other studies in rats dosed at either 1 mg/kg or 10 mg/kg bodyweight showed some inhibition of developmental processes but no teratological effects.
Pyrimethamine was not teratogenic in rabbits at dose levels up to 100 mg/kg bodyweight/day administered on days 6 to 18 of pregnancy. Pyrimethamine markedly reduced early stage cell division in rabbit embryos but implantation and foetal development were normal.
A study in rats dosed with 5 mg/kg bodyweight/day for 6 weeks resulted in reduced sperm concentrations and testis weights, but there were no effects on fertility. Reversible arrest of spermatogenesis was shown in a study on mice dosed with 200 mg/kg/day for 50 days. However, this dose is far in excess of human therapeutic doses.
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