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

  1. Masamichi Kuwajima1,
  2. Hideyoshi Harashima2,
  3. Miyuki Hayashi1,
  4. Saori Ise2,
  5. Masako Sei1,
  6. Kang-mo Lu1,
  7. Hiroshi Kiwada2,
  8. Yuichi Sugiyama3 and
  9. Kenji Shima1
  1. 1Department of Laboratory Medicine, School of Medicine (M.K., M.H., M.S., K.L., K.S.) and 2Faculty of Pharmaceutical Sciences (H.H., S.I., H.K.), The University of Tokushima, Japan; and 3Faculty of Pharmaceutical Sciences, University of Tokyo, Japan, (Y.S.)

    Abstract

    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 Kiof 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 estimatedKi 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.

    Footnotes

    • Send reprint requests to: Dr. Masamichi Kuwajima, M.D., Ph.D., Department of Laboratory Medicine, School of Medicine, The University of Tokushima, 3–18-15 Kuramoto-cho, Tokushima, 770-8503 Japan.

    • ↵1 This work was partly supported by grants-in-aid from the Ministry of Education, Science, and Culture of Japan.

    • Abbreviations:
      THP
      3-(2,2,2-trimethylhydrazinium)propionate
      CPT
      carnitine palmitoyltransferase
      BME
      Basal Medium Eagle
      fp
      unbound fraction of free carnitine
      Kp
      heart to serum concentration ratio
      Cthp
      concentration of THP in serum or medium
      Ccar
      concentration of free carnitine in serum or medium
      GFR
      glomerular filtration rate
      CLr
      renal clearance of free carnitine
      FBS
      fetal bovine serum
      • Received June 30, 1998.
      • Accepted October 28, 1998.
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    1. JPET April 1, 1999 vol. 289 no. 1 93-102
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