0090-9556/97/2507-0798-0804$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 7

Cellular Uptake of ³H-Bestatin in Tissues of Mice after Its Intravenous Injection

Oscar A. Scornik and Violeta Botbol

Department of Biochemistry, Dartmouth Medical School

Bestatin, a dipeptide analog, is a potent aminopeptidase inhibitor of bacterial origin. We have previously shown that bestatin inhibits cytosolic exopeptidases in mammalian cells, and results in the accumulation of di- and tripeptide intermediates in cellular protein degradation. Our primary interest is the uptake of bestatin in liver and muscle, 10 min after its intravenous injection into mice. In this short interval, peptide intermediates accumulate linearly in these tissues and permit an estimate of their rates of cellular protein breakdown. Male, CD-1 adult mice received the intravenous injection of ³H-bestatin and ¹⁴C-sucrose. The disappearance of ³H-bestatin from the plasma, when normalized by the injected radioactivity, was indistinguishable from that of ¹⁴C-sucrose. They both drop rapidly during the first 10 min after the injection, followed by a slower exponential disappearance of 3.4% per min, which extrapolates to an apparent volume of distribution of 25 ml/100 g body weight. In two mice, 3 hr after the injection, the urine contained 77.4% and 79.8% of the injected ¹⁴C-sucrose, and 70.9% and 73.9% of the injected ³H-bestatin. Other mice were killed 10 min after the injection of 5 mg of bestatin, and the concentration of ³H-bestatin and ¹⁴C-sucrose was determined in the plasma and various tissues. Using sucrose as a nonpermeant marker of the extracellular space, extracellular ³H-bestatin was calculated and subtracted from the total to estimate the cellular uptake of bestatin. Bestatin was taken up readily in the liver (383-452 µg/g), kidneys (175-191 µg/g), and intestine (137-179 µg/g), but much less in red cells (11 µg/g) or skeletal muscle (4.8 µg/g). Bestatin also entered slowly into erythrocytes in vitro (0.3%/min) by a nonsaturable process. It is suggested that bestatin is taken up through transporter-mediated processes in some cells but not others.