Decreased hepatic elimination of pyrimethamine during malaria infection. Studies in the isolated perfused rat liver.

The elimination of the antimalarial drug pyrimethamine was studied in isolated liver preparations from young rats (80-100 g) infected with merozoites of Plasmodium berghei two weeks earlier. Perfusate half-life of pyrimethamine was increased in livers from M.I. rats (t1/2 beta control group = 56 +/- 11 min vs M.I. group = 101 +/- 12, P less than 0.01), reflecting a decrease in hepatic clearance (3.6 +/- 1.1 ml/min vs 1.9 +/- 0.5 ml/min, P less than 0.01). There was no significant difference in volume of distribution between livers from M.I. and control groups. Intrahepatic concentration of unchanged drug at 3 hr was 4-5-fold greater in livers from infected rats (control group = 4725 +/- 2287 ng/ml vs M.I. group = 22,324 +/- 6824 ng/ml), while liver: perfusate concentration ratios were not significantly different (control group = 30.8 +/- 24.1 vs M.I. group = 35.6 +/- 20.3). We conclude that the hepatic elimination of pyrimethamine is substantially impaired in the malaria-infected rat.