Pharmacokinetics And Tissue Distribution Of Agomelatine

The drug treatment is a common method for depression. The firstgeneration of classic antidepressants includes monoamine oxidaseinhibitors （MAOI） and tricyclic antidepressants （TCA）. The secondgeneration of classic antidepressants includes selective serotoninreuptake inhibitors （SSRIs）, selective serotonin and norepinephrinereuptake inhibitors （SSNRIs）, noradrenergic and specific serotonergicantidepressant. The development of the new antidepressants is veryquickly. In1980s, the first generation of antidepressants has beenreplaced because of their more adverse reactions. Compared withtraditional antidepressants, they have different chemical structures andmechanisms which make them be of more safety and greater efficiency.In this study, a new antidepressant agomelatine was studied. Anumber of experimental results, including animal experiments andclinical trials, proved that agomelatine had good antidepressant effect,especially in patients with major depressive disorder associated withsleep disorders, and moreover it had less residual effects, adversereactions. Compared with other antidepressants, agomelatine had a new pharmacological effect. It can stimulate melatonin receptor specificallyso as to regulate the patient’s circadian rhythms and improve sleepquality. At the same time, as an antagonist of5-HT2C receptors, it alsocan play the role of its antidepressant.In order to explore the mechanism of agomelatine deeply and findits rational and effective application in clinic, the study ofpharmacokinetics and tissue distribution of agomelatine has a greattheoretical and practical significance.1. Developing a RP-HPLC method for the determination of agomelatinein biological samples.Objective To develop a RP-HPLC method for the determination ofagomelatine in biological samples. Method Column was C18（4.6×250mm，5μm，Bnentnach）; mobile phase was methanol-water（75:25, V/V）; the flow rate was0.8mL·min-1, the detection wavelengthwas230nm, the column temperature was25℃. Result The linear rangewas0.50⁸0.00μg·mL^-1in the biological samples. LOD was3ng·10μL^-1.The biological samples were removed protein with methanol. Theaverage recovery of plasma samples was100.85%, and the RSD was lessthan3%. The mean recovery of tissue samples were more than85%, theRSD were less than4%. Conclusion The method was simply, sensitiveand repeatability for the determination of agomelatine in biologicalsamples. 2. Pharmacokinetics study of agomelatineThe kinetic characteristics of agomelatine in rat was studied bypharmacokinetic experiments. The results showed that thepharmacokinetics of agomelatine in three dosage groups fitted with twocompartment model in rat. The weight coefficient was1. In three dosagegroups, peak concentration were3.98μg·mL^-1，7.97μg·mL^-1，11.31μg·mL^-1respectively. Peak time were0.82h，0.83h and0.72h afteradministration which were independent of dose. The mean eliminationhalf-life was3to4hours. Elimination of half-life was dependent on dose.Clearance were9.15L·kg^-1·h^-1，7.07L·kg^-1·h^-1，6.98L·kg^-1·h^-1.3. Tissue distribution study of agmelatineThe tissue distribution of agmelatine was studied. The resultsshowed that agomelatine can be rapidly distributed in mouse body. After1¹.5h, peak concentration was observed in tissues. The largest numberof agomelatine was concentrated in liver, the second place was in thebrain. The distribution behavior was similar in three dosage groups. Thehigher concentration of agomelatine in brain was just consistent with thedistribution of melatonin receptor and5-HT2C receptor, which was justembodying agomelatine’s particular antidepressive effect.