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 poor metabolizer and the 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, mercaptopurine, and 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.

As for the poor metabolizer, two points apply. TPMT should be tested together with the parallel gene NUDT15, because NUDT15 produces the same thiopurine-myelosuppression phenotype with a nearly complementary ancestry distribution. And co-prescription of 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