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Abstract
1. 14C-Labelled 2,3-dihydro-8-[2-hydroxy-3-[4-[1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-1-piperazinyl]propoxy]-1,4-benzodioxin-5-carboxylic acid, isopentyl ester (TPBE) was administered orally and intravenously to rats and dogs and excretion in urine and faeces studied. Large amounts of radioactivity were present in faeces after i.v. drug administration, indicating that biliary excretion was important.
2. Biliary excretion in bile-duct cannulated rats and dogs showed that within one hour after i.v. dosage, > 50% dose was excreted in the bile of both species. Much lower amounts of radioactivity were excreted in bile after oral administration, indicating that absorption was incomplete.
3. T.l.c. of urine, bile and faeces showed that the hydrolysis product of TPBE was the major metabolite in urine and bile of the rat, but was less predominant in dog.
4. Incubation of TPBE in rat whole blood, and with homogenates of liver and small intestine, demonstrated hydrolysis of the drug. Hydrolysis by small intestine and colon contents was low. In the dog, only liver homogenates were capable of extensive hydrolysis of the drug. Hydrolysis also occurred in human blood in vitro; hydrolysis was most rapid in blood of rat then man and finally dog.
5. Experiments in vitro indicate that hydrolysis of TPBE in dog in vivo is likely to be mainly hepatic, whereas in rat hydrolysis in vivo is likely to be both hepatic and extrahepatic (blood and intestines). Results from rat, dog and man indicate that man is likely to be similar to the rat in hydrolysis of TPBE.