Zimmerman J, Selhub J, Rosenberg I H
Am J Clin Nutr. 1987 Sep;46(3):518-22. doi: 10.1093/ajcn/46.3.518.
Trimethoprim and pyrimethamine, inhibitors of dihydrofolate reductase (DHFR), cause folate deficiency in some patients. We investigated impairment of intestinal folate absorption by these drugs. By use of the in vivo intestinal-loop methods in rats, absorption of [3H] folic acid was significantly decreased in the presence of either drug. Kinetic studies using the influx chamber method demonstrated a pattern of competitive inhibition of folate transport. [3H] folic acid absorption from jejunal loops was determined 3-16 h after IV administration of methotrexate; this treatment abolished DHFR activity in the small intestine. In rats pretreated with methotrexate, luminal disappearance and systemic absorption of folic acid were significantly enhanced with respect to controls. Trimethoprim and pyrimethamine are weak competitive inhibitors of intestinal folate transport and folate absorption inhibition occurs at the site of membrane transport and appears to be unrelated to concurrent inhibition of DHFR activity in enterocytes.
甲氧苄啶和乙胺嘧啶是二氢叶酸还原酶（DHFR）的抑制剂，可导致部分患者出现叶酸缺乏。我们研究了这些药物对肠道叶酸吸收的损害。通过在大鼠体内采用肠袢法，在任何一种药物存在的情况下，[3H]叶酸的吸收均显著降低。使用流入室法进行的动力学研究表明存在叶酸转运的竞争性抑制模式。静脉注射甲氨蝶呤3 - 16小时后，测定空肠袢中[3H]叶酸的吸收；该处理消除了小肠中的DHFR活性。与对照组相比，在经甲氨蝶呤预处理的大鼠中，叶酸的肠腔消失和全身吸收均显著增强。甲氧苄啶和乙胺嘧啶是肠道叶酸转运的弱竞争性抑制剂，叶酸吸收抑制发生在膜转运部位，似乎与同时抑制肠细胞中的DHFR活性无关。
