Pyrimethamine pharmacokinetics and its tissue localization in mice: effect of dose size: effect of dose size

The plasma pharmacokinetics and mass fate of [14 C]pyrimethamine were investigated in the mouse, following dosage with 12.5, 25, 50, and 75 mg kg−1 (i.p.). Peak plasma concentrations of pyrimethamine were reached between 1 and 2 h and then declined monoexponentially. The mean values for AUC 0 → 30 h increased linearly in relation to the administered dose of pyrimethamine (r = 0.979, P < 0.001). The mean values for intraperitoneal clearance and half‐life were not significantly different between dose groups, indicating that the plasma pharmacokinetics of pyrimethamine were independent of dose. The percentage of the administered dose excreted in urine as pyrimethamine (1.3−3.5%) and 14 C‐radioactivity (21.7−29.1%) did not change with increasing dose. In contrast, the cumulative percentage of the dose excreted as 14 C‐radioactivity in faeces (16.7−22.8%) after the three highest doses 25, 50 and 75 mg kg−1 was significantly less than that seen with the lowest dose of 12.5 mg (50.3%). This suggests extensive biliary excretion of radioactivity, and that the capacity of this process may have been exceeded with the highest doses. Seven days after the administration of each of the three highest doses, a significantly greater percentage of [14 C]pyrimethamine was localized in the soft tissues; i.e. heart, lung and kidney (7.8−13.8%), gut (5.4−9.4%) and particularly the liver (25.0−27.9%) when compared with the lowest dose of the drug (1.2, 1.0, 0.3% respectively). Following each dose, between 85 and 97% of the administered radioactivity was accounted for. These studies indicate, that with higher doses of pyrimethamine, the parent drug and/or metabolites may accumulate in soft tissue, particularly the liver, but without appreciable effects on the plasma disposition and urinary excretion of the drug. 1985 Royal Pharmaceutical Society of Great Britain