5: Thiopurine Methyltransferase Pharmacogenetics

Key Points

• Clinical utility of thiopurine methyltransferase analysis:

  • Various guidelines recommend pre-thiopurine therapy thiopurine methyltransferase (TPMT) assessment in managing chronic inflammatory conditions.

  • There is insufficient evidence base to recommend pretherapy TPMT assessment.

  • Decreased or absent TPMT activity is associated with increased risk of myelotoxicity and leukopenia in patients treated with thiopurine medications (azathioprine [AZA] or 6-mercaptopurine [6-MP]).

  • Decreased or absent TPMT activity is not associated with hepatitis or pancreatitis in patients treated with thiopurine medications (AZA or 6-MP).

  • Reduced or absent TPMT activity does not place patients at risk of disease.

• Medication(s) affected:

  • Thiopurine drugs AZA and 6-MP. Limited effects on 6-thioguanine (6-TG), as TPMT is not the major metabolic enzyme.

• Drug-related adverse events:

  • Thiopurine treatment may be associated with anemia, myelotoxicity and leukopenia, hepatitis, and pancreatitis.

• TPMT deficiency:

  • The presence of mutant TPMT alleles or decreased TPMT enzymatic activity increases the risk of thiopurine treatment-related myelotoxicity and leukopenia.

• Non-TPMT–associated myelosuppression:

  • Normal TPMT testing does not rule out all the risk of myelotoxicity for patients on thiopurine medications.

• Analytic methods:

  • Genotyping—most common mutant alleles (TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C) are routinely available through reference laboratories.

  • Enzymatic analysis—less commonly available, but is the preferred method as it will also detect rare mutations not identified by genetic screening. Recent blood transfusions (within 90 days) can produce incorrect results.

Thiopurine Drugs and Metabolic Pathway

Biochemistry

AZA, 6-MP, and 6-TG are thiopurine-based prodrugs that have no intrinsic biologic activity, and require extensive metabolism for activity (Fig. 5-1). After oral administration of AZA or 6-MP, between 27% and 83% is available as biologically active metabolites. AZA is often used clinically, as it is more stable and soluble than 6-MP. AZA doses are higher because the molecular weight of 6-MP is 55% of that of AZA.

In the gut, approximately 90% of AZA is converted to 6-MP, a thiopurine analogue of the purine base hypoxanthine, by cleavage of the imidazolyl moiety which is thought to be catalyzed through the action of glutathione transferase. 6-MP is then enzymatically converted to its active metabolite, deoxy-6-thioguanosine 5’ triphosphate (6-tGN), through successive enzymatic conversions by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine monophosphate dehydrogenase (IMPDH). Inactivation of 6-MP (and hence AZA) occurs primarily through S-methylation by thiopurine S-methyltransferase (TPMT), and to a minor degree by catabolism, to thiouric acid by xanthine oxidase (XO). 6-TG is converted to its active metabolite (6-tGN) in a single step involving HGPRT, while inactivation occurs through two pathways. The major ...