Excretion and Metabolism of Propionyl-L-carnitine in the Isolated Perfused Rat Kidney

Propionyl-L-carnitine (PLC) is an ester of L-carnitine (LC) under evaluation for the treatment of cardiovascular disorders. The renal disposition of PLC was studied in the isolated perfused rat kidney with deuterium-labeled derivative (PLC-CD3). Kidneys of male Sprague-Dawley rats were perfused at initial PLC-CD3 concentrations of 10 (n = 4) and 200 microM (n = 5). High-performance liquid chromatography/mass spectrometry was used to quantify PLC-CD3, deuterated L-carnitine (LC-CD3) and acetyl-L-carnitine (ALC-CD3) in perfusate and urine. PLC-CD3 in perfusate decreased in a monoexponential manner with a half-life of 90 +/- 24 min (S.D.) (10 microM) and 94 +/- 11 min (200 microM). The renal excretory clearance of PLC-CD3 was significantly lower (P < .05, unpaired t test) at an initial concentration of 10 microM (45 +/- 23 microl/min) than at 200 microM (85 +/- 28 microl/min), but in both cases it was substantially less than the glomerular filtration rate, which indicates extensive tubular reabsorption. The renal excretory clearance of PLC-CD3 represented less than 6% of the total clearance, which suggests that metabolism is the major renal elimination route for this compound. The appearance in perfusate and urine of LC-CD3 and ALC-CD3 provided additional evidence for a metabolic role of the kidney. The apparent renal excretory clearance values for these metabolites were always significantly higher than the values obtained for the corresponding endogenous compounds, which suggests that LC-CD3 and ALC-CD3, as formed metabolites, underwent passive or carrier-mediated movement directly into urine.