Hans Lengsfeld

Hydrolysis of dietary fat by pancreatic lipase stimulates cholecystokinin release

BACKGROUND & AIMS The hypothesis that cholecystokinin release requires adequate dietary fat digestion in the small intestine was investigated in 10 healthy volunteers, and the consequences of reduced fat hydrolysis on pancreaticobiliary secretions were assessed. METHODS Fat hydrolysis was inhibited by intraduodenal perfusion of tetrahydrolipstatin, an irreversible lipase inhibitor. An oil emulsion containing 0, 30, 60, or 120 mg tetrahydrolipstatin was perfused. After a 40-minute basal period, a test meal was eaten to stimulate cholecystokinin release and pancreaticobiliary responses. RESULTS In the control without tetrahydrolipstatin, lipase output increased threefold with meal ingestion and remained doubled for 4 hours. At the ligament of Treitz, free fatty acid concentration averaged 60% of total fatty acids. Increasing doses of tetrahydrolipstatin induced a dose-dependent inhibition of duodenal lipase activity (P < 0.01); 120 mg tetrahydrolipstatin eliminated the postprandial lipase peak activity, free fatty acid levels decreased to < 5% of total fatty acids, and plasma cholecystokinin levels were suppressed by 77% (P < 0.01). Amylase and trypsin outputs were reduced by 77% and 59%, respectively, and bilirubin secretion was virtually abolished (P < 0.01). CONCLUSIONS These findings show that tetrahydrolipstatin prevents triglyceride hydrolysis and that plasma cholecystokinin release, gallbladder emptying, and pancreatic enzyme secretion require adequate triglyceride digestion. These data also support the concept of negative feedback regulation of cholecystokinin secretion.

Magnetic Resonance Imaging for the in Vivo Evaluation of Gastric-Retentive Tablets

AbstractPurpose. To develop a magnetic resonance imaging (MRI) technique for assessing in vivo properties of orally ingested gastric-retentive tablets under physiologic conditions. Methods. Tablets with different floating characteristics (tablet A-C) were marked with superparamagnetic Fe3O4 particles to analyze intragastric tablet position and residence time in human volunteers. Optimal Fe3O4 concentration was determined in vitro. Intragastric release characteristic of one slow-release tablet (tablet D) was analyzed by embedding gadolinium chelates (Gd-DOTA) as a drug model into the tablet. All volunteers underwent MRI in the sitting position. Tablet performance was analyzed in terms of relative position of tablet to intragastric meal level (with 100% at meal surface), intragastric residence time (min) and Gd-DOTA distribution volume (% of meal volume). Results. Intragastric tablet floating performance and residence time of tablets (tablet A-D) as well as the intragastric Gd-DOTA distribution of tablet D could be monitored using MRI. Tablet floating performance was different between the tablets (A, 93%(95 − 9%); B, 80%(80 − 68%); C, 38%(63 − 32%); p < 0.05). The intragastric distribution volume of Gd-DOTA was 19.9% proximally and 35.5% distally. Conclusions. The use of MRI allows the assessment of galenic properties of orally ingested tablets in humans in seated position.

[10] Covalent inactivation of lipases

Publisher Summary This chapter presents and discusses results chiefly concerning the covalent inhibition of gastric and pancreatic lipases. Lipolysis is catalyzed by preduodenal and pancreatic lipases. In humans, the hydrolysis of alimentary triacylglycerols begins in the stomach and is catalyzed by human gastric lipase (HGL) that is able to hydrolyze short- and long-chain triacylglycerols at comparable rates. Under acidic pH conditions, HGL has been shown to be remarkably stable and active, whereas pancreatic lipase irreversibly loses its lipolytic capacity. Achieving specific and covalent inhibition of lipolytic enzymes is a difficult task, because of nonmutually exclusive processes such as interfacial denaturation, changes in “interfacial quality,” and surface dilution phenomena. Furthermore, the interfacial enzyme binding and/or the catalytic turnover can be diversely affected by the presence of potential amphipathic inhibitors. The chapter provides selected experimental data illustrating the specific problems encountered during the covalent inhibition of digestive lipases.

Surface behaviour of bile salts and tetrahydrolipstatin at air/water and oil/water interfaces

The surface behaviour of two bile salts, sodium deoxycholate (NaDC) and sodium taurodeoxycholate (NaTDC), as well as that of tetrahydrolipstatin (THL), a potent gastrointestinal lipase inhibitor, was studied at air/water and oil/water interfaces, using interfacial tensiometry methods. The surface behaviour of NaDC and NaTDC was comparable at both oil/water and air/water interfaces. A fairly compact interfacial monolayer of bile salts is formed well below the critical micellar concentration (CMC) and can help to explain the well-known effects of bile salts on the kinetic behaviour of pancreatic lipases. Using the Wilhelmy plate technique, the surface pressure-molecular area curves recorded with THL at the air/water interface showed a collapse point at a surface pressure of 24.5 mN.m(-1), corresponding to a molecular area of 70 A(2). Surprisingly, using the oil drop method, a limiting molecular area of 160 A(2) was found to exist at the oil/water interface. On the basis of the above data, space-filling models were proposed for bile salts and THL at air/water and oil/water interfaces.

Analysis of the meal-dependent intragastric performance of a gastric-retentive tablet assessed by magnetic resonance imaging

Background : Modern medical imaging modalities can trace labelled oral drug dosage forms in the gastrointestinal tract, and thus represent important tools for the evaluation of their in vivo performance. The application of gastric‐retentive drug delivery systems to improve bioavailability and to avoid unwanted plasma peak concentrations of orally administered drugs is of special interest in clinical and pharmaceutical research.

Role of Free Fatty Acids in Regulating Gastric Emptying and Gallbladder Contraction

The limited effectiveness of orlistat, an inhibitor of gastrointestinal lipases, in inhibiting fat digestion is not completely understood. Therefore we studied the effect of orally and duodenally administered orlistat on gastric emptying, cholecystokinin (CCK) secretion, and gallbladder contraction. In healthy males, gastric emptying of solids and fat were quantified scintigraphically, gallbladder contraction by ultrasound and CCK release by radioimmunoassay. Three studies were performed: (1) oral and (2) duodenal orlistat with a fat-containing meal, and (3) duodenal orlistat with a fat-free meal. Gastric emptying rates of solids and fat (T50% accelerated by 16 and by 22%, p< 0.05, respectively) were significantly faster after duodenal perfusion of orlistat; gallbladder contraction and CCK release were reduced under these conditions (p < 0.005, respectively). With oral orlistat no significant effect was documented on these parameters. We conclude that fat hydrolysis is essential in the regulation of fat-induced gastric emptying and gallbladder contraction.

Monitoring the intragastric distribution of a colloidal drug carrier model by magnetic resonance imaging

AbstractPurpose. Monitoring the distribution of drugs or drug delivery systems in the human gastrointestinal tract is an important prerequisite for the design of orally administered drugs. We investigated the intragastric distribution of a colloidal drug delivery system (liposomes containing the contrast agent Gd-DOTA) by magnetic resonance imaging. Methods. Following ingestion of a liquid or a solid meal, gastric distribution of liposomes released from a capsule and the fat component of the solid meal were tracked in 7 healthy subjects for 90 min. Liposomes were identified in gastric content by the increased signal intensity provided by the encapsulated Gd-DOTA. Results. With the liquid meal, liposomes initially formed a layer on the surface before distributing in 86 ± 2% of gastric content (maximum distribution volume) within 42 ± 6 min. With the solid meal, maximum distribution (7 ± 1%, reached within 24 ± 6 min) was confined to a small volume in the fundus without forming a layer, suggesting that distribution was related to the accessible liquid compartment. Fat distribution was inhomogeneous and concentrated in the fundus. Conclusions. Intragastric distribution of a colloidal drug carrier model, such as Gd-DOTA-filled liposomes, varies between meals of different composition. These differences can be monitored in three dimensions in humans by MRI.

Transfer of orlistat through oil–water interfaces

The transfer of radiolabelled orlistat ([14C]orlistat), a potent gastrointestinal lipase inhibitor, through an oil-water interface from a single oil droplet to an aqueous phase was investigated, using an oil drop tensiometer. The absolute transfer fluxes were found to be very low, even in the presence of micellar concentrations of bile salts, which increased their values from 0.2 to 2.5 and 6.5 pmol cm(-2) min(-1) in the presence of 0, 4 and 15 mM NaTDC, respectively. Adding either a lipid emulsion or pure human pancreatic lipase (HPL) or human serum albumin or beta-lactoglobulin had no effect on the flux of transfer of orlistat. The presence of colipase or a mixture of colipase and HPL was found, however, to reduce the flux of orlistat transfer, probably because it partly covered the single oil drop surface, even in the presence of bile salts. Using a finely emulsified system, we investigated the partitioning of orlistat between the aqueous and oil phases, in the absence or presence of bile salts above their CMC (4 mM NaTDC, final concentration). Under these emulsified conditions, orlistat was found to be mostly associated with the oil phase, since more than 98.8% of the total radioactivity was recovered after decantation with the oil phase. The low transfer rates of orlistat, as well as its partitioning coefficient between the oil and the aqueous phases, should help us to better understand the inhibitory effects of orlistat on lipid digestion in humans.

Effects of chronic aortic coarctation on atherosclerosis and arterial lipid accumulation in the Watanabe hereditary hyperlipidemic (WHHL) rabbit

The effects of high blood pressure on atherosclerosis were examined in the Watanabe heritable hyperlipidemic (WHHL) rabbit. For this purpose, the subdiaphragmatic aorta of rabbits was partially ligated (coarctation) to increase blood pressure. Atherosclerosis was assessed 4 months later by morphometric analyses and quantitation of arterial lipids. Results were compared to control WHHL rabbits with matched plasma triglycerides and cholesterol levels. A marked increase in atherosclerotic lesions was observed in the thoracic aorta of the hypertensive rabbits without qualitative changes in its morphometric features. The cross sectional area of the atherosclerotic plaques of the ascending and descending aorta in the hypertensive rabbits was two- and six-times larger than in normotensive rabbits, respectively. Lesions represented 12.0% +/- 3.5% of the total medial cross sectional area of the descending aorta of normotensive rabbits, versus 45.0% +/- 5.7% in hypertensive rabbits. No lesions were observed downstream of the coarctation in hypertensive rabbits, nor in the normotensive rabbits. Accumulation of cholesterol and choline-containing phospholipids in the descending aorta of hypertensive rabbits was increased 3.2- and 1.5-fold, respectively, when compared to normotensive rabbits. Hypertension did not change the unesterified cholesterol/total cholesterol and sphingomyelin/lecithin + lysolecithin molar ratios. In conclusion, chronic coarctation enhances the atherosclerotic response in WHHL rabbits in the high blood pressure compartment, and reduces the variability of this response.