| Summary: | 碩士 === 國立成功大學 === 臨床藥學與藥物科技研究所 === 105 === INTRODUCTION
Lurasidone is a novel atypical antipsychotic drug that was recently approved for the treatment of schizophrenia and bipolar depression by the the Food and Drug Administration of United States. Lurasidone has potent blocking activities for the dopamine D2 and serotonin 5-HT2A receptors, but weak or negligible actions for histamine H1, acetylcholine M1 receptors. Based on the mechanism of action, lurasidone which was associated with less weight gain, sedative effects and anticholinergic effects, has a better tolerability than the other antipsychotic drugs.
CYP3A isozymes, one of the most important and abundant CYP450 subfamilies in the liver, are the major enzymes that are responsible for the metabolism of lurasidone. Thus, drugs that induce or inhibit CYP3A enzymes would be expected to change the clearance of lurasidone. Currently, more and more patients have taken Chinese herbal drugs or nutraceuticals as complementary and alternative treatment for insomnia or emotion disorders. Among these Chinese herbal drugs, a lot of them are involved in the drug metabolism by CYP3A. To date, research on drug interactions of lurasidone and Chinese herbal drugs or food is rare and worthy of further study.
The use of selected drugs as in vivo CYP3A probes in drug therapy is of great importance. Previous studies have demonstrated that the clearance of a CYP3A substrate mosapride was well correlated with hepatic and intestinal CYP3A contents and reflected the in vivo CYP3A activity. Therefore, mosapride could be a potential CYP3A probe applicable to drug interactions of lurasidone.
PURPOSE
The objectives of this study were to investigate pharmacokinetics and drug interactions of lurasidone in rats. In addition, in vivo CYP3A probe-mosapride was used for measuring hepatic CYP3A activity and evaluating the lurasidone clearance in rats to support the application of mosapride. A new HPLC method for determination of lurasidone in rat plasma was also developed and applied to explore its kinetics.
METHODS
Two sensitive high-performance liquid chromatography (HPLC) methods, one for quantification of lurasidone using delavirdine as an internal standard, the other for simultaneous determination of mosapride, lurasidone and two metabolites of lurasidone in rat plasma were developed. The analytes and internal standards were separated on Thermo Hypurity C18 column (4.6 mm × 250 mm, 5 μm) and protected by an ODS guard column (10 mm × 4 mm, 5 μm). Fluorescence and ultraviolet detectors were used in this study. Since lurasidone has fluorophoric properties, fluorescent detection (FD) was expected to provide an inexpensive, sensitive, and specific detection of lurasidone in biological samples. The two methods have been fully validated in terms of selectivity, linearity, accuracy, precision, stability, matrix effect and recovery. To investigate the applicability of mosapride as a CYP3A probe, each rat was received mosapride and lurasidone simultaneously by iv route in the control group. CYP3A activities of rats were modulated by the pretreatment with ip dexamethasone or iv ketoconazole for the induction and inhibition group, respectively. Co-medication of wu wei zi or cranberry juice with lurasidone via iv and oral routes were employed to investigate potential drug interactions. The plasma concentrations of lurasidone, its metabolites and mosapride were determined by HPLC methods and the kinetics parameters were estimated by compartmental analysis.
RESULTS
The developed HPLC methods were found to be specific, precise and accurate. Calibration curves for lurasidone was constructed over a range of 0.001 μg/mL to 10 μg/mL. The two sensitive HPLC methods were developed and successfully applied to quantify lurasidone and its metabolites in small volume of rat plasma. The disposition kinetics of lurasidone in rats displayed two-compartmental characteristics, with a distribution half-life of 30 minutes and an elimination half-life of 800 minutes. The clearance of lurasidone and mosapride remained unaltered in rats after induction with dexamethasone, but the elimination rate of the metabolites was obviously accelerated. In the presence of CYP3A inhibitor, ketoconazole, clearance of lurasidone and mosapride decreased significantly. Moreover, disposition kinetics of metabolites were changed. Clearance of mosapride and lurasidone can be well predicted by using a single point of plasma concentration of mosapride. When wu wei zi or cranberry juice was orally administered 30 minutes before oral administration of lurasidone, the AUC of lurasidone increased significantly. However, when wu wei zi was orally administered 2 or 12 hours before lurasidone, the AUC of lurasidone showed no significant difference. In the aged group, cranberry juice did not affect the systemic exposure of lurasidone. Interestingly, the iv disposition of lurasidone remained unchanged after oral intake of wu wei zi or cranberry juice.
CONCLUSION
The correlation between the clearances of mosapride and lurasidone supports the applicability of mosapride as an in vivo hepatic CYP3A probe. Mosapride concentration at 90 min after a single intravenous dose was useful in predicting total body clearance of lurasidone. The fact that wu wei zi and cranberry juice affect only the absorption but not disposition kinetics of lurasidone suggested that the interactions were due to inhibition of intestinal but not hepatic CYP3A activity.
|
|---|
