Lipids and obesity: Assessment of chemical inhibitors of intestinal lipid absorption and the evaluation of the pharmacokinetics of potential obesity-modifying drugs in the rat
Creators: Al Nebaihi, Hamdah
Publisher: name: University of Alberta Library
Year: 2024

<p>Fats constitute an essential component of our diets, and have implications in oral absorption of drugs and disease. In the gastrointestinal tract, fats are processed and most are mostly incorporated into chylomicrons, then shunted into the intestinal lymphatic vessels. Most orally administered drugs are absorbed into the bloodstream via intestinal blood vessels, subsequently traveling through the portal vein to the liver where they may be metabolizing, thus reducing their systemic availability and efficacy. The intestinal lymphatic system is an alternative absorption pathway that is exist, allowing certain drugs to bypass the liver. This pathway may also involve the association of lipophilic drugs with fats, which are naturally processed into lipoproteins (mainly chylomicrons). Chylomicrons are formed in enterocytes, and with lipophilic drugs enter the lymphatic circulation circumventing the liver and hence hepatic first pass metabolism of those drugs. This possibly represents a therapeutic benefit to certain drugs, and pharmaceutical scientists may try to modify formulations to enhance this pathway of drug absorption.To guide this effort, invasive surgical cannulation of the intestinal lymphatics has been used to measure lymph as a pathway of drug absorption. However, invasive surgery is not ideal. Chylomicron inhibitors that suppress lymph flow have also been identified, which presents many potential advantages over surgery. Yet, these agents (colchicine “COL” and cycloheximide “CHX”) have been poorly studied from the perspective of their systemic blood levels and have been used at toxic doses and after parenteral administration. Part 1 of this thesis was directed towards systematically understanding these compounds disposition and action further. Jugular-vein cannulated (JVC) male Sprague Dawley rats (n=3-4) were administered these lymphatic blockers at low doses (≤0.5 mg/kg COL and ≤2.5 mg/kg CHX) by intravenous, oral, and intraperitoneal routes to evaluate their pharmacokinetics (PK).  The results indicated that CHX had a high clearance (CL) exceeding hepatic blood flow and extensive distribution. Its oral absolute bioavailability (F) was greater than expected based on the CL. Its F after ip doses was over 3. CHX was associated with unique dose- and route-dependent pharmacokinetics. CHX had low plasma protein binding and minor urinary excretion. COL had a lower CL but like CHX a high volume of distribution that exceeding total body water in rats while its bioavailability was very small (&lt;5%). The effects of COL and CHX as blockers of intestinal lymph absorption are based on their ability to reduce the triglyceride (TG) and cholesterol (CHOL) levels after oral dosing. Oral dose of 2.5 mg/kg CHX reduced the TG and CHOL by 40% and 24%, respectively. While not as effective, COL decreased CHOL plasma concentrations by 8% with no significant reduction in TG. Some evidence of liver toxicity was seen with both agents. These observations seem to justify their use as a non-surgical tool to evaluate the lymphatic pathway of absorption of drugs, but liver toxicity is a potential issue even with low oral doses. Part 2 of the thesis involved a PK evaluation of compounds with a possible novel action against cardiometabolic syndrome; pimozide (PMZ) and a brain impermeable SCOT inhibitor 51 (BISI-51). Both inhibit ketone body oxidation in skeletal muscle by inhibiting succinyl-CoA:3-ketoacid CoA transferase, causing a blood glucose-lowering effect. Due to the association of obesity with type 2 diabetes, it was important to understand the effects of obesity on their PK as well. JVC adult Sprague Dawley male rats (n=4-5) were administered 10 mg/kg PMZ or BISI-51 where the PK parameters were calculated based on rich sampling. Bayesian forecasting was utilized for sparse saphenous vein blood sampling of rats fed a high-fat or standard rat chow for 10-13 weeks. PMZ and BISI-51had high oral CL and Vd with half lives of less that 4 h. Obesity impacted the PK parameters of PMZ by reducing the oral CL and Vd significantly. However, obesity lacked an effect on BISI-51 PK. In line with in vivo estimates, in vitro BISI-51 had faster intrinsic CL and shorter half-life than PMZ. While BISI-51 had a faster CL in rats, its potency was retained in murine models where it was given as repeated doses.</p>