Excretion and Metabolism of Propionyl-l-carnitine in the Isolated Perfused Rat Kidney
- 1School of Pharmacy and Medical Sciences (A.M.E.), 2University of South Australia, Adelaide, South Australia, and Sigma Tau SpA (A.M., A.L.), Pomezia, Rome, Italy
Abstract
Propionyl-l-carnitine (PLC) is an ester ofl-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-CD3represented 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.
Footnotes
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Send reprint requests to: Dr. Allan M. Evans, School of Pharmacy and Medical Sciences, University of South Australia, North Terrace, Adelaide, South Australia, 5000.
- Abbreviations:
- PLC
- propionyl-l-carnitine
- LC
- l-carnitine
- ALC
- acetyl-l-carnitine
- PLC-CD3
- propionyl-l-[N-methyl-D3]carnitine HCl
- ALC-CD3
- acetyl-l-[N-methyl-D3]carnitine HCl
- LC-CD3
- l-[N-methyl-D3]carnitine
- 14C-PLC
- propionyl-l-[N-methyl-14C]carnitine HCl
- CLT
- renal total clearance
- CLR
- apparent renal (excretory) clearance
- CLM
- renal metabolic (non-excretory) clearance
- fu
- fraction unbound in perfusate
- IPK
- isolated perfused rat kidney
- GFR
- glomerular filtration rate
- %TR
- percent tubular reabsorption
- HPLC
- high performance liquid chromatography
- MS
- mass spectrometry
- ANOVA
- analysis of variance
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- Received August 7, 1996.
- Accepted February 3, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
