Masimirembwa C M, Hasler J A
Department of Biochemistry, University of Zimbabwe, Mt Pleasant, Harare.
Biochem Pharmacol. 1994 Nov 1;48(9):1779-83. doi: 10.1016/0006-2952(94)90464-2.
The metabolism of praziquantel (PZQ) was studied in microsomes isolated from livers of differently pretreated rats and in the presence of various inhibitors of cytochrome P450 (P450) isoforms. Microsomes from phenobarbitone (PB)-pretreated rats metabolised PZQ to its major metabolite 4OH-praziquantel (4OH-PZQ) at a greater rate than those from 20-methylcholanthrene (MC) and saline (SA) pretreated rats. The Vmax for the PB microsomes was 600 nmol 4OH-PZQ formed/mg/min x 10(-3) compared to 91.4 nmol/mg/min x 10(-3) for MC and 238 nmol/mg/min x 10(-3) for SA microsomes. These results indicate that PZQ is metabolised by PB-inducible isoforms of P450. Inhibitor studies were conducted with microsomes from SA-pretreated animals. In these studies, caffeine, disulfuram, and tolbutamide were poor inhibitors of the metabolism of PZQ to 4OH-PZQ, with I50 values not determinable. Quinidine and quinine inhibited the hydroxylation of PZQ but with high Ki values. 17 alpha-Ethynylestradiol, cimetidine and diphenylhydramine were effective inhibitors of the formation of 4OH-PZQ, with 17 alpha-ethynylestradiol being the most potent with a Ki of 0.5 +/- 0.05 microM. From the known specificities of these P450 inhibitors, it is therefore concluded that cytochromes P450 1A2, 2E1, 2C9-10, and 2D6 probably do not contribute significantly to the metabolism of PZQ to its major metabolite in rats. It is likely that cytochromes P450 2B1 and 3A, both inducible by PB, are predominantly responsible for the formation of 4OH-PZQ.
在从不同预处理大鼠肝脏中分离出的微粒体以及存在各种细胞色素P450（P450）同工酶抑制剂的情况下，对吡喹酮（PZQ）的代谢进行了研究。苯巴比妥（PB）预处理大鼠的微粒体将PZQ代谢为其主要代谢产物4-羟基吡喹酮（4OH-PZQ）的速率高于20-甲基胆蒽（MC）和生理盐水（SA）预处理大鼠的微粒体。PB微粒体的Vmax为形成600 nmol 4OH-PZQ/毫克/分钟×10⁻³，而MC微粒体为91.4 nmol/毫克/分钟×10⁻³，SA微粒体为238 nmol/毫克/分钟×10⁻³。这些结果表明PZQ由PB诱导的P450同工酶代谢。使用SA预处理动物的微粒体进行了抑制剂研究。在这些研究中，咖啡因、双硫仑和甲苯磺丁脲对PZQ代谢为4OH-PZQ的抑制作用较弱，I50值无法确定。奎尼丁和奎宁抑制PZQ的羟基化，但Ki值较高。17α-乙炔雌二醇、西咪替丁和苯海拉明是4OH-PZQ形成的有效抑制剂，其中17α-乙炔雌二醇最有效，Ki为0.5±0.05微摩尔。根据这些P450抑制剂的已知特异性，因此得出结论，细胞色素P450 1A2、2E1、2C9-10和2D6可能对大鼠体内PZQ代谢为其主要代谢产物的过程贡献不大。很可能PB可诱导的细胞色素P450 2B1和3A主要负责4OH-PZQ的形成。
