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Pharmacological Studies of the Antitumor Agent 6-Methylthiopurine Ribonucleoside¹

The University of Texas, M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77025

The distribution of 6-methylthiopurine ribonucleoside (MMPR) and its metabolites was studied in BDF/1 mice after a single i.p. injection of MMPR-³⁵S. One hr following the administration of MMPR, almost one-half of the administered radioactivity could be accounted for in the liver and red blood cells, with 7% in the intestinal mucosa and very small amounts in the kidney, spleen, and plasma. Almost all of the radioactivity in these tissues could be accounted for as MMPR and its 5'-monophosphate, 6-methylthiopurine ribonucleotide (MMPR-P). The biological half-time of the total radioactivity in the different tissues varied from 10 to 18 hr. The disappearance rate for the unchanged drug, MMPR, or the metabolite, MMPR-P, was parallel to that of the total radioactivity. In red blood cells, all of the radioactivity was in the form of MMPR-P. There was progressively less MMPR-P and more MMPR in the liver, kidney, and intestinal mucosa.

Adenosine kinase and purine nucleotide phosphohydrolase (MMPR-P to MMPR) activities were determined in a variety of human and mouse tissues. There was some correlation between the uptake of MMPR and the ratios of MMPR-P to MMPR and adenosine kinase to phosphohydrolase activity in mouse tissues. With one exception, the enzyme activities for the tissues studied were very similar for the mouse and man. The exception is the extremely high phosphohydrolase activity in the mouse kidney.

The urinary excretion of MMPR and its metabolites following MMPR-³⁵S administration was studied in mouse and man. Approximately 40% of the total radioactivity was excreted in 24 hr in the mouse, compared to 37% in man. There were 6 products in the urine of mouse, but only three were found in man. The major identified products were MMPR and inorganic sulfate, and little or no MMPR-P could be detected in the urine of either species. As early as 2 hr following MMPR-³⁵S injection, an appreciable amount of inorganic sulfate could be detected in the urine of both mouse and man, and the sulfate excretion increased steadily with time. However, the rate of sulfate excretion was faster in man, and, at 4 hr, 80% of the excreted radioactivity was inorganic sulfate. This level was maintained for at least 5 days.

The pharmacological studies of MMPR in the mouse and in man are compared and discussed.

¹ This investigation was supported in part by Contract PH 43-67-1156 and Grant CA 05831 from the National Cancer Institute, Bethesda, Md.

Received 6/15/70. Accepted 8/ 6/70.