Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing - PubMed (original) (raw)

Practice Guideline

Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing

M V Relling et al. Clin Pharmacol Ther. 2011 Mar.

Erratum in

Clin Pharmacol Ther. 2011 Dec;90(6):894

Abstract

Thiopurine methyltransferase (TPMT) activity exhibits monogenic co-dominant inheritance, with ethnic differences in the frequency of occurrence of variant alleles. With conventional thiopurine doses, homozygous TPMT-deficient patients (~1 in 178 to 1 in 3,736 individuals with two nonfunctional TPMT alleles) experience severe myelosuppression, 30-60% of individuals who are heterozygotes (~3-14% of the population) show moderate toxicity, and homozygous wild-type individuals (~86-97% of the population) show lower active thioguanine nucleolides and less myelosuppression. We provide dosing recommendations (updates at http://www.pharmgkb.org) for azathioprine, mercaptopurine (MP), and thioguanine based on TPMT genotype.

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Conflict of interest statement

CONFLICT OF INTEREST

W.E.E. and M.V.R. have received patent royalties from TPMT genotyping tests. The other authors declared no conflict of interest.

Figures

Figure 1

Azathioprine (Aza), mercaptopurine (MP), and thioguanine (TG) are all prodrugs that are inactivated by thiopurine methyltransferase (TPMT). All three agents give rise to the same active thioguanine nucleotide (TGN) metabolites. Methylthioinosine monophosphate (MeTIMP) is a form of methylmercaptopurine nucleotide (MeMPN) which also has some activity (see text) and is formed from the secondary metabolite thioinosine monophosphate (TIMP). GMPS, guanosine monophosphate synthetase; HPRT1, hypoxanthine phosphoribosyltransferase; IMPDH1, inosine monophospate dehydrogenase; TGMP, thioguanosine monophosphate; TXMP, thioxanthosine monophosphate.

References

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Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing - PubMed (original) (raw)