Transport and metabolism of 6-thioguanine and 6-mercaptopurine in mouse small intestine

Bronk, J. R.; Lister, Norma; Shaw, M. I.

doi:10.1042/cs0740629

Cited by 18 publications

(7 citation statements)

References 16 publications

(9 reference statements)

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“…3 and 4; Table 1). The highest AUC value for inactive metabolites was obtained in the intestine that has high xanthine oxidase activity (Bronk et al, 1988). Because 6-MP is a substrate of xanthine oxidase, whereas 6-TG must be deaminated before it is oxidized by xanthine oxidase, the higher concentrations of inactive metabolites detected in the intestine after cis-AVTP treatment than after trans-AVTG or 6-TG treatments agree well with previously published results (Bronk et al, 1988).…”

Section: Discussionsupporting

confidence: 81%

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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: Discussionsupporting

confidence: 81%

“…Inactivation of the thiopurines occurs primarily through oxidation of 6-MP to form thiouric acid (TU) and deamination of 6-TG to yield thioxanthine (TX) that can be further oxidized to TU ( Fig. 2; Bronk et al, 1988).…”

mentioning

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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“…Loops of small intestine (from stomach to ileal–caecal valve) were perfused in single‐pass mode for 60 min as described previously (Bronk et al 1987, 1988; Lister et al 1995, 1997) and modified to include the entire small intestine. Viability was assessed by ability to maintain steady water flow and to actively transport d ‐glucose.…”

Section: Methodsmentioning

confidence: 99%

The regulation of K‐ and L‐cell activity by GLUT2 and the calcium‐sensing receptor CasR in rat small intestine

Mace¹,

Schindler²,

Patel³

2012

The Journal of Physiology

214

260

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Key points• In intestine, nutrients including glucose and amino acids and non-nutrients including bile acids increase secretion of anti-diabetic gut peptides such as gluco-insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY).• Facilitative glucose transporter pathways in addition to active electrogenic transporter pathways contribute to GIP, GLP-1 and PYY secretion; in particular, the facilitative glucose transporter 2 (GLUT2) is involved.• Sucralose, in the presence of glucose, can strongly and acutely upregulate GIP, GLP-1 and PYY secretion in a time scale of minutes.• Amino acid-stimulated GIP, GLP-1 and PYY secretion is acutely regulated by the calcium-sensing receptor (CasR).• The results establish new functions for GLUT2 and CasR as regulators of gut peptide secretion that sense nutrients and provide signalling pathways for the release of GIP, GLP-1 and PYY.Abstract Intestinal enteroendocrine cells (IECs) secrete gut peptides in response to both nutrients and non-nutrients. Glucose and amino acids both stimulate gut peptide secretion. Our hypothesis was that the facilitative glucose transporter, GLUT2, could act as a glucose sensor and the calcium-sensing receptor, CasR, could detect amino acids in the intestine to modify gut peptide secretion. We used isolated loops of rat small intestine to study the secretion of gluco-insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) secretion stimulated by luminal perfusion of nutrients or bile acid. Inhibition of the sodium-dependent glucose cotransporter 1 (SGLT1) with phloridzin partially inhibited GIP, GLP-1 and PYY secretion by 45%, suggesting another glucose sensor might be involved in modulating peptide secretion. The response was completely abolished in the presence of the GLUT2 inhibitors phloretin or cytochalasin B. Given that GLUT2 modified gut peptide secretion stimulated by glucose, we investigated whether it was involved in the secretion of gut peptide by other gut peptide secretagogues. Phloretin completely abolished gut peptide secretion stimulated by artificial sweetener (sucralose), dipeptide (glycylsarcosine), lipid (oleoylethanolamine), short chain fatty acid (propionate) and major rat bile acid (taurocholate) indicating a fundamental position for GLUT2 in the gut peptide secretory mechanism. We investigated how GLUT2 was able to influence gut peptide secretion mediated by a diverse range of stimulators and discovered that GLUT2 affected membrane depolarisation through the closure of K + ATP -sensitive channels. In the absence of SGLT1 activity (or presence of phloridzin), the secretion of GIP, GLP-1 and PYY was sensitive to K + ATP -sensitive channel modulators tolbutamide and diazoxide. L-Amino acids phenylalanine (Phe), tryptophan (Trp), asparagine (Asn), arginine (Arg) and glutamine (Gln) also stimulated GIP, GLP-1 and PYY secretion, which was completely abolished when extracellular Ca 2+ was absent. The gut peptide response stimulated by the amino acids...

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“…(Erb et al ., 1998; Lancaster et al ., 2001; Josefine et al ., 2009) Previous studies reported that 6‐TG bioavailability resembles 6‐MP bioavailability and varies between 5% and 37%, which is consistent with the exposure of 6‐TGN of 15% observed in this study. (Bronk et al ., 1988; Deibert et al ., 2003).…”

Section: Discussionmentioning

confidence: 99%

Biotransformation of 6‐thioguanine in inflammatory bowel disease patients: a comparison of oral and intravenous administration of 6‐thioguanine

Jharap

Boer

Vos

et al. 2011

British J Pharmacology

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Although 6-mercaptopurine and azathioprine are effective treatments in inflammatory bowel disease (IBD), many patients discontinue treatment because of side effects. 6-Thioguanine (6-TG) may be an alternative rescue therapy in these intolerant patients but the pharmacokinetics of 6-TG are not fully described. Here we have measured the pharmacokinetics of the biotransformation of 6-TG into the pharmacologically active metabolites, 6-thioguanine nucleotides (6-TGN), in IBD patients. EXPERIMENTAL APPROACHIn 12 patients with IBD, levels of 6-TGN and activities of thiopurine S-methyltransferase, xanthine oxidase and hypoxanthine guanine-phosphoribosyl-transferase were measured in a two-stage (i.v. and p.o. administration of 0.3 mg·kg -1 6-TG), prospective study. Median exposure of 6-TGN in red blood cells (RBC) was expressed as the ratio of the area under the curve (AUC) per mg 6-TG after i.v. dosing and that after p.o. dosing. KEY RESULTSThe median AUC per mg 6-TG was 1068 (p.o.) and 7184 (i.v.) pmol·h (8 ¥ 10 8 RBC). Median exposure of 6-TGN in RBC was 15% (9-28). Hypoxanthine guanine-phosphoribosyl-transferase activity correlated with peak 6-TGN and with AUC per mg (r = 0.7, P = 0.02 and r = 0.6, P = 0.03 respectively). Thiopurine S-methyltransferase activity was inversely related to AUC per mg (r = -0.8, P = 0.001), whereas that of xanthine oxidase was correlated with a lower peak 6-TGN (r = -0.7, P = 0.02).

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Transport and metabolism of 6-thioguanine and 6-mercaptopurine in mouse small intestine

Cited by 18 publications

References 16 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

The regulation of K‐ and L‐cell activity by GLUT2 and the calcium‐sensing receptor CasR in rat small intestine

Biotransformation of 6‐thioguanine in inflammatory bowel disease patients: a comparison of oral and intravenous administration of 6‐thioguanine

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