Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease

被引:197
作者
Gearry, RB
Barclay, ML
机构
[1] Christchurch Hosp, Dept Gastroenterol, Christchurch, New Zealand
[2] Christchurch Hosp, Dept Clin Pharmacol, Christchurch, New Zealand
[3] Christchurch Sch Med & Hlth Sci, Christchurch, New Zealand
关键词
azathioprine; efficacy; inflammatory bowel disease; 6-mercaptopurine; metabolite monitoring; pharmacogenetics; toxicity; TPMT;
D O I
10.1111/j.1440-1746.2005.03832.x
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
The thiopurine drugs azathioprine and 6-mercaptopurine (6-MP) are well-established in the treatment of inflammatory bowel disease (IBD). However, there is a wide inter-and intra-patient variation in the concentrations of active and toxic metabolites due to their complex metabolism and genetic polymorphisms in metabolizing enzymes. Serious drug toxicity leads to cessation of therapy in 9-25% of patients, and there is failure to achieve efficacy in approximately 15% of cases. Advances in the understanding of thiopurine drug metabolism have led to new genetic and metabolite tests to help clinicians optimize thiopurine use. Thiopurine methyltransferase (TPMT) enzyme activity can predict life-threatening myelotoxicity in the one in 300 patients who are TPMT-deficient. However, myelotoxicity can also occur in the presence of norma TPMT activity so blood count monitoring should remain standard practice. TPMT testing may also aid in dose individualization. 6-Thioguanine nucleotides (6-TGN) are thought to be the predominant active metabolites of the thiopurines. 6-Thioguanine nucleotide concentration is correlated with bone marrow toxicity and may also correlate with efficacy in IBD. Measurement of 6-TGN and 6-methylmercaptopurine (6-MMP) concentration is most useful in determining why a patient is not responding to a standard dose of a thiopurine drug and may help in avoiding myelosuppression. The ratio of these metabolites can help distinguish non-compliance, under-dosing, thiopurine-resistant and thiopurine-refractory disease. Some of these investigations are entering routine clinical practice but more research is required to determine their optimal use in patients with IBD. (C) 2005 Blackwell Publishing Asia Pty Ltd.
引用
收藏
页码:1149 / 1157
页数:9
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