Modulation of 3'-azido-3'-deoxythymidine catabolism by probenecid and acetaminophen in freshly isolated rat hepatocytes.
Modulation of 3'-azido-3'-deoxythymidine catabolism by probenecid and acetaminophen in freshly isolated rat hepatocytes.
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丙磺舒和对乙酰氨基酚在新鲜分离的大鼠肝细胞中调节 3-叠氮基-3-脱氧胸苷分解代谢。
DOI：
10.1016/0006-2952(91)90461-d
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发表时间：
1991
影响因子：
5.8
通讯作者：
Sommadossi,JP
中科院分区：
文献类型：
--
作者：
Cretton,EM;Sommadossi,JP
人体内3 '-叠氮基-3'-脱氧胸苷（AZT）的代谢研究表明，该化合物主要以5 '-O-葡糖苷酸、3'-叠氮基-3 '-脱氧-5'-β-d-吡喃葡萄糖醛酸胸苷（GAZT）的形式消除，约占给药剂量的80%。最近，我们在新鲜分离的大鼠肝细胞悬液中表征了AZT的完整分解代谢途径，证明了三种催化剂的广泛形成，包括GAZT、3 '-氨基-3'-脱氧胸苷（AMT）和3 '-氨基-3'-脱氧-5 '-β-D-吡喃葡萄糖醛酸胸苷（GAMT）。本研究评价了丙磺舒（PROB）和对乙酰氨基酚（ACET），这两种药物也被UDP-葡萄糖醛酸转移酶代谢，对AZT在大鼠肝细胞中的代谢和跨膜分布的影响。在加入10 μM [3 H]AZT之前，将细胞预先暴露于350 μM PROB 30分钟，使细胞内GAZT水平降低约10倍。有趣的是，在PROB的存在下，AMT形成增加了约1.5倍，可能是由于AZT的可用性增加。相反，在加入10 μM [3 H]AZT前30分钟预先暴露于50 μM ACET不会显著改变AZT葡萄糖醛酸化。此外，PROB降低AZT的催化活性并不促进AZT 5 '-磷酸化衍生物的形成。因此，发生葡萄糖醛酸化的药物可能不一定影响AZT转化为GAZT，在与AZT联合给药前，应在体外系统中研究其潜在的相互作用。
Metabolic studies of 3'-azido-3'-deoxythymidine (AZT) in humans have demonstrated that this compound is primarily eliminated as a 5′-O-glucuronide, 3'-azido-3'-deoxy-5'-β-d-glucopyranuronosylthymidine (GAZT), accounting for approximately 80% of the administered dose. Recently, we characterized the complete catabolic pathway of AZT in freshly isolated rat hepatocytes in suspension, demonstrating extensive formation of three catabolites, including GAZT, 3'-amino-3'-deoxythymidine (AMT), and 3'-amino-3'-deoxy-5'-β-d-glucopyranuronosylthymidine (GAMT). The present study evaluated the effects of probenecid (PROB) and acetaminophen (ACET), two agents which are also metabolized by UDP-glucuronyltransferase, on the metabolism and transmembrane distribution of AZT in rat hepatocytes. Pre-exposure of cells to 350 μM PROB 30min prior to the addition of 10 μM [3H]AZT decreased intracellular GAZT levels by approximately 10-fold. Interestingly, AMT formation was enhanced approximately 1.5-fold in the presence of PROB, probably resulting from increased AZT availability. In contract, pre-exposure to 50 μM ACET 30 min prior to addition of 10 μM [3H]AZT did not substantially alter AZT glucuronidation. Additionally, decreased AZT catabolism by PROB did not contribute to the formation of 5'-phosphorylated derivatives of AZT. Agents which undergo glucuronidation may thus not necessarily affect AZT conversion to GAZT, and their potential interactions should be investigated usingin vitrosystems prior to co-administration with AZT.