Azathioprine undergoes extensive metabolism after administra

Azathioprine undergoes extensive metabolism after administration, which affects both its efficacy and safety. During azathioprine treatment, efficacy is not achieved in approximately 15–20% of cases and serious ADR leads to cessation of therapy in 9–28% of patients. Thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are two key caged compounds responsible for the metabolism of azathioprine. More than 25 TPMT polymorphisms exist (TPMT∗2–28), and both TPMT and ITPA polymorphisms differ within different races. However, only 29% of leukopenic patients had TPMT mutant polymorphism. Therefore, the relationship between these two gene polymorphisms and ADR is not conclusive. Polymorphisms in these two enzymes have been suggested to correlate with ARD and efficacy during azathioprine use but existing data is inconsistent. For example, the significance of ITPA polymorphism as proposed by Marinaki et al was not duplicated in two subsequent studies.
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Discussion ADR from azathioprine may be under reported in Taiwan. Although pretherapeutic screening of TPMT and ITPA polymorphisms has been recommended in patients treated with azathioprine in recent guidelines, a major portion of hematopoietic toxicity and/or hepatotoxicity is not predictable or cannot be avoided by genetic testing. The importance of TPMT and ITPA polymorphism seems to differ among Eastern versus Western people, and even in Asians. Azathioprine is a prodrug of 6-mercaptopurine (6-MP). The initial success in kidney transplantation in 1962 broadened its clinical applications thereafter. In dermatology, it is used for the treatment of various dermatoses. However, a high unresponsive rate and a wide range of ADR of azathioprine exist. Nausea and malaise are the most frequent dose-dependent ADR. Myelosuppression is also a dose-dependent ADR and was experienced in 5% of patients with IBD. After oral administration, azathioprine is absorbed almost completely by the gut. It is then converted nonenzymatically to 6-MP and then undergoes complex metabolism by three key competing enzymes. TPMT converts azathioprine to form inactive methyl-thiopurine metabolites. At least 28 TPMT allele polymorphisms have has been identified, with TPMT∗2, ∗3A, and ∗3C accounting for over 95% of the TPMT deficiency. TPMT∗3A (G460A and A719G) is frequently expressed in white Americans and South-West Asians. TPMT∗3C (A719G) is the only TPMT variant in the Chinese population and is also found in Ghanaian, Korean, and Japanese populations. The other variants are rare and may represent mutation rather than true polymorphism. TPMT activity can be categorized into high (88.6%, homozygous for wild-type alleles, TPMT ∗1/∗1), intermediate (11.1%, heterozygous for mutant allele, TPMT ∗1/∗2, ∗1/∗3A, ∗1/∗3B, ∗1/∗3C, ∗1/∗4), and undetectable (0.3%, homozygous or compound heterozygous for mutant alleles, TPMT ∗3A/∗3A, ∗2/∗3A, ∗3C/∗3A, ∗3C/∗4, ∗3C/∗2, ∗3A/∗4). Although a systematic review showed that the enzymatic test is more likely to detect cases at risk for azathioprine toxicity because a decrease in activity can also be caused by any known or unknown mutations or external confounding factors (e.g., drug interactions, blood transfusions), the enzymatic tests are limited by recent blood transfusions, other medications, alcohol, and food. A high concordance (98.4%) between TPMT genotypes and phenotypes has been reported. Thus genotyping offers a more convenient way in clinical studies. TPMT∗3C (719A > G) is the most common variant allele in Taiwanese with allelic frequencies from 0.12% to 1.28%. TPMT∗3C allele in our series is all heterozygous TPMT ∗1/∗3C (TPMTH/TPMTL, TPMT A/G), which is compatible with the results in the Japanese group (0.8–1.6% and all heterozygous) and the enzyme activity of TPMT ∗1/∗3C is about 25% lower than that of the wild-type. Low or absent TPMT activity may be correlated with risk of acute severe neutropenia, due to excessive accumulation of intercellular 6-thioguanine nucleotides (an active metabolite), when individuals were exposed to standard doses of azathioprine.