First-Pass Metabolism Limits the Intestinal Absorption of Enteral α-Ketoglutarate in Young Pigs

Abstract

Our results in a previous study indicated that the portal absorption of intragastrically fed alpha-ketoglutarate (AKG) was limited in young pigs. Our aim was to quantify the net portal absorption, first-pass metabolism, and whole-body flux of enterally infused AKG. In study 1, we quantified the net portal nutrient absorption in young pigs (n = 9) given an intraduodenal infusion of milk replacer [10 mL/(kg . h)] and either saline (control) or 930 micromol/(kg . h) AKG for 4 h. In study 2, we quantified the luminal disappearance of a duodenal AKG bolus in young pigs (n = 7). In study 3, we quantified the whole-body kinetics of (13)C-AKG metabolism when infused either enterally (n = 9) or intravenously (n = 9) in young pigs. In study 1, when compared with the control group, enteral AKG infusion increased (P < 0.01) the arterial (13.8 +/- 1.7 vs. 27.4 +/- 3.6 micromol/L) and portal (22.0 +/- 1.4 vs. 64.6 +/- 5.9 micromol/L) AKG concentrations and the net portal absorption of AKG [19.7 +/- 2.8 vs. 95.2 +/- 12.0 micromol/(kg . h)]. The mean fractional portal appearance of enterally infused AKG was 10.23 +/- 1.3%. In study 2, the luminal disappearance of AKG was 663 micromol/(kg . h), representing 63% of the intraduodenal dose. In study 3, the whole-body (13)C-AKG flux [4685 +/- 666 vs. 801 +/- 67 micromol/(kg . h)] was higher (P < 0.05) when given enterally than intravenously, but (13)CO(2) recovery was not different (37.3 +/- 1.0 vs. 36.2 +/- 0.7%dose). The first-pass splanchnic (13)C-AKG utilization was approximately 80%, of which 30% was oxidized to (13)CO(2). We conclude that the intestinal absorption of AKG is limited in young pigs largely due to substantial first-pass gastrointestinal metabolism.

Accelerated stability and bioassay of a new oralα-ketoglutarate formulation for treating cyanide poisoning

“…Previous study in rats showed that 2.0 g/kg a-KG produced a plasma C max of 36.9 mg/ml a-KG only, indicating that bioavailability of oral a-KG did not commensurate with the dose (Patra, 2005). Intestinal absorption of a-KG in pigs was reported to be very limited, possibly due to mucosal metabolism and substantial first-pass gastrointestinal metabolism (Buddington et al, 2004;Lambert et al, 2006). We also observed considerable gastric retention in animals and humans after oral administration of highly concentrated a-KG, but significant plasma a-KG levels could be achieved by $7-fold dilution of a-KG (Mittal et al, 2010).…”

Dietary supplementation with glutamate precursor α-ketoglutarate attenuates lipopolysaccharide-induced liver injury in young pigs

“…Because almost all of dietary glutamate is utilized by the pig small intestine in the first pass (Burrin and Stoll 2009;Wu 2009), it is a practical challenge to increase the availability of glutamate in extra-intestinal tissues (including the liver) directly through supplementation with glutamate to the enteral diet (Rezaei et al 2013b). In this regard, α-ketoglutarate, which is an effective precursor of glutamate (Hou et al 2011a) and can be absorbed in a significant quantity from the lumen of the gut into the portal circulation (Lambert et al 2002(Lambert et al , 2006, may provide a useful means to increase glutamate concentrations in extra intestinal tissues.…”

Enteral Pancreatic-like Enzymes of Microbial Origin affect Insulin Release during an Intravenous Glucose Tolerance Test

“…This could be achieved by using appropriate functional dietary supplements, which in turn could trigger alternative mechanisms of glucose assimilation. Results from previous studies in our lab have suggested that both pancreatic enzymes and AKG are involved in the regulation of blood glucose [2,3].…”

“…It was found that AKG, as well as digestive enzymes, interacts with enterocytes and is involved in amino acid biosynthesis, offering advantages in a catabolic state and thus may also affect the rate of gluconeogenesis in mucosa cells [2,21,34,[36][37][38]. On the other hand, AKG in enterocytes undergoes amination and appears in the plasma as glutamate [36] which may stimulate insulin exocytosis from β-cells in response to glucose stimulation [39].…”

“…Thus, we were interested to investigate whether exogenous digestive enzymes could alter glucose tolerance or insulin response in healthy pigs, especially during the growth period, using microbial enzymes, which mimic endogenous digestive pancreatic enzymes and are widely available. We also hypothesized that another potential supplement, α-ketoglutaric acid (AKG), could have an impact on post-loading glycaemic control, based on several previous reports [2,13,14]. An intravenous glucose tolerance test (IVGTT) was chosen as a convenient and appropriate method for testing the glucose-stimulated insulin response and capacity for blood glucose clearance [15].…”