Inosine triphosphate pyrophosphatase 94C>A polymorphism: clinical implications for patients with systemic lupus erythematosus treated with azathioprine.
BACKGROUND
Azathioprine (AZA) has immunosuppressive property and has been widely used in organ transplantation and in several autoimmune diseases including systemic lupus erythematosus. The use of AZA is limited by the occurrence of adverse drug reactions (ADRs) leading to treatment discontinuation. Under AZA therapy, inosine triphosphate pyrophosphatase (ITPA) deficiency presumably leads to accumulation of unusual thioinosine metabolites with the potential for ADRs. Japanese patients require lower doses of AZA compared with Caucasian patients to achieve the same concentration of active metabolites. This ethnic difference in part is probably due to genetic polymorphisms of ITPA.


METHODS
Relationships between ITPA genotype and enzyme activity, and efficacy and toxicity of AZA in both Caucasian and Asian populations are reviewed.


CONCLUSIONS
Clinical studies using a dose of < 1.5 mg/kg/day in various autoimmune diseases have shown no association between ITPA genotype and ADRs. In studies using higher doses, ITPA deficiency appears to increase the risk for AZA toxicity. Genotyping of ITPA may be useful to achieve dose optimization. It is important to maintain the dose of AZA < 1.5 mg/kg/day for Asian patients with ITPA 94A allele, with careful monitoring of the therapeutic efficacy.
Yamamoto
Koujirou
K
Gunma University Graduate School of Medicine, Department of Clinical Pharmacology, Maebashi, Japan. koujirou@med.gunma-u.ac.jp
Okada
Yuko
Y
Nakamura
Katsunori
K
Hiromura
Keiju
K
Nojima
Yoshihisa
Y
Nakamura
Tomonori
T
D044466:Asian People / Q000235:genetics; D001379:Azathioprine / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D000097630:Inosine Triphosphatase
D001379:Azathioprine; D011755:Pyrophosphatases; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase