吡喹酮在诱导和未诱导大鼠肝微粒体内的羟化代谢概貌及其羟化物的质谱鉴定

用细胞色素P450（P450）特异诱导剂研?究参与吡喹酮（PQT）代谢的P450同工酶，在未诱导肝微粒体内，PQT代谢仅生成其D环单羟化物. 在β-萘黄酮诱导肝微粒体内，PQT代谢后也生成其D环单羟化物. PQT在苯巴比妥诱导的肝微粒体内代谢生成D环，B环和A环三个单羟化物. 在地塞米松和红霉素诱导的肝微粒体内，PQT代谢生成七个代谢产物. 结果表明参与PQT分子羟化的P450同工酶至少包括CYP1A，CYP2B和CYP3A亚家族，每个亚家族代谢PQT的概貌各不相同，CYP3A优先羟化A环，CYP2B优先羟化D环和B环，CYP1A则几乎仅羟化D环.

Metabolic profile and mass spectroscopic identification of metabolites of praziquantel in induced and non-induced rat liver microsomes

The cytochrome P450(P450) isoforms which might be responsible for the hydroxylation of PQT were investigated in rat liver microsomes by using P450 specific inducers. After PQT was incubated with untreated or CYP1A inducer β-NF treated rat liver microsomes, only one major metabolite was found from high performance liquid chromatogram. Mass spectrum showed that both of them were D-Ring monohydroxylate. The content of P450 and the formation rate of PQT D-Ring monohydroxylate in liver microsomes with pretreatment of β-NF was enhanced to 1.55 and 2.12 fold respectively as compared with that in the control. In the CYP2B inducer PB treated rat liver microsomes, the content of P450 was enhanced to 4.31 fold. Three major metabolites were found after PQT incubated with the PB induced microsomes. Mass spectra showed that they were PQT D-Ring, B-Ring and A-Ring monohydroxylated products and the formation rate of D-Ring monohydroxylate was 6.05 fold increased. In liver microsomes obtained from rats pretreated with DEX, the CYP3A inducer, P450 content was increased about 2.69 fold. Seven PQT hydroxylated metabolites, including one D-Ring, two B-Rings, one A-Ring, one C-Ring position 1 and one position 11b monohydroxylate and one D- and B-ring dihydroxylate were found. The formation rate of D-Ring monohydroxylate was increased to 1.94 fold. These results suggest that at least three subfamilies CYP1A, CYP2B and CYP3A are involved in the metablism of PQT. Metabolic profile of PQT is different in different specific inducer pretreated microsomes. CYP3A preferentially catalyzes A-Ring, CYP2B preferentially cytalyzes D-Ring and B-Ring hydroxylation, while CYP1A seems to catalyze D-Ring hydroxylation only in our study conditions.