Vol. 289, Issue 1, 93-102, April 1999

Pharmacokinetic Analysis of the Cardioprotective Effect of 3-(2,2,2-Trimethylhydrazinium) Propionate in Mice: Inhibition of Carnitine Transport in Kidney¹

Masamichi Kuwajima, Hideyoshi Harashima, Miyuki Hayashi, Saori Ise, Masako Sei, Kang-mo Lu, Hiroshi Kiwada, Yuichi Sugiyama and Kenji Shima

Department of Laboratory Medicine, School of Medicine (M.K., M.H., M.S., K.L., K.S.) and Faculty of Pharmaceutical Sciences (H.H., S.I., H.K.), The University of Tokushima, Japan; and Faculty of Pharmaceutical Sciences, University of Tokyo, Japan, (Y.S.)

The site of action of 3-(2,2,2-trimethylhydrazinium) propionate (THP), a new cardioprotective agent, was investigated in mice and rats. I.p. administration of THP decreased the concentrations of free carnitine and long-chain acylcarnitine in heart tissue. In isolated myocytes, THP inhibited free carnitine transport with a K_i of 1340 µM, which is considerably higher than the observed serum concentration of THP. The major cause of the decreased free carnitine concentration in heart was found to be the decreased serum concentration of free carnitine that resulted from the increased renal clearance of carnitine by THP. The estimated K_i of THP for inhibiting the reabsorption of free carnitine in kidneys was 52.2 µM, which is consistent with the serum THP concentration range. No inhibition of THP on the carnitine palmitoyltransferase activity in isolated mitochondrial fractions was observed. These results indicate that the principal site of action of THP as a cardioprotective agent is the carnitine transport carrier in the kidney, but not the carrier in the heart.