GLUCURONIDATION OF 3'-AZIDO-3'-DEOXYTHYMIDINE CATALYZED BY HUMAN LIVER UDP-GLUCURONOSYLTRANSFERASE - SIGNIFICANCE OF NUCLEOSIDE HYDROPHOBICITY AND INHIBITION BY XENOBIOTICS

被引:56
作者
RESETAR, A
MINICK, D
SPECTOR, T
机构
[1] BURROUGHS WELLCOME CO, DIV EXPTL THERAPY, RES TRIANGLE PK, NC 27709 USA
[2] UNIV N CAROLINA, DEPT PHARMACOL, CHAPEL HILL, NC 27514 USA
[3] BURROUGHS WELLCOME CO, DIV ORGAN CHEM, RES TRIANGLE PK, NC 27709 USA
关键词
D O I
10.1016/0006-2952(91)90319-Z
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The enzymatic glucuronidation of 3'-azido-3'-deoxythymidine (AZT) catalyzed by human liver microsomal UDP-glucuronosyltransferase (EC 2.4.1.17, UDPGT) was inhibited by a number of nucleoside analogs. The inhibitory potency of these nucleoside analogs correlated with their hydrophobicity (r2 = 0.90, N = 13). Since similar results were obtained with solubilized UDPGT (r2 = 0.87, N = 7), the affinity of the nucleosides for UDPGT was probably being assessed rather than the ability of the compounds to access the membrane-bound enzyme. Three homologous inhibitors, 3'-azido-2',3'-dideoxyuridine (AzddU), 5-ethyl-AzddU, and 5-propyl-AzddU, were also studied as substrates of UDPGT. The substrate efficiency (V(max)/K(m)) of these three compounds and AZT also correlated with their hydrophobicity (r2 = 0.94). Sixteen drugs that are structurally unrelated to nucleosides also inhibited the glucuronidation of AZT. The mechanism of inhibition was competitive for seven compounds tested. K(i) values were estimated from Dixon plots for nine other less soluble inhibitors; their mechanism of inhibition was assumed to be competitive. Since the peak physiological drug concentrations of the tested inhibitors are considerably less than their K(i) values, none of these compounds are expected to strongly inhibit AZT glucuronidation in humans. However, the rank order of these drugs with respect to their inhibitory potential is probenecid > chrloramphenicol > naproxen > phenylbutazone >> other drugs tested.
引用
收藏
页码:559 / 568
页数:10
相关论文
共 72 条
[61]  
STEFFE E, 1989, 5TH INT C AIDS MONTR
[62]   TREATMENT OF THE ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) AND AIDS-RELATED COMPLEX WITH A REGIMEN OF 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE (AZIDOTHYMIDINE OR ZIDOVUDINE) AND ACYCLOVIR - A PILOT-STUDY [J].
SURBONE, A ;
YARCHOAN, R ;
MCATEE, N ;
BLUM, MR ;
MAHA, M ;
ALLAIN, JP ;
THOMAS, RV ;
MITSUYA, H ;
LEHRMAN, SN ;
LEUTHER, M ;
PLUDA, JM ;
JACOBSEN, FK ;
KESSLER, HA ;
MYERS, CE ;
BRODER, S .
ANNALS OF INTERNAL MEDICINE, 1988, 108 (04) :534-540
[63]   INHIBITED DISSOLUTION OF DRUG CRYSTALS BY CERTIFIED WATER-SOLUBLE DYES - IN-VIVO EFFECT [J].
TAWASHI, R ;
PICCOLO, J .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1972, 61 (11) :1857-&
[64]   ENDOGENOUS SUBSTRATES FOR UDP-GLUCURONSYLTRANSFERASES [J].
TEPHLY, T ;
GREEN, M ;
PUIG, J ;
IRSHAID, Y .
XENOBIOTICA, 1988, 18 (11) :1201-1210
[65]   UDP-GLUCURONOSYLTRANSFERASES - A FAMILY OF DETOXIFYING ENZYMES [J].
TEPHLY, TR ;
BURCHELL, B .
TRENDS IN PHARMACOLOGICAL SCIENCES, 1990, 11 (07) :276-279
[66]  
UNADKAT JD, 1988, 28TH INT C ANT AG CH, P345
[67]  
UNO T, 1963, CHEM PHARM BULL, V11, P709
[68]  
UNO T, 1963, J PHARM SOC JPN, V82, P1660
[69]  
YARCHOAN R, 1986, LANCET, V1, P575
[70]   RESPONSE OF HUMAN-IMMUNODEFICIENCY-VIRUS-ASSOCIATED NEUROLOGICAL DISEASE TO 3'-AZIDO-3'-DEOXYTHYMIDINE [J].
YARCHOAN, R ;
BROUWERS, P ;
SPITZER, AR ;
GRAFMAN, J ;
SAFAI, B ;
PERNO, CF ;
LARSON, SM ;
BERG, G ;
FISCHL, MA ;
WICHMAN, A ;
THOMAS, RV ;
BRUNETTI, A ;
SCHMIDT, PJ ;
MYERS, CE ;
BRODER, S .
LANCET, 1987, 1 (8525) :132-135