目的 基于細(xì)胞色素P450(CYP450)代謝酶探究補(bǔ)骨脂素和異補(bǔ)骨脂素對(duì)黃獨(dú)乙素在大鼠體內(nèi)代謝的影響。方法 采用大鼠離體循環(huán)肝灌流方法,考察大鼠分別給予補(bǔ)骨脂素或異補(bǔ)骨脂素1、3、7 d后,黃獨(dú)乙素在肝臟中的代謝情況;利用UPLC-MS/MS檢測(cè)循環(huán)灌流液中剩余黃獨(dú)乙素的含量;通過大鼠眼內(nèi)眥取血的方法研究大鼠分別給予補(bǔ)骨脂素或異補(bǔ)骨脂素干預(yù)1周,再給予黃藥子提取物(10 g·kg^-1)后體內(nèi)黃獨(dú)乙素的藥動(dòng)學(xué)變化,藥動(dòng)學(xué)參數(shù)采用DAS 2.0軟件中的非房室模型法進(jìn)行計(jì)算。結(jié)果 大鼠給予補(bǔ)骨脂素或異補(bǔ)骨脂素后,循環(huán)灌流液中黃獨(dú)乙素的含量相對(duì)增加,且補(bǔ)骨脂素或異補(bǔ)骨脂素給藥時(shí)間延長(zhǎng)后,對(duì)酶的抑制程度更強(qiáng);當(dāng)大鼠給予補(bǔ)骨脂素或異補(bǔ)骨脂素干預(yù)后,與非干預(yù)組(黃藥子提取物組)相比,藥時(shí)曲線下面積(AUC_0~t)和平均駐留時(shí)間(MRT_0~t)增加,消除半衰期(t_1/2Z)減小。結(jié)論 補(bǔ)骨脂素/異補(bǔ)骨脂素可通過抑制肝臟中CYP450酶的活性降低其對(duì)黃獨(dú)乙素的代謝,使黃獨(dú)乙素在肝臟中代謝減少,造成蓄積,臨床用藥應(yīng)注意含有補(bǔ)骨脂素/異補(bǔ)骨脂素或黃獨(dú)乙素中藥在合用時(shí)可能產(chǎn)生的藥物相互作用。

Objective To investigate the effect of psoralen and isopsoralen on the metabolism of diosbulbin B in rats based on cytochrome P450 enzyme system (CYP450). Methods After administration of psoralen or isopsoralen for 1, 3, 7 days, respectively, isolated circulatory liver perfusion was used to study the metabolism of diosbulbin B in the liver of rats. UPLC-MS /MS was used to detect the content of diosbulbin B in circulating perfusate. When rats were treated with psoralen/isopsoralen for one week before administration of extraction of Dioscorea bulbifera L. (10 g·kg^-1), blood was taken from the inner canthus of rats and the pharmacokinetic parameters of diosbulbin B were calculated by non-compartment model in DAS 2.0 software. Results After orally administration of psoralen/isopsoralen for different days, the amount of diosbulbin B in circulating perfusate was relatively increased, and psoralen/isopsoralen showed stronger inhibition to the enzyme after prolonged administration. Compared with the non-intervention group, after treating with psoralen/isopsoralen, the values of area under the curve (AUC_0～t) and mean residence time (MRT_0～t) were increased and the elimination half life (t_1/2Z) values was decreased. Conclusion Psoralen/isopsoralen can inhibit the activity of CYP450 enzyme in the liver, reduce its metabolism of diosbulbin B, reduce the metabolism of diosbulbin B in the liver and cause accumulation. In clinical medication, attention should be paid to the drug interaction that can be produced when Chinese medicine containing psoralen/isopsoralen or diosbulbin B is combined.

R969.1

國(guó)家自然科學(xué)基金資助項(xiàng)目(82174209);廣東省普通高校青年創(chuàng)新人才項(xiàng)目(2021KQNCX039)