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Vol. 289, Issue 1, 224-230, April 1999

Decreased Tissue Distribution of L-Carnitine in Juvenile Visceral Steatosis Mice1

Koichi Yokogawa, Yasuhiko Higashi, Ikumi Tamai , Masaaki Nomura, Noriyoshi Hashimoto, Hiroko Nikaido, Jun-Ichiro Hayakawa, Ken-Ichi Miyamoto and Akira Tsuji

Department of Pharmacology and Pharmaceutics, Graduate School of Natural Science and Technology (K.Y., Y.H., M.N., K.-I.M.), Department of Pharmacobiodynamics, Faculty of Pharmaceutical Sciences (I.T., A.T). and Institute for Experimental Animals, School of Medicine (N.H., H.N., J.-I.H.), Kanazawa University, Kanazawa, Japan; and CREST, Japan Science and Technology Corporation, Kawaguchi, Japan (I.T., A.T.)

We kinetically analyzed the disposition of L-carnitine of juvenile visceral steatosis (JVS) mice compared with that of normal mice to elucidate the mechanism of the systemic L-carnitine deficiency of JVS mice. There were significant differences in the plasma concentration-time course of total radioactive carnitine (L-[3H]carnitine, [acetyl-3H]carnitine, and other [acyl-3H]carnitines) between normal and JVS mice after a single i.v. or p.o. administration of L-[3H]carnitine (250 ng/kg). The oral bioavailability of L-[3H]carnitine in JVS mice (0.341) was about half of that in normal mice (0.675). The cumulative urinary excretion of total radioactive carnitine in JVS mice was about 10-fold more than that in normal mice, and the total clearance of unchanged L-[3H]carnitine for JVS mice (6.70 ml/min) was significantly higher than that for normal mice (2.45 ml/min). The distribution volume at the steady state of unchanged L-[3H]carnitine in JVS mice (1.10 liters/kg) was significantly smaller than that in normal mice (8.16 liters/kg). At 4 h after an i.v. administration, the apparent tissue-to-plasma concentration ratios of unchanged L-[3H]carnitine for various tissues of JVS mice, except for brain, were about one half to one 20th of those in normal mice. In conclusion, this in vivo disposition kinetic study of L-carnitine supports the previous in vitro finding that the L-carnitine transporter is absent or functionally deficient in JVS mice because the renal reabsorption, the intestinal absorption, and the apparent tissue-to-plasma concentration ratios in JVS mice are significantly lower than those in normal mice. The JVS mouse should be a useful experimental model for studying carnitine deficiency diseases.

0022-3565/99/2891-0224$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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