Kostrubsky Seva E, Sinclair Jacqueline F, Strom Stephen C, Wood Sheryl, Urda Ellen, Stolz Donna Beer, Wen Yuan H, Kulkarni Shaila, Mutlib Abdul
Department of Safety Science, Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA.
Toxicol Sci. 2005 Sep;87(1):146-55. doi: 10.1093/toxsci/kfi211. Epub 2005 Jun 2.
Here we present a preclinical model to assess drug-drug interactions due to inhibition of glucuronidation. Treatment with the antiepileptics phenobarbital (PB) or phenytoin (PH) has been associated with increased incidence of acetaminophen (APAP) hepatotoxicity in patients. In human hepatocytes, we found that the toxicity of APAP (5 mM) was increased by simultaneous treatment with phenobarbital (2 mM) or phenytoin (0.2 mM). In contrast, pretreatment with PB for 48 h prior to APAP treatment did not increase APAP toxicity unless both drugs were present simultaneously. Cells treated with APAP in combination with PB or PH experienced decreases in protein synthesis as early as 1 h, ultrastructural changes by 24 h, and release of liver enzymes by 48 h. Toxicity correlated with inhibition of APAP glucuronidation. PB or PH also inhibited APAP glucuronidation in rat and human liver microsomes and expressed human UGT1A6, 1A9, and 2B15. As with intact hepatocytes, PB and PH were neither hydroxylated nor glucuronidated, suggesting the direct inhibition of UGTs. Our findings suggest that, in multiple drug therapy, an inhibitory complex between UGT and one of the drugs can lead to decreased glucuronidation and increased systemic exposure and toxicity of a coadministered drug.
在此，我们展示了一种临床前模型，用于评估因葡糖醛酸化抑制导致的药物相互作用。抗癫痫药物苯巴比妥（PB）或苯妥英（PH）治疗与患者对乙酰氨基酚（APAP）肝毒性发生率增加有关。在人肝细胞中，我们发现，同时用苯巴比妥（2 mM）或苯妥英（0.2 mM）处理会增加APAP（5 mM）的毒性。相比之下，在APAP处理前用PB预处理48小时并不会增加APAP毒性，除非两种药物同时存在。用APAP与PB或PH联合处理的细胞早在1小时就出现蛋白质合成减少，24小时出现超微结构变化，48小时出现肝酶释放。毒性与APAP葡糖醛酸化抑制相关。PB或PH也抑制大鼠和人肝微粒体以及表达的人UGT1A6、1A9和2B15中的APAP葡糖醛酸化。与完整肝细胞一样，PB和PH既不被羟基化也不被葡糖醛酸化，提示对UGTs的直接抑制。我们的研究结果表明，在多药治疗中，UGT与其中一种药物之间的抑制性复合物可导致葡糖醛酸化减少，并增加共同给药药物的全身暴露和毒性。
