View source for Phenotype:TPMT intermediate metabolizer

A '''TPMT intermediate metabolizer''' (IM) is a person who carries one normal-function and one no-function ''TPMT'' allele, and therefore has reduced but not absent thiopurine S-methyltransferase activity. It is one of the three metabolizer phenotypes assigned from ''TPMT'' genotype, sitting between the [[Phenotype:TPMT poor metabolizer|poor metabolizer]] and the [[Phenotype:TPMT normal metabolizer|normal metabolizer]]. TPMT has no rapid or ultrarapid phenotype. This page describes the intermediate-metabolizer phenotype; the enzyme itself is covered at [[Enzyme:TPMT]].

The intermediate metabolizer follows the same inverted logic as the poor metabolizer, in milder form. With one functioning ''TPMT'' allele, the competing methylation route is reduced but still operating, so a smaller-than-normal fraction of a thiopurine is diverted from the pathway that forms the cytotoxic 6-thioguanine nucleotides. The intermediate metabolizer therefore accumulates active thioguanine nucleotides to a degree that is meaningful, and clinically actionable, but well short of the poor metabolizer.

== Genotype basis ==
The intermediate-metabolizer phenotype is produced by a ''TPMT'' diplotype that pairs one normal-function allele with one no-function allele, for example ''\*1/\*2'', ''\*1/\*3A'', or ''\*1/\*3C''. The four clinically important no-function alleles, ''\*2'', ''\*3A'', ''\*3B'', and ''\*3C'', are described on the [[Enzyme:TPMT]] page.

== Population frequency ==
The TPMT intermediate-metabolizer phenotype is found in roughly 3 to 14% of most populations, far more common than the poor-metabolizer phenotype because it requires only a single no-function allele.

== Clinical consequences ==
For the thiopurine medicines [[Azathioprine|azathioprine]], [[Mercaptopurine|mercaptopurine]], and [[Thioguanine|thioguanine]], the Clinical Pharmacogenetics Implementation Consortium recommends that a TPMT intermediate metabolizer start at a reduced dose, in the range of roughly 30 to 80% of the standard dose, with blood-count monitoring and upward titration as tolerated. This is a meaningful reduction but far less drastic than the roughly 10% dose advised for the poor metabolizer.<ref name="relling2019">Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. ''Clinical Pharmacology and Therapeutics''. 2019 May;105(5):1095-1105. PMID: 30447069.</ref>

As for the poor metabolizer, two points apply. ''TPMT'' should be tested together with the parallel gene [[Enzyme:NUDT15|NUDT15]], because NUDT15 produces the same thiopurine-myelosuppression phenotype with a nearly complementary ancestry distribution. And co-prescription of [[Allopurinol|allopurinol]] intensifies thiopurine toxicity regardless of TPMT phenotype and must be accounted for.

== See also ==
* [[Enzyme:TPMT]], the enzyme, its history, and the inverted-logic explanation in full.
* [[Phenotype:TPMT poor metabolizer]], [[Phenotype:TPMT normal metabolizer]], the sibling phenotypes.
* [[Enzyme:NUDT15]], the parallel thiopurine-safety gene.
* [[Azathioprine]], [[Mercaptopurine]], [[Thioguanine]] (the entire clinical TPMT substrate set).
* [[:Category:Pharmacogenomic phenotypes]]

== References ==

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[[Category:Pharmacogenomic phenotypes]]