TY - JOUR
T1 - The disposition of pyrimethamine in the isolated perfused rat liver
AU - Coleman, M. D.
AU - Mihaly, G. W.
AU - Ward, Steve
AU - Edwards, G.
AU - Howells, R. E.
AU - Breckenridge, A. M.
PY - 1985/6/15
Y1 - 1985/6/15
N2 - We have investigated the disposition of pyrimethamine base in the isolated perfused rat liver (IPRL) preparation after the administration of pyrimethamine (0.5 mg, 5 μCi). In the first half hour of the study, pyrimethamine underwent marked hepatic uptake, thereafter perfusate plasma drug levels declined monoexponentially with a half life (t 1 2) of 3.0 ± 1.0 hr. Area under the perfusate plasma concentration/time curve (AUC)0→ ∝ was 6.9 ± 1.9 μg/hr/ml. Pyrimethamine was found to be a low clearance compound (78.4 ± 25.3 ml/hr 8.6% of liver perfusate flow) with a large volume of distribution (267.5 ± 55.3 ml) in the IPRL. The combined AUCs(0→5hr) for pyrimethamine (AUC 4.8 ± 0.5 μg/hr/ml) and pyrimethamine 3-N-oxide (AUC0→5hr 0.9 ± 0.6 μg/hr/ml) accounted for 57% of the total AUC0→5hr of [14C] radioactivity (10.0 ± 2.6 μg/hr/ml). This indicates the presence of metabolites of pyrimethamine as yet unidentified in the perfusate. Biliary excretion of [14C] during the course of the IPRL preparations was extensive (29.0 ± 10.3%) though only a small proportion was due to pyrimethamine and the 3-N-oxide metabolite. The majority of radioactivity in the bile was attributable to highly polar, but unidentified metabolites of pyrimethamine. At the conclusion of each experiment (5 hr), a significant proportion of [14C] radioactivity was recovered from the livers (22.9 ± 5.3%). Subsequent HPLC analysis of the liver tissue indicated this to be unchanged pyrimethamine, with trace levels of the 3-N-oxide metabolite. Sub-cellular fractionation of the homogenized livers revealed the most pronounced localisation of pyrimethamine to be in the lipid rich 10,000 g pellet (13.0 ± 2.6%), the remainder being distributed equally between the 105,000 g pellet and supernatant. Neither pyrimethamine, [14C] radioactivity, nor pyrimethamine 3-N-oxide were extensively taken up by red cells throughout the study. Therefore, the large volume of distribution (267.5 ± 55.3 ml) underlines the extent of pyrimethamine localisation in the liver.
AB - We have investigated the disposition of pyrimethamine base in the isolated perfused rat liver (IPRL) preparation after the administration of pyrimethamine (0.5 mg, 5 μCi). In the first half hour of the study, pyrimethamine underwent marked hepatic uptake, thereafter perfusate plasma drug levels declined monoexponentially with a half life (t 1 2) of 3.0 ± 1.0 hr. Area under the perfusate plasma concentration/time curve (AUC)0→ ∝ was 6.9 ± 1.9 μg/hr/ml. Pyrimethamine was found to be a low clearance compound (78.4 ± 25.3 ml/hr 8.6% of liver perfusate flow) with a large volume of distribution (267.5 ± 55.3 ml) in the IPRL. The combined AUCs(0→5hr) for pyrimethamine (AUC 4.8 ± 0.5 μg/hr/ml) and pyrimethamine 3-N-oxide (AUC0→5hr 0.9 ± 0.6 μg/hr/ml) accounted for 57% of the total AUC0→5hr of [14C] radioactivity (10.0 ± 2.6 μg/hr/ml). This indicates the presence of metabolites of pyrimethamine as yet unidentified in the perfusate. Biliary excretion of [14C] during the course of the IPRL preparations was extensive (29.0 ± 10.3%) though only a small proportion was due to pyrimethamine and the 3-N-oxide metabolite. The majority of radioactivity in the bile was attributable to highly polar, but unidentified metabolites of pyrimethamine. At the conclusion of each experiment (5 hr), a significant proportion of [14C] radioactivity was recovered from the livers (22.9 ± 5.3%). Subsequent HPLC analysis of the liver tissue indicated this to be unchanged pyrimethamine, with trace levels of the 3-N-oxide metabolite. Sub-cellular fractionation of the homogenized livers revealed the most pronounced localisation of pyrimethamine to be in the lipid rich 10,000 g pellet (13.0 ± 2.6%), the remainder being distributed equally between the 105,000 g pellet and supernatant. Neither pyrimethamine, [14C] radioactivity, nor pyrimethamine 3-N-oxide were extensively taken up by red cells throughout the study. Therefore, the large volume of distribution (267.5 ± 55.3 ml) underlines the extent of pyrimethamine localisation in the liver.
U2 - 10.1016/0006-2952(85)90417-4
DO - 10.1016/0006-2952(85)90417-4
M3 - Article
SN - 0006-2952
VL - 34
SP - 2193
EP - 2197
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 12
ER -