STUDIES ON THE REACTIVITY OF ACYL GLUCURONIDES .4. COVALENT BINDING OF DIFLUNISAL TO TISSUES OF THE RAT

被引:45
作者
KING, AR [1 ]
DICKINSON, RG [1 ]
机构
[1] ROYAL BRISBANE HOSP, UNIV QUEENSLAND, DEPT MED, CLIN SCI BLDG, BRISBANE, QLD 4029, AUSTRALIA
基金
英国医学研究理事会;
关键词
D O I
10.1016/0006-2952(93)90248-U
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Acyl glucuronides have been shown to be reactive electrophilic metabolites capable of undergoing hydrolysis, rearrangement (isomerization via acyl migration) and covalent binding reactions to plasma protein. The present study was undertaken to explore the occurrence and extent of in vivo formation of covalent adducts of diflunisal (DF), a salicylate derivative which forms a reactive acyl glucoronide, with tissues and plasma protein of rats. Groups of rats were given 50 mg DF/kg i.v. twice daily for periods of up to 7 days. Steady state plasma concentrations of reversibly bound DF and its conjugates (as measured 6 hr after a dose) were achieved by the third day of dosing. T1/2 values after cessation of dosing were about 5-10 hr. By contrast, covalent DF-tissue adducts steadily accumulated over the 7-day dosing period. Maximum concentrations, measured 6 hr after the last dose, were 4.8 (liver), 1.0 (kidney), 0.74 (plasma), 0.26 (small intestine minus contents), 0.27 (large intestine minus contents) and 0.20 (skeletal muscle) mug DF/g tissue or/mL plasma. T1/2 values of about 50, 67, 18, 38 and 43 hr were obtained for liver, kidney, plasma and small and large intestine (respectively) after cessation of dosing. Thus, the study of acyl glucuronide reactivity and the question of any derived toxicity or immune responses should consider the formation of long-lived adducts in tissues as well as in plasma.
引用
收藏
页码:1043 / 1047
页数:5
相关论文
共 25 条
[1]  
COOK DJ, 1988, CAN MED ASSOC J, V138, P1029
[2]  
DICKINSON RG, 1979, J PHARMACOL EXP THER, V211, P583
[3]   STUDIES ON THE REACTIVITY OF ACYL GLUCURONIDES .2. INTERACTION OF DIFLUNISAL ACYL GLUCURONIDE AND ITS ISOMERS WITH HUMAN SERUM-ALBUMIN INVITRO [J].
DICKINSON, RG ;
KING, AR .
BIOCHEMICAL PHARMACOLOGY, 1991, 42 (12) :2301-2306
[4]   ELIMINATION OF DIFLUNISAL AS ITS ACYL GLUCURONIDE, PHENOLIC GLUCURONIDE AND SULFATE CONJUGATES IN BILE-EXTERIORIZED AND INTACT RATS [J].
DICKINSON, RG ;
KING, AR ;
VERBEECK, RK .
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 1989, 16 (12) :913-924
[5]   THE SULFATE CONJUGATE OF DIFLUNISAL - ITS SYNTHESIS AND SYSTEMIC STABILITY IN THE RAT [J].
DICKINSON, RG ;
KING, AR ;
HANSENMOLLER, J .
XENOBIOTICA, 1991, 21 (05) :635-640
[6]   REACTIVITY CONSIDERATIONS IN THE ANALYSIS OF GLUCURONIDE AND SULFATE CONJUGATES OF DIFLUNISAL [J].
DICKINSON, RG ;
KING, AR .
THERAPEUTIC DRUG MONITORING, 1989, 11 (06) :712-720
[8]  
Gillette J R, 1986, Adv Exp Med Biol, V197, P63
[9]   PERSPECTIVE ON ROLE OF CHEMICALLY REACTIVE METABOLITES OF FOREIGN COMPOUNDS IN TOXICITY .1. CORRELATION OF CHANGES IN COVALENT BINDING OF REACTIVITY METABOLITES WITH CHANGES IN INCIDENCE AND SEVERITY OF TOXICITY [J].
GILLETTE, JR .
BIOCHEMICAL PHARMACOLOGY, 1974, 23 (20) :2785-2794
[10]   DISPOSITION AND IRREVERSIBLE PLASMA-PROTEIN BINDING OF TOLMETIN IN HUMANS [J].
HYNECK, ML ;
SMITH, PC ;
MUNAFO, A ;
MCDONAGH, AF ;
BENET, LZ .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 1988, 44 (01) :107-114