Oral Communication 2, Monday Sept. 24th 3.30 pm-4.30 pm; Room: Lecture Hall 2: Internal medicine and basic sciences--Part 1

Presentation OC2-1 Investigating the effects of acetaldehyde on the gastro-intestinal oligopeptide transporter, PEPT1 Fisher SJ, Lee IJ, Swaan PW, Eddington ND (USA) Aims. The effects of alcohol consumption and its subsequent metabolism on drug transport, absorption and pharmacokinetics are poorly understood. We seek to examine the effects of acetaldehyde (AcH) on the clinically relevant drug transporter, PEPT1. Our hypothesis is that the in vivo metabolism of ethanol and the following acetaldehyde formation modulates the uptake capacity of PEPT1 within the gastro-intestinal tract, for a variety of clinically important peptidomimetic drug compounds. Methods. We have made use of Glycylsarcosine ([sup]3H-GlySar), a non-hydrolysable PEPT1 specific substrate, in our studies. In vitro uptake studies were performed in the CHO-hPEPT1 and Caco-2 cell models, measuring cellular uptake of labeled compound against increasing levels of unlabeled compound in the presence of acetaldehyde. In vivo absorption of [sup]3H-GlySar was measured in Aldh2 knockout mice and in Sprague-Dawley rats that were treated with oral dose of ethanol (5 g/kg) for periods of either two or six days, respectively. These results were compared to control mice or rats treated with ethanol or saline. Results. In vitro uptake of [sup]3H-GlySar in CHO-hPEPT1 cells treated with 1 mM AcH was significantly decreased (p < 0.05) as compared to untreated controls, 17.8 ± 0.6 and 33.7 ± 1.6 nmol/mg/30 min, respectively. The uptake of [sup]3H-GlySar in Caco-2 cell monolayers treated with 1 mM AcH was also significantly decreased as compared to the untreated control cells, 1598.3 ± 442.3 110.7 ± 5.2 and pmol/mg/30 min, respectively. In vivo absorption of [sup]3H-GlySar in ethanol treated rats, as measured by AUC0-12 hr were found to be 2-fold lower 34.6 ± 4.0μCi*min/ml) vs the control rat group (67.3 ± 1.9 μCi*min/ml). Acetaldehyde treatment of Aldh2 KO mice was found to significantly (p < 0.05) lower the gastrointestinal uptake of [sup]3H-GlySar at 60 minutes. Plasma levels of [sup]3HGlySar were 10-fold lower in KO mice as compared to control mice, 4.0 ± 0.7 nCi/ml and 40.4 ± 7.9 nCi/ml, respectively. Conclusions. The effects of acetaldehyde due to consumption of ethanol on the uptake and bioavailability of therapeutic drug compounds transported by the PEPT1 oligopeptide transporter have not been documented. In the present studies, we demonstrate that acetaldehyde significantly modulates PEPT1 function and,