Pharmacokinetics And Tissue Distribution Of Iloperidone

Atypical antipsychotics （AAP） were developed in1980s. In the past10years, AAP had been more and more widely applied in clinic as thesecond generation drugs for the treatment of schizophrenia disease. AAPwere effective in the treatment of schizophrenia disease by improvingpositive symptoms, negative symptoms and cognitive defect. Theimprovement of negative symptoms is especially a breakthrough in thetraditional antipsychotic. Its mechanism is to block the5-HT2Areceptor andD₂receptor, and it produces less extrapyramidal reaction system （EPS）. Thesecond generation antipsychotics compared with other traditionalantipsychotics is more safe and effective. Iloperidone， an atypicalantipsychotic was studied in this scientific dissertation.Large number of animal experiments and clinical trials have provedthat IPRD is a dual bloker of the5-HT2Aand D₂rceptor. It can not onlydecrease the dopaminergic activity in cerebral limbic system but alsoincrease the prefrontal cortex’s dopaminergic activity. So it is effective inthe the treatment of schizophrenia’s positive or negative symptoms.Moreover, it can reduce the EPS.In this dissertation the pharmacokinetic and tissue distribution were studied in order to explore its mechanism deeply and provide theoreticalguidance for its combine use with other drugs.for its mechanism of actionresearch, and other drugs combined with the Feasibility Exploration toprovide theoretical guidance.The work developed in this dissertation is as follows,1. Develop a RP-HPLC method for the determination of iloperidone inbiological samples The chromatographic column was C18column（4.6×250mm，5μm， Bnentnach）, mobile phase:V（methanol）:V(10mmol·L^-1potassium dihydrogen phosphate)=80:20（pH7）, flow rate:0.8mL·min^-1, UV detection was282nm and the columntemperature was25℃.In various biological samples, iloperidone get agood linear relationship in the concentration range of1.00^-100.00μg·mL^<sup>-1（r≥0.999）, the limitation of detection is1ng. In plasma samples, the averagerecovery was95.50%and RSD was1.25%. The average recovery in thevarious tissue samples is greater than87%and RSD is less than2%. TheRSD of within-day precision and between-day precicion are less than2.0%and less than2.5%respectively. Overall, the HPLC method for IPRDdeveloped here is simple, accurate and rapid, which can be used in theIPRD determination in various biological samples. precision （RSD） is lessthan2.5%, and during the days the precision is less than2.5%, the methodis simple, accurate and rapid, iloperidone can be used in the determinationof various biological samples. 2. The kinetic characteristics of IPRD in rat was studied bypharmacokinetic experiments. The results Showed that thepharmacokinetics of IPRD in rat fitted with two compartment model. Peakconcentration of three dosage groups were3.14μg·mL^-1、5.78μg·mL^-1、7.90μg·mL^-1. The mean elimination half-life was200mins to300mins.Clearance were0.12μg·mL^-1·min^-1，0.13μg·mL^-1·min^-1，0.13μg·mL^-1·min^-1. Elimination of half-life was dependent on dose.3. The distribution study of iloperidone in mouse showed thatiloperidone can be rapidly and extensively distributed. After30-60minutes,the peak concentration of IPRD in different tissues was observed. Amongall studied tissues, the most concentration is detected in the lung, othertissue distribution order was, spleen> kidney>brain>liver>heart. As a dualantagonist of5-HT2Aand D₂receptor, it showed extremely high affinitywith alpha1-adrenoceptor, high affinity with5-HT2Areceptor and loweraffinity with D₂receptor. Therefore IPRD was distributed in the tissueswhere those three kinds of receptors were focused, which was justconsistent with its pharmacological effects.