Formation and protein binding of the acyl glucuronide of a leukotriene B4 antagonist (SB-209247):: Relation to species differences in hepatotoxicity

被引:9
作者
Kenny, JR
Maggs, JL
Tettey, JNA
Harrell, AW
Parker, SG
Clarke, SE
Park, BK
机构
[1] Univ Liverpool, Dept Pharmacol & Therapeut, Liverpool L69 3GE, Merseyside, England
[2] GlaxoSmithKline, Preclin Dev, Welwyn Garden City, Herts, England
关键词
D O I
10.1124/dmd.104.001677
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
SB-209247 [(E)-3-[6-[[(2,6-dichlorophenyl)-thio] methyl]-3-(2-phenylethoxy)2- pyridinyl]-2-propenoic acid], an anti-inflammatory leukotriene B-4 receptor antagonist, was associated in beagle dogs but not male rats with an inflammatory hepatopathy. It also produced a concentration-dependent ( 10 - 1000 muM) but equal leakage of enzymes from dog and rat precision-cut liver slices. The hepatic metabolism of SB-209247 was investigated with reference to the formation of reactive acyl glucuronides. [C-14] SB-209247 (100 mumol/ kg) administered i.v. to anesthetized male rats was eliminated by biliary excretion of the acyl glucuronides of the drug and its sulfoxide. After 5 h, 1.03 +/- 0.14% ( mean +/- S. E. M., n = 4) of the dose was bound irreversibly to liver tissue. The sulfoxide glucuronide underwent pH-dependent rearrangement in bile more rapidly than did the SB-209247 conjugate. [C-14] SB-209247 was metabolized by sulfoxidation and glucuronidation in rat and dog hepatocytes, and approximately 1 to 2% of [C-14] SB-209247 (100 muM) became irreversibly bound to cellular material. [C-14] SB-209247 sulfoxide and glucuronide were the only metabolites produced by dog, rat, and human liver microsomes in the presence of NADPH and UDP-glucuronic acid (UDPGA), respectively. V-max values for [C-14] SB-209247 glucuronidation by dog, rat, and human microsomes were 2.6 +/- 0.1, 1.2 +/- 0.1, and 0.4 +/- 0.0 nmol/min/mg protein, respectively. Hepatic microsomes from all three species catalyzed UD-PGA-dependent but not NADPH-dependent irreversible binding of [C-14] SB-209247 (100 - 250 muM) to microsomal protein. Although a reactive acyl glucuronide was formed by microsomes from every species, the binding did not differ between species. Therefore, neither the acute cellular injury nor glucuronidation-driven irreversible protein binding in vitro is predictive of the drug-induced hepatopathy.
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页码:271 / 281
页数:11
相关论文
共 40 条
[1]   Acyl glucuronide reactivity in perspective: biological consequences [J].
Bailey, MJ ;
Dickinson, RG .
CHEMICO-BIOLOGICAL INTERACTIONS, 2003, 145 (02) :117-137
[2]  
Bergmeyer H. U., 1974, METHOD ENZYMAT AN, V2, P574
[3]  
Birke FW, 2001, J PHARMACOL EXP THER, V297, P458
[4]   Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity [J].
Boelsterli, UA .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2003, 192 (03) :307-322
[5]  
Boelsterli Urs A, 2002, Curr Drug Metab, V3, P439, DOI 10.2174/1389200023337315
[6]  
Bort R, 1999, J PHARMACOL EXP THER, V288, P65
[7]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[8]   Modulators of leukotriene biosynthesis and receptor activation [J].
Brooks, CDW ;
Summers, JB .
JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (14) :2629-2654
[9]   Discovery of CP-199,330 and CP-199,331:: Two potent and orally efficacious cysteinyl LT1 receptor antagonists devoid of liver toxicity [J].
Chambers, RJ ;
Marfat, A ;
Antognoli, GW ;
Cheng, JB ;
Damon, DB ;
Kuperman, AV ;
Liston, TC ;
Mebus, C ;
Pillar, JS ;
Shirley, JT ;
Watson, JW .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1999, 9 (18) :2773-2778
[10]   Liver inflammation during monocrotaline hepatotoxicity [J].
Copple, BL ;
Ganey, PE ;
Roth, RA .
TOXICOLOGY, 2003, 190 (03) :155-169