代谢
代谢物从给予[(14)C-苯基]苯并环唑或[(14)C-三唑]苯并环唑单次口服剂量为0.5或300 mg/kg bw的雄性和雌性大鼠的尿液和粪便中分离出来，或者在预先用未标记的苯并环唑以0.5 mg/kg bw连续口服14剂后再给予0.5 mg/kg bw。苯基和三唑环标签的平衡数据显示，在所有情况下，超过97%的放射性标记物被排出，其中超过78%通过粪便排出。三种主要代谢物A、B和C从粪便中分离出来，平均占给药剂量的68%。代谢物B（羟基-CGA 169374）在外侧苯环上发生羟基化，光谱分析显示它包含两种异构体，其中一种在外侧苯环上的氯原子发生了重排，归因于类似于NIH位移的机制。代谢物C（CGA 205375）是二氧戊环环从苯并环唑分子断裂的羟基产物，仅在给予较高剂量的老鼠粪便中存在。代谢物A（羟基-CGA 205375）是代谢物C的外侧苯环羟基化产物，包含两种对映异构体，与代谢物B的描述相同。尿液代谢物的轮廓更为复杂，并且在两种放射性标记形式之间表现出更多的变异性。自由的1,2,4-三唑在雄性尿液中被发现，占给药剂量的不到10%，表示环系统之间的烷基桥断裂。其他尿液代谢物包括代谢物C，其硫酸结合物，环羟基化代谢物C及其硫酸结合物，以及氯苯氧基-氯苯基部分的羟基醋酸代谢物，它们都以微量存在，每种都代表给药剂量的不到3%。一种代谢物CGA 189138（氯苯氧基-氯苯甲酸）也从肝脏中分离出来。因此，苯并环唑分子被广泛代谢，尽管三唑和二氧戊环环的裂解有限。观察到的广泛胆汁排泄与主要代谢物具有相对较高的分子质量一致。
Metabolites were isolated from the urine and feces of male and female rats given [(14)C-phenyl] difenoconazole or [(14)C-triazole]difenoconazole as single oral dose at 0.5 or 300 mg/kg bw, or 0.5 mg/kg bw after pre-treatment with 14 daily oral doses of unlabelled difenoconazole at 0.5 mg/kg bw. Balance data for the phenyl and triazole ring labels ... showed that > 97% of the radiolabel in all cases was excreted with > 78% in all cases eliminated in the feces. Three main metabolites, A, B and C, were isolated from feces and together accounted for an average of 68% of the administered dose. Metabolite B (hydroxy-CGA 169374) was hydroxylated in the outer phenyl ring and spectral analysis showed that that it comprised two isomers, one with a rearrangement of the chlorine on the outer phenyl ring, attributed to a mechanism analogous to an NIH shift. Metabolite C (CGA 205375) was the hydroxyl product of cleavage of the dioxolane ring from the difenoconazole molecule and was present only in the feces of rats given the higher dose. Metabolite A (hydroxy-CGA 205375) was the outer phenyl-ring hydroxylated product of metabolite C and comprised two diastereoisomers, as described for metabolite B. The profile of urinary metabolites was more complex and showed more variability between the two radiolabelled forms. Free 1,2,4-triazole was identified in male urine, accounting for less than 10% of the administered dose and represented cleavage of the alkyl bridge between the ring systems. Other urinary metabolites included metabolite C, its sulfate conjugate, ring-hydroxylated metabolite C and its sulfate conjugate, as well as an hydroxyacetic acid metabolite of the chlorophenoxy-chlorophenyl moiety, all of which were present in minor quantities, each representing less than 3% of the administered dose. One metabolite CGA 189138 (chlorophenoxy-chlorobenzoic acid) was also isolated from the liver. The difenoconazole molecule was therefore extensively metabolized, although with limited cleavage of the triazole and dioxolane rings. The extensive biliary elimination observed was consistent with the major metabolites being of relatively high molecular mass.
来源:Hazardous Substances Data Bank (HSDB)
