罗通定和羟考酮体外代谢的相互作用

目的体外实验考察罗通定(RTD)和羟考酮(OCD)对细胞色素P450(CYP)同工酶的抑制和诱导作用,分析预测两药合用时潜在的药物代谢性相互作用。方法将混合人肝微粒体与RTD,OCD或阳性抑制剂与CYP探针底物孵育30min,用高效液相色谱-质谱法测定孵育液中特异性探针底物代谢产物的生成率、得到各同工酶的相对活性并计算相应的CYP同工酶的IC50值,评价两药对CYP1A2,CYP2C9,CYP2C19,CYP2D6和CYP3A4的潜在抑制作用。RTD(20,200和2000μg·L-1)、OCD(2,20和200μg.L-1)或阳性诱导剂与原代SD大鼠肝细胞孵育72h后加入特异性探针底物再孵育60min、测定细胞孵育液中探针底物的清除率、计算得到相对酶活性,通过与阳性诱导剂组的比较评价RTD和OCD对CYP1A和CYP3A的诱导作用。结果OCD对CYP1A2,CYP2C9,CYP2C19,CYP2D6和CYP3A4均无诱导和抑制作用。RTD对CYP2D6有一定的抑制作用,IC50值为3.72μmol·L-1,除此之外对其他的CYP同工酶无诱导和抑制作用。结论RTD是CYP2D6的一个中等程度的抑制剂,在体内血浆水平相当或高于其IC50值(3.72μmol·L-1)时,RTD对OCD经CYP2D6酶介导的O-去甲基化代谢途径有一定的抑制作用,但是在临床常用剂量水平上RTD和OCD临床合用产生明显的代谢性相互作用的可能性很小。

Metabolic interaction between rotundine and oxycodone in vitro

AIM To investigate inhibitory and inducing potencies of rotundine (RTD) and oxycodone (OCD) on liver cytochrome P450 (CYP) isoforms, and assess the potential metabolic drug-drug interaction of the two drugs when they are clinically coadministrated. METHODS RTD and OCD (0-50 μmol·L^-1) were incubated with human liver microsome for 20 min at a series of concentrations, in the presence of NADPH and a group of CYP probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. CYP isoform- specific inhibitors were tested in parallel as positive controls. The relative activities of CYP isoforms were determined by analyzing the formation of the substrate metabolites using LC-MS. Subsequently the IC₅₀ value was calculated for each CYP isoforms tested. The inhibitory potencies of RTD and OCD on CYP1A2, CYP2C9, CYP2D6 and CYP3A4 were then evaluated. RTD 20, 200 and 2000 μg·L^-1, OCD 2, 20 and 200 μg·L^-1 or CYP specific inducers were incubated with primary rat hepatocytes for 72 h, which was followed by incubating the hepatocytes with a group of CYP substrates for additional 60 min. The metabolic clearance for each substrate in incubates was measured, which was used to calculate the relative CYP activities of CYP1A and 3A. The data obtained from the groups treated with RTD and OCD were then compared with those from known inducers to assess their inducing potencies. RESULTS Under the experimental conditions applied in this study, OCD did not show any inhibitory or inducing potencies on all the CYP isoforms tested. RTD only demonstrated a moderate inhibitory potency on CYP2D6, with IC50 of 3.72 μmol·L^-1. CONCLUSION RTD is classified as a moderate inhibitor of CYP2D6. Inhibition of CYP2D6 by RTD at a plasma level equal to or higher than its IC₅₀ (3.72 μmol·L^-1) may result in the decrement of OCD O-demethylation in vivo. However, it is expected that the metabolic interaction between RTD and OCD will not be clinically significant at the ordinary clinical dose levels of these two drugs.