6-Mercaptopurine: Total Body Autoradiograms and Plasma Concentration-Time Curves of 6MP and Metabolites from Marmoset Monkeys

Schouten, Teunis J.; Abreu, Ronney A. De; Schretlen, E. D. A. M.; Vaan, G. A. M. de; Kleijn, Eppo van der

doi:10.3109/08880018609031212

Cited by 4 publications

(1 citation statement)

References 7 publications

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“…When marmoset monkeys were given radioactive 6-MP, radioactivity was detected in liver, bile, intestinal content, central nervous system, and bone marrow, whereas mice treated with radioactive 6-MP had radioactivity in blood, kidney, lung, liver, gut, spleen, sternum, and brain (Elion et al, 1954;Schouten et al, 1986). Similarly, radioactivity was detected in blood, kidney, lung, heart, liver, small intestine, spleen, and leg muscle of mice given radioactive 6-TG (Moore and LePage, 1958).…”

Section: Discussionmentioning

confidence: 99%

DISTINCT TISSUE DISTRIBUTION OF METABOLITES OF THE NOVEL GLUTATHIONE-ACTIVATED THIOPURINE PRODRUGSCIS-6-(2-ACETYLVINYLTHIO)PURINE ANDTRANS-6-(2-ACETYLVINYLTHIO)GUANINE AND 6-THIOGUANINE IN THE MOUSE

Gunnarsdottir¹,

Elfarra²

2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The compounds cis-6-(2-acetylvinylthio)purine (cis-AVTP) and trans-6-(2-acetylvinylthio)guanine (trans-AVTG) are glutathioneactivated prodrugs of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), respectively, that have comparable or lower IC 50 values in tumor cells than 6-MP and 6-TG. Previously, we showed that cis-AVTP-and trans-AVTG-treated mice exhibited less bone marrow and intestinal toxicity and excreted a lower fraction of the administered dose in urine than did mice treated with equivalent 6-TG doses. To explain these results, the tissue distribution and levels of metabolites of cis-AVTP, trans-AVTG, and 6-TG were examined at 15, 30, and 45 min after i.p. treatment of mice with equimolar doses of these compounds. After prodrug treatment, the thiopurines, the corresponding thiopurine ribosides and nucleotides, thioxanthine (TX), and thiouric acid (TU) were quantitated in plasma, red blood cells, liver, and intestine. Thiopurine and thiopurine riboside and nucleotide area under the curve between 15 and 45 min [AUC (15-45) ] values were generally comparable after cis-AVTP and trans-AVTG treatments but were lower than those after 6-TG treatment. A higher liver/plasma metabolite ratio was evident after trans-AVTG treatment than after cis-AVTP or 6-TG treatments, which exhibited similar liver/plasma ratios. Treatment with cis-AVTP yielded the highest AUC (15-45) for TX and TU in plasma, liver, and intestine. Prodrug treatment did not change the concentration of reduced or oxidized glutathione in tissue homogenates. Collectively, these results show distinct patterns of metabolites depending upon the compound used and suggest that differences in metabolite levels and composition after cis-AVTP, trans-AVTG, and 6-TG treatments may partially explain the different toxicity and urinary metabolite excretion profiles previously observed among cis-AVTP, trans-AVTG, and 6-TG.

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Section: Discussionmentioning

confidence: 99%

DISTINCT TISSUE DISTRIBUTION OF METABOLITES OF THE NOVEL GLUTATHIONE-ACTIVATED THIOPURINE PRODRUGSCIS-6-(2-ACETYLVINYLTHIO)PURINE ANDTRANS-6-(2-ACETYLVINYLTHIO)GUANINE AND 6-THIOGUANINE IN THE MOUSE

Gunnarsdottir¹,

Elfarra²

2003

Drug Metab Dispos

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6-Mercaptopurine: high-dose 24-h infusions in goats

Schouten¹,

Abreu²,

Schretlen³

et al. 1986

J Cancer Res Clin Oncol

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In vitro investigations have indicated the need for both prolonged exposure to 6-mercaptopurine (6MP) and the use of high concentrations to achieve maximal cell kill. After the customary oral administration the bioavailability of 6MP appeared to be low, and i.v. bolus injections resulted in short-lived high concentrations of 6MP, so prolonged infusions seemed rational. To test the feasibility of this approach 24-h infusions were given to goats. We used our improved HPLC method to quantitate 6MP and 6MP riboside (6MPR) in plasma, CSF, and urine. The concentrations of 6MPR were in excess of those of 6MP. Since 6MPR can easily be converted to 6MP, 6MPR acts as a depot for 6MP. Penetration of both 6MP and 6MPR into CSF was excellent. Of the total dose administered, 38% to 68% could be accounted for in the urine, with about equal amounts of 6MP and 6MPR. At doses of 20 and 10 mg kg-1 h-1 total concentrations of 6MP and 6MPR in excess of 100 microM were reached during 24-h infusions. However, all three experimental animals died due to toxicity. A dose of 2 mg kg-1 h-1 was tolerated; the total steady state concentration of 6MP and 6MPR in two experiments was about 10 microM. We conclude that the prolonged infusion of 6MP is feasible, and in view of the excellent penetration of 6MP and 6MPR into CSF, studies using prolonged infusions of thiopurines are warranted in man.

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6-Thioguanine: High-dose 2-H infusions in goats

Schouten¹,

Abreu²,

Schretlen³

et al. 1985

J Cancer Res Clin Oncol

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6-Thioguanine (6TG) is poorly absorbed after oral administration. Bolus injections of 6TG result in high peak concentrations with relatively short-lived plasma concentrations. In vitro studies have shown the importance of prolonged exposure to 6TG. Therefore we administered 6TG by infusion at a dose rate of 2 mg/h over 2 h. In three goats we determined the plasma concentration-time curves of 6TG and its riboside (6TGR). A steady state was reached for 6TG and was almost reached for 6TGR within the 2 h of infusion. In one experiment we obtained several samples of CSF and observed good penetration of 6TG and 6TGR into CSF. Urinary excretion of 6TG and 6TGR was also quantitated. The amount of drug and metabolite excreted later than 4 h after the end of the infusion was negligible. By infusing 6TG, the problems of both erratic absorption after oral administration and acute renal toxicity after bolus injection, can be averted. In our opinion prolonged infusions of 6TG may be of advantage in humans suffering from actively proliferating malignant diseases, and thus should be studied.

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6-Mercaptopurine: Total Body Autoradiograms and Plasma Concentration-Time Curves of 6MP and Metabolites from Marmoset Monkeys

Cited by 4 publications

References 7 publications

DISTINCT TISSUE DISTRIBUTION OF METABOLITES OF THE NOVEL GLUTATHIONE-ACTIVATED THIOPURINE PRODRUGSCIS-6-(2-ACETYLVINYLTHIO)PURINE ANDTRANS-6-(2-ACETYLVINYLTHIO)GUANINE AND 6-THIOGUANINE IN THE MOUSE

DISTINCT TISSUE DISTRIBUTION OF METABOLITES OF THE NOVEL GLUTATHIONE-ACTIVATED THIOPURINE PRODRUGSCIS-6-(2-ACETYLVINYLTHIO)PURINE ANDTRANS-6-(2-ACETYLVINYLTHIO)GUANINE AND 6-THIOGUANINE IN THE MOUSE

6-Mercaptopurine: high-dose 24-h infusions in goats

6-Thioguanine: High-dose 2-H infusions in goats

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