Evaluation of drug absorption and presystemic metabolism using an in situ intestinal preparation.

An in situ rat intestinal preparation was modified to include portal and jugular venous blood collection techniques as well as sampling from the intestinal lumen. Viability could be maintained for 3 h. The utility of the preparation was examined by studying the disposition of four model drugs, each with differing characteristics with respect to absorption and presystemic metabolism. Haloperidol (4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1- butanone), a reference compound used for model development, disappeared from the intestinal lumen with a half-life of 14 +/- 3 min. When the antiarthritic agent, tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate), was studied in the preparation, it was rapidly absorbed (t1/2 for disappearance from the intestinal lumen = 8 min), achieved plasma concentrations comparable to in vivo data, and underwent little presystemic elimination. In contrast, fenoctimine sulfate (4-(diphenylmethyl)-1-[(octylimino)methyl]piperidine sulfate), an antisecretory compound, disappeared more slowly from the intestinal lumen (t1/2 = 60 min), was present in portal plasma, but was not detected in systemic plasma. Extensive hepatic first-pass elimination of fenoctimine was evident. Tolmetin glycine amide (N-([1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetyl)glycine), a tolmetin prodrug, disappeared from the intestinal lumen very slowly (t1/2 approximately 3 h) compared with the other agents tested. It was determined that this drug was being hydrolyzed presystemically to tolmetin by the intestinal mucosa and the liver. These results establish the utility of this intestinal preparation for studying drug absorption and presystemic elimination.