CATABOLIC DISPOSITION OF 3'-AZIDO-2',3'-DIDEOXYURIDINE IN HEPATOCYTES WITH EVIDENCE OF AZIDO REDUCTION BEING A GENERAL CATABOLIC PATHWAY OF 3'-AZIDO-2',3'-DIDEOXYNUCLEOSIDES

被引:7
作者
CRETTON, EM
XIE, MY
GOUDGAON, NM
SCHINAZI, RF
CHU, CK
SOMMADOSSI, JP
机构
[1] UNIV ALABAMA,DEPT PHARMACOL,CTR AIDS RES,CTR COMPREHENS CANC,DIV CLIN PHARMACOL,VOLKER 600,BIRMINGHAM,AL 35294
[2] VET AFFAIRS MED CTR,DECATUR,GA 30033
[3] EMORY UNIV,SCH MED,DEPT PEDIAT,BIOCHEM PHARMACOL LAB,ATLANTA,GA 30322
[4] UNIV GEORGIA,COLL PHARM,DEPT MED CHEM & PHARMACOL,ATHENS,GA 30602
关键词
D O I
10.1016/0006-2952(92)90130-B
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
3'-Azido-2',3'-dideoxyuridine (AzddU, CS-87) is a potent inhibitor of human immunodeficiency virus replication in vitro with low bone marrow toxicity. Although AzddU is currently being evaluated in clinical trials, its catabolic disposition is unknown. Pharmacokinetic studies in rhesus monkeys have demonstrated that a 5'-O-glucuronide is excreted in urine. The present study examined the catabolic disposition of AzddU is isolated rat hepatocytes, a model for the study at the cellular level of biosynthetic, catabolic and transport phenomena in the liver. Following exposure of cells to 10-mu-M [H-3]AzddU, low intracellular levels of two catabolites, identified as 3'-azido-2',3'-dideoxy-5'-beta-D-glucopyranosyluridine (GAzddU) and 3'-amino-2',3'-dideoxyuridine (AMddU), were detected. Studies using rat microsomes demonstrated that GAzddU formation was only detected in the presence of uridine 5'-diphosphoglucuronic acid, and that the rate of AMddU formation increased significantly in the presence of NADPH. Under similar conditions, reduction of the 3'-azido function was also demonstrated herein with 3'-azido-2',3'-dideoxycytidine (AzddC), 3'-azido-2',3'-dideoxy-5-methylcytidine (AzddMeC) and 3'-azido-2',3'-dideoxyguanine (AzddG), suggesting that enzymatic reduction to a 3'-amino derivative is a general catabolic pathway of 3'-azido-2',3'-dideoxynucleosides at the hepatic site.
引用
收藏
页码:973 / 980
页数:8
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