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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Uptake of L-Carnitine and Its Short-Chain Ester Propionyl-L-carnitine in the Isolated Perfused Rat Liver

Sigma-Tau SpA, Pomezia, Rome, Italy (A.M., A.L.); Centre for Pharmaceutical Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia (A.M.E.); and Department of Pharmacy Practice, Victorian College of Pharmacy, Monash University, Melbourne, Victoria, Australia (R.L.N.)

Hepatic uptake of propionyl-L-carnitine (PLC) and L-carnitine (LC) was assessed with the impulse-response technique in the single-pass perfused rat liver. The experiments involved a rapid injection (impulse) of a mixture of the radiolabeled test compound (PLC or LC) and a reference compound (sucrose) into portal vein inflow and collection and radiochemical analysis (response) of the venous outflowing perfusate samples. The impulse injection was made in the presence of increasing unlabeled background concentrations of PLC (0–50 µM) or LC (50–500 µM) perfusing the liver. The hepatic uptake was minimal or negligible for LC, whereas the hepatic influx clearance was found to be low (0.095 ml/s equivalent to 5.7 ml/min) for PLC relative to the perfusate flow rate (30 ml/min). When background concentrations of PLC were increased (from 1–50 µM), the influx clearance was reduced in a concentration-dependent behavior, indicating partial saturation of the entry of compound into hepatocytes. PLC was taken up into hepatocytes via a unidirectional transport process with negligible efflux. The hepatic uptake of PLC was significantly reduced in the presence of unlabeled LC (500 µM), indicating an inhibition of the sinusoidal membrane transport of PLC by LC. The study showed the sinusoidal membrane is a permeability barrier to the entry of PLC and LC into hepatocytes, and it is the site of a common carrier-mediated transporter for both compounds.

Address correspondence to: Angelo Mancinelli, Sigma-Tau SpA, Via Pontina Km 30,400, Pomezia (Rome), Italy, 00040. E-mail: angelo.mancinelli{at}sigma-tau.it