DISPOSITION AND BIOTRANSFORMATION OF ¹⁴C-PIPEMIDIC ACID IN RATS AND MICE

Abstract

Disposition and biotransformation of pipemidic acid (PPA) were studied in rats and mice orally given a single or multiple doses of 50 mg ¹⁴C-PPA/kg/day with the following results.
1) After a single dosing to rats and mice, ¹⁴C-PPA was absorbed rapidly to give maximum blood levels (5.0 μg Eq/ml in rats and 7. 7 ug Eq/ml in mice) within 1 hour post administration, followed by gradual decreases.
2) In both species, the levels in most of organs and tissues examined changed in parallel with the blood levels. The highest tissue levels were found in liver, gastrointestinal tracts, kidneys and urinary bladder, whereas lower levels as compared with blood levels were found in brain, eye balls, fat and testes. Other tissue levels were found to be higher than blood levels.
3) Twenty-four hours post dosing, tissue levels in both species were so decreased that the recoveries of radioactivity from liver, an organ showing the highest level, were about 0. 1 % of the dose administered.
4) Twenty-four hours, after a single dose, about 40% of the administered dose was recovered from rat urine, about 50% from rat feces, about 10% from rat bile, about 25% from mouse urine and about 60% from mouse feces.
5) When administered to rats once a day for 7 days, the blood level at 1 hour after dosing was gradually elevated to attain a twice higher level on the 7th dosing as that on the 1st dosing.
6) Tissue distribution of ¹⁴C-PPA in rats after 8 consecutive doses was found to be similar to that after a single dose, suggesting no appreciable tissue accumulation of the drug. Daily excretions into urine and feces were also found to be virtually unchanged.
7) Whole-body autoradiographic studies of rats given a single or multiple doses showed tissue distributions being in good agreement with those obtained by radiometric assay.
8) Whole-body autoradiograms of pregnant mice given a single dose showed that fetal tissue levels were similar to maternal blood levels, and elimination rates of the label from fetal tissues were also similar to those of maternal tissues.
9) Both in rats and mice, 90% of either 24-hour urinary or fecal radioactivity was associated with unchanged PPA and the remainder with its glucuronide and an unidentified metabolite.
10) TLC of 6-hour rat bile showed three major peaks together with a minor peak. Major peaks were found to be unchanged PPA, its glucuronide and an unidentified metabolite, respectively.