Vol. 281, Issue 3, 1071-1076, 1997

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

Allan M. Evans, Angelo Mancinelli and Antonio Longo

School of Pharmacy and Medical Sciences (A.M.E.), University of South Australia, Adelaide, South Australia, and Sigma Tau SpA (A.M., A.L.), Pomezia, Rome, Italy

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 µM (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 µM) and 94 ± 11 min (200 µM). The renal excretory clearance of PLC-CD₃ was significantly lower (P < .05, unpaired t test) at an initial concentration of 10 µM (45 ± 23 µl/min) than at 200 µM (85 ± 28 µl/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.