Abstract

1. The kinetics of metabolism of deltamethrin (DLM) and cis- and trans-permethrin (CPM and TPM) was studied in male Sprague-Dawley rat and human liver microsomes. DLM metabolism kinetics was also studied in isolated rat hepatocytes, liver microsomes and cytosol.

2. Apparent intrinsic clearance (CL_int) values for the metabolism of DLM, CPM and TPM by cytochrome P450 (CYP) and carboxylesterase (CES) enzymes in rat and human liver microsomes decreased with increasing microsomal protein concentration. However, when apparent CL_int values were corrected for nonspecific binding to allow calculation of unbound (i.e., corrected) CL_int values, the unbound values did not vary greatly with microsomal protein concentration.

3. Unbound CL_int values for metabolism of 0.05-1 μM DLM in rat liver microsomes (CYP and CES enzymes) and cytosol (CES enzymes) were not significantly different from rates of DLM metabolism in isolated rat hepatocytes.

4. This study demonstrates that the nonspecific binding of these highly lipophilic compounds needs to be taken into account in order to obtain accurate estimates of rates of in vitro metabolism of these pyrethroids. While DLM is rapidly metabolised in vitro, the hepatocyte membrane does not appear to represent a barrier to the absorption and hence subsequent hepatic metabolism of this pyrethroid.

摘要

1. 在雄性Sprague-Dawley大鼠和人肝微粒体中研究了溴氰菊酯（DLM）和顺式和反式-氯菊酯（CPM和TPM）的代谢动力学。在分离的大鼠肝细胞，肝微粒体和细胞质中也研究了DLM代谢动力学。

2. 大鼠和人肝微粒体中细胞色素P450（CYP）和羧酸酯酶（CES）酶对DLM，CPM和TPM代谢的表观固有清除率（CL _int）值随着微粒体蛋白浓度的增加而降低。然而，当针对非特异性结合校正表观CL _int值以允许计算未结合（即，校正的）CL _int值时，未结合值不会随微粒体蛋白浓度变化很大。

3. 大鼠肝脏微粒体（CYP和CES酶）和胞浆（CES酶）中0.05-1μMDLM的代谢的未结合CL _int值与分离的大鼠肝细胞中DLM代谢的速率没有显着差异。

4. 这项研究表明，为了获得这些拟除虫菊酯的体外代谢速率的准确估计值，必须考虑这些高度亲脂性化合物的非特异性结合。虽然DLM在体外迅速代谢，但肝细胞膜似乎并不代表该拟除虫菊酯的吸收障碍，并因此不影响其随后的肝代谢。