Guys and St Thomas NHS Hospitals Foundation Trust

London, United Kingdom

Guys and St Thomas NHS Hospitals Foundation Trust

London, United Kingdom

Time filter

Source Type

Blaker P.A.,Guys and St Thomas NHS Hospitals Foundation Trust | Arenas-Hernandez M.,Guys and St Thomas NHS Hospitals Foundation Trust | Smith M.A.,Guys and St Thomas NHS Hospitals Foundation Trust | Shobowale-Bakre E.A.,Guys and St Thomas NHS Hospitals Foundation Trust | And 4 more authors.
Biochemical Pharmacology | Year: 2013

Up to 1/5 of patients with wildtype thiopurine-S-methyltransferase (TPMT) activity prescribed azathioprine (AZA) or mercaptopurine (MP) demonstrate a skewed drug metabolism in which MP is preferentially methylated to yield methylmercaptopurine (MeMP). This is known as thiopurine hypermethylation and is associated with drug toxicity and treatment non-response. Co-prescription of allopurinol with low dose AZA/MP (25-33%) circumvents this phenotype and leads to a dramatic reduction in methylated metabolites; however, the biochemical mechanism remains unclear. Using intact and lysate red cell models we propose a novel pathway of allopurinol mediated TPMT inhibition, through the production of thioxanthine (TX, 2-hydroxymercaptopurine). In red blood cells preincubated with 250 mM MP for 2 h prior to the addition of 250 mM TX or an equivalent volume of Earle's balanced salt solution, there was a significant reduction in the concentration of MeMP detected at 4 h and 6 h in cells exposed to TX (4 h, 1.68, p = 0.0005, t-test). TX acts as a direct TPMT inhibitor with an apparent Ki of 0.329 mM. In addition we have confirmed that the mechanism is relevant to in vivo metabolism by demonstrating raised urinary TX levels in patients receiving combination therapy. We conclude that the formation of TX in patients receiving combination therapy with AZA/MP and allopurinol, likely explains the significant reduction of methylated metabolites due to direct TPMT inhibition. © 2013 Elsevier Inc. All rights reserved.


PubMed | Guys and St Thomas NHS Hospitals Foundation Trust
Type: Journal Article | Journal: Biochemical pharmacology | Year: 2013

Up to 1/5 of patients with wildtype thiopurine-S-methyltransferase (TPMT) activity prescribed azathioprine (AZA) or mercaptopurine (MP) demonstrate a skewed drug metabolism in which MP is preferentially methylated to yield methylmercaptopurine (MeMP). This is known as thiopurine hypermethylation and is associated with drug toxicity and treatment non-response. Co-prescription of allopurinol with low dose AZA/MP (25-33%) circumvents this phenotype and leads to a dramatic reduction in methylated metabolites; however, the biochemical mechanism remains unclear. Using intact and lysate red cell models we propose a novel pathway of allopurinol mediated TPMT inhibition, through the production of thioxanthine (TX, 2-hydroxymercaptopurine). In red blood cells pre-incubated with 250 M MP for 2h prior to the addition of 250 M TX or an equivalent volume of Earles balanced salt solution, there was a significant reduction in the concentration of MeMP detected at 4h and 6h in cells exposed to TX (4 h, 1.68, p=0.0005, t-test). TX acts as a direct TPMT inhibitor with an apparent Ki of 0.329 mM. In addition we have confirmed that the mechanism is relevant to in vivo metabolism by demonstrating raised urinary TX levels in patients receiving combination therapy. We conclude that the formation of TX in patients receiving combination therapy with AZA/MP and allopurinol, likely explains the significant reduction of methylated metabolites due to direct TPMT inhibition.

Loading Guys and St Thomas NHS Hospitals Foundation Trust collaborators
Loading Guys and St Thomas NHS Hospitals Foundation Trust collaborators