Studies on the Metabolic Fate of TA-510, a Hepatic Anti-inflammatory Agent (I)
: Blood Concentration, Distribution and Excretion in Rats and Dogs
2000 Volume 15 Issue 4 Pages 318-326
Details
2000 Volume 15 Issue 4 Pages 318-326
Pharmacokinetics in the plasma, tissue distribution and excretion of TA-510, a novel hepatic agent, were investigated after a single oral (30 mg/kg) or intravenous (3 mg/kg) administration of 14C-labeled TA-510 to male rats and dogs.
1. The absorption extent of TA-510 across the intestinal barrier was estimated to be about 80% and 100% of the administered dose in rats and dogs, respectively. The absorption extent was calculated from the ratios of the urinary excretion of radioactivity after oral and intravenous administration of 14C-TA-510.
2. After oral administration, the plasma Cmax and AUC of the unchanged TA-510 in rats were approximately fifty- and eighty-fold lower than those in dogs, respectively. The AUC ratio of unchanged drug to total radioactivity accounted for only 2% in rat plasma, suggesting that TA-510 is susceptible to first-pass metabolism in male rats.
3. The radioactivity in most tissues reached the highest levels 6 hr after oral administration to male rats, the tissues showing higher level of radioactivity than that in blood were liver, a target tissue, and kidney, except gastrointestinal tract. The radioactivity levels in the lung and skin were similar to that in blood. The distribution into the other tissues such as brain, spleen and testis were shown to be extremely low. The radioactivity thereafter disappeared gradually from the tissues and was only detectable in the intestinal contents and liver 72 hr after administration.
4. Within 72 hr after oral administration to rats, 27.5% and 68.9% of the radioactivity was excreted into urine and feces, respectively. The cumulative excretion of radioactivity, within 48 hr after oral administration, in bile and urine of bile-duct cannulated rats were 72.2% and 5.5% of the dose, respectively. After intraduodenal injection of the bile to recipient rats, 35.9% of the radioactivity was reabsorbed. In dogs, 51.4% and 44.7% of the radioactivity was recovered from the urine and feces, respectively, within 72hr after oral administration.
