Pharmacokinetic analysis of the cardioprotective effect of 3-(2,2,2-trimethylhydrazinium) propionate in mice: Inhibition of carnitine transport in kidney

The site of action of 3-(2,2,2-trimethylhydrazinium) propionate (THP), a ne w cardioprotective agent, was investigated in mice and rats. l.p. administr ation of THP decreased the concentrations of free carnitine and long-chain acylcarnitine in heart tissue, In isolated myocytes, THP inhibited free car nitine transport with a Ki of 1340 mu M, which is considerably higher than the observed serum concentration of THP. The major cause of the decreased f ree carnitine concentration in heart was found to be the decreased serum co ncentration of free carnitine that resulted from the increased renal cleara nce of carnitine by THP. The estimated K-i of THP for inhibiting the reabso rption of free carnitine in kidneys was 52.2 mu M, which is consistent with the serum THP concentration range. No inhibition of THP on the carnitine p almitoyltransferase activity in isolated mitochondrial fractions was observ ed. These results indicate that the principal site of action of THP as a ca rdioprotective agent is the carnitine transport carrier in the kidney, but not the carrier in the heart.