INTESTINAL TRANSPORT AND METABOLISM OF ANALGESIC DIPEPTIDE, KYOTORPHIN - RATE-LIMITING FACTOR IN INTESTINAL-ABSORPTION OF PEPTIDE AS DRUG

Intestinal transport and metabolism of kyotorphin (KTP) were studied i n rat everted small intestine. KTP on the mucosal side was metabolized completely within 60 min, and any amounts of KTP were not detected on the serosal side. On the other hand, [D-Arg(2)]-KTP (D-KTP) was stabl e on the mucosal side to appear on the serosal side. However, N-t-buto xycarbonyl-KTP (Boc-KTP), which was metabolized on the mucosal side fa ster than KTP, appeared on the serosal side. In intestinal homogenate, KTP was metabolized, and the metabolic clearance (CLmet) was decrease d by peptidase inhibitors, bestatin, o-phenanthrolin and tryptophan hy droxamate, In the presence of these peptidase inhibitors, the absorpti on clearance (CLabs) of KTP was increased. The less the CLmet of KTP w as, the more the CLabs of KTP was. Meanwhile, Boc-KTP in intestinal ho mogenate was stable even in the absence of peptidase inhibitors. The C Labs of Boc-KTP was constant irrespective of the stability on the muco sal side. Kinetic analysis by the metabolic inhibition model indicated that the stabilization of KTP in the intestinal tissue could increase the CLabs up to 0.247 mu l/min per cm, which was as much as the CLabs of stable D-KTP. These results led to the conclusion that rate-limiti ng process in intestinal absorption of KTP is metabolic degradation in intestinal tissue during the absorption.