Prediction of Human Intestinal Absorption of the Prodrug Temocapril by In Situ Single-Pass Perfusion Using Rat Intestine with Modified Hydrolase Activity

Abstract

ABSTRACT:Intestinal absorption of temocapril, a prodrug of temocaprilat, was evaluated in an in situ rat jejunal perfusion model under various conditions of luminal pH and in the presence and absence of carboxylesterase-mediated hydrolysis. Temocapril was more easily taken up by mucosal cells at a luminal pH of 5.4 than at pH 6.4 or 7.4 and was extensively hydrolyzed to temocaprilat in mucosal cells. The hydrolysis was limited by the intrinsic clearance and the influx rate at luminal perfusate pHs of 5.4 and 7.4, respectively. Temocaprilat, derived from temocapril, was transported into both mesenteric vein and jejunal lumen according to pH partition theory. The net absorption of both temocapril and temocaprilat was highest at a luminal perfusate pH of 5.4. When both the luminal and venous fluid were at pH 7.4, temocaprilat was transported approximately 3-fold faster into the lumen than into the vein, due presumably to the greater surface area of the brush border membrane because of the presence of microvilli. Under carboxylesteraseinhibited conditions, the hydrolysis of temocapril was inhibited by only 50%. It is postulated that serine esterases located on the membranes of the epithelial cells were responsible for the residual hydrolysis. We have confirmed that temocapril is most easily absorbed in the proximal intestine after meals, due to prolongation of the gastric emptying time, the lower intraluminal pH caused by secretion of bile acid, and the interaction between serine esterases and the digesta.

Evaluation of Transport Mechanism of Prodrugs and Parent Drugs Formed by Intracellular Metabolism in Caco-2 Cells with Modified Carboxylesterase Activity: Temocapril as a Model Case

“…It is clear that transport of temocapril across the AP membrane increases with the fraction of its non–ionic form, which in turn depends on the pH of the AP solution. We have found that decreasing the pH in the intestinal lumen leads to an increase in the membrane permeability of temocapril in rat jejunal single‐pass perfusion following pre‐perfusion with BNPP 38. These findings suggest that temocapril is mainly transported by passive diffusion in human proximal intestine.…”

Galactosylated PLGA nanoparticles for the oral delivery of resveratrol: enhanced bioavailability and in vitro anti-inflammatory activity

“…To appreciate the effect of unmodified NPs and GNPs on the intestinal permeability of RES, in situ single-pass intestinal perfusion was carried out following the reported procedure. 23,24 SD rats were fasted overnight prior to the experiment but allowed free access to water. The rats were anesthetized with 20% urethane (1.0 g/kg) by intraperitoneal injection.…”

Design of Fexofenadine Prodrugs Based on Tissue-Specific Esterase Activity and Their Dissimilar Recognition by P-Glycoprotein

“…However, a parent drug formed by intestinal metabolism is transported into the lumen as well as the mesenteric vein. In addition, the transport rate through the luminal membrane is threefold to fourfold faster than through the basolateral membrane, resulting in low absorption of prodrug . Therefore, it is desired that the prodrug is resistant to intestinal metabolism, but can be easily converted into the parent drug by a hydrolytic enzyme abundantly expressed in the liver.…”