Disposal of alpha-ketoisocaproate: roles of liver, gut, and kidneys.
The alpha-keto analogues of the branched-chain amino acids, and particularly that of leucine, alpha-ketoisocaproate (KIC), have been found to reduce urea synthesis and as a result have been proposed for the treatment of uremia and portal systemic encephalopathy. Because little is known about the fate of these keto acids in the intact animal, we examined the disposal of a KIC load in five conscious overnight-fasted dogs with catheters previously implanted in an artery, and in the portal, hepatic, and renal veins. During the absorptive period (54 +/- 9 min; range, 20-75 min), 62 +/- 5% of the administered load (6,358 +/- 662 mumol) of the keto acid was absorbed as KIC and 23 +/- 3% was transaminated across the gut and entered as leucine. The hepatic uptake of KIC was equivalent to 35 +/- 5% (2.316 +/- 419 mumol) of the administered load, and of that, one-third was transaminated to leucine and two-thirds were converted to ketone bodies. The splanchnic output of KIC amounted to 1,732 +/- 256 mumol of 27 +/- 2% of the administered load, half of which was transaminated across the kidneys to leucine. As a result, the amount of KIC reaching the extrahepatic extrarenal tissues as KIC carbon amounted to 15% of the load administered. We conclude that the majority of an intragastrically administered KIC load reaches the (extrarenal) peripheral tissues in the form of leucine or ketone bodies. The study also underscores the importance of the "gut," the kidneys, and the liver in metabolism of the absorbed KIC load.
D000597:Amino Acids, Branched-Chain / Q000097:blood; D000818:Animals; D001158:Arteries; D004285:Dogs; D005260:Female; D005934:Glucagon / Q000097:blood; D007328:Insulin / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism*; D007651:Keto Acids / Q000032:analysis / Q000378:metabolism*; D007657:Ketone Bodies / Q000096:biosynthesis / Q000097:blood; D007668:Kidney / Q000378:metabolism*; D007930:Leucine / Q000032:analysis; D008099:Liver / Q000378:metabolism*; D008297:Male
D000597:Amino Acids, Branched-Chain; D007328:Insulin; D007651:Keto Acids; D007657:Ketone Bodies; C013082:alpha-ketoisocaproic acid; D005934:Glucagon; D007930:Leucine