Letter: thiopurines during pregnancy and intrauterine exposure to metabolites
Letter: thiopurines during pregnancy and intrauterine exposure to metabolites
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信件：怀孕期间的硫嘌呤和子宫内代谢物的暴露
DOI：
10.1111/j.1365-2036.2012.05025.x
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发表时间：
2012
影响因子：
7.6
通讯作者：
A. A. Bodegraven
中科院分区：
文献类型：
--
作者：
N. Boer;B. Jharap;M. Seinen;A. A. Bodegraven
SIRS，我们怀着极大的兴趣阅读了文献综述，并提出了关于炎症性肠病（IBD）患者生育和妊娠的经常具有挑战性的问题的管理算法。硫唑嘌呤（AZA）或巯基嘌呤（MP）治疗的风险和利益的持续确实应该在每个怀孕IBD患者平衡。一般来说，在整个妊娠期间维持巯基嘌呤治疗是安全的，没有必要停止给药。作者指出，由于胎儿缺乏将AZA或MP转化为其活性代谢物所需的肌苷酸磷酸化酶，因此可保护胎儿免受硫嘌呤的潜在致畸作用。我们认为这一发言需要作一些改进。未出生的婴儿仅少量暴露于母体化合物AZA或MP本身，因为这些药物被肠细胞和肝细胞迅速吸收并在细胞内代谢成几种代谢产物。因此，预计胎儿本身不会代谢AZA或MP，或代谢有限。最近，我们证明了人类胎儿暴露于母体使用AZA产生的代谢物6-硫鸟嘌呤核苷酸。令人惊讶的是，在绝大多数新生儿中，在分娩后直接从脐带中抽取的红细胞中无法检测到巯基嘌呤代谢物6甲巯基嘌呤。基于这些观察结果，似乎胎盘在母体巯基嘌呤代谢物的转移中起着关键作用。据我们所知，肌苷酸磷酸化酶在硫嘌呤的代谢中不起作用。因此，胎儿因缺乏肌苷酸磷酸化酶而免受致畸作用的说法不成立。也许手稿应该说明，尽管宫内暴露于硫嘌呤代谢物6-硫鸟嘌呤核苷酸，但妊娠期间维持硫嘌呤治疗被认为是安全的。
SIRS, We read with great interest the review of literature and proposed management-algorithm concerning the often challenging questions on fertility and pregnancy in inflammatory bowel disease (IBD) patients. The risks and benefits of continuation of azathioprine (AZA) or mercaptopurine (MP) therapy should indeed be balanced in each pregnant IBD patient. In general, maintenance thiopurine therapy throughout pregnancy is considered safe and there is no necessity for cessation of administration. The authors state that the foetus is protected from potential teratogenic effects of thiopurines, as it lacks the enzyme inosinate phosphorylase, which is required to convert AZA or MP to its active metabolites. We feel that this statement needs some refinement. The unborn child is only marginally exposed to the parent compounds AZA or MP themselves, as these drugs are rapidly absorbed and metabolised intracellularly by enterocytes and hepatocytes into several metabolites. Therefore, it is to be expected that there will be no, or limited, metabolism of AZA or MP in the foetus itself. Recently, we demonstrated that the human foetus is exposed to the pharmacologically active metabolite 6-tioguanine nucleotides generated from maternal AZA use. Surprisingly, in the vast majority of newborns, the thiopurine metabolite 6methylmercaptopurine could not be detected in red blood cells directly drawn from the umbilical cord after delivery. Based on these observations, it appears that the placenta plays a critical role in the transfer of maternal thiopurine metabolites. To our knowledge, the enzyme inosinate phosphorylase does not play a role in the metabolism of thiopurines. Therefore, the statement that the foetus is protected from teratogenic effects as it lacks the enzyme inosinate phosphorylase cannot hold true. Perhaps the manuscript should have stated that maintenance thiopurine therapy during pregnancy is considered safe, despite intrauterine exposure to thiopurine metabolite 6-tioguanine nucleotides.