| OBJECTIVESTo study the multiple dose pharmacokinetics of Ziprasidone (ZIP), an atypical antipsychotic drug, and the relationships between its plasma concentration and clinical efficacy of it for Chinese schizophrenic, as well as the influence on blood sugar and lipo-metabolism; at the same time, to study the interaction between ZIP and P-glycoprotein (P-gp) by assessing the effects of ZIP on the function of P-gp and the effects of P-gp on transportation of ZIP across Caco-2 monolayer model.METHODS1,Determination of Ziprasidone by Ultra-performance Liquid Chromatography-tandem Mass SpectrometryThe UPLC separation was carried out with an acquity UPLCTM BEH C18 column (50×2.1mm i.d.,1.7μm particle size) and methanol-water (50:50, v/v, the water phase including 15 mM NH4Ac and 0.125% methanoic acid) as a mobile phase. The detection was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI). The column temperature was 40℃, and was run at a flow rate of 0.25 mL/min.2,Steady-State Pharmacokinetic Properties of ziprasidone 60 mg PO q12h in Chinese Adults with Schizophrenia:Sixteen (eight male and eight female) Chinese schizophrenics were given ziprasidone hydrochloride 60 mg PO q12h according to the experimental procedure designed. Plasma was collected at nine time-points after the last dosing. These samples were analyzed using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The data analysis of pharmacokinetic parameters was performed by using the DRUG AND STATISTICS software (DAS, version 2.0; Mathematical Pharmacology Professional Committee of China). The peak concentrations of ziprasidone (Cmax) and the time to Cmax (Tmax) were determined by inspecting the individual plasma concentration-time profiles of the drug.3,The relationships between plasma concentration and clinical efficacy of ziprasidone for Chinese schizophrenicFifty-two Chinese schizophrenics participated in the study and forty-one completed it. Patients were given ziprasidone hydrochloride according to the designed experimental procedure designed, and the plasma was collected at different time-points during the study. The efficacy was assessed by PANSS before and after 1,2,3 and 4 weeks of therapy.4,To study the influence of ZIP on blood sugar and lipo-metabolism for Chinese schizophrenic, as well as its clinical safety.Fasting blood samples of the forty-one Chinese schizophrenics were assayed for a complete blood count and concentrations of plasma glucose, cholesterol (total, HDL and LDL), and triglycerides at baseline and week 4 using standard laboratory procedures. Insulin immunometric assays were performed using an Immulite Analyzer. There was no significant difference in any of the above outcomes measures comparing baseline to week 4 (p>0.05). Ziprasidone had no effects on blood sugar, blood lipid and body-weight of patients. The dosage of 120 mg·d-1 of ziprasidone was well tolerated for Chinese schizophrenics.5,Cell culture and establishment of Caco-2 cell monolayer modelCaco-2 cell and ECV304 cell were cultured with MEM (Modified Eagle's Medium) and were applied to study the effects of ziprasidone on the function of P-gp, as well as the effects of P-gp on the transportation of ZIP. 6,Cytotoxicity in vitroMTT (Methyl thiazolyl tetrazolium) assay was applied to determine the maximum non-cytotoxic dose of test drug, ZIP, to ensure the activity of cells during the test and to consult the maximum test concentration of ZIP.7,Rho-123 uptake experiments assay the the function of P-gpECV304 cell was used as negative control.. Verapamil was used as positive control of the inhibitory effect on the function of P-glycoprotein. Flowcytometry was used to study the effects of ZIP on the uptake of rhodamine-123 which was a substrate of P-gp in Caco-2 cell.8,Effects of P-gp on the transportation of ZIP using Caco-2 cell monolayer modelTo study the effects of P-glyeoprotein on transportation of Ziprasidone across Caco-2 monolayer model. The cell monolayer model on transwell plate was used. The effects of duration,drug concentration and P-gp inhibitor (verapamil) on the transportation of Ziprasidone were detected by studying the bi-direction transportation of the drug through transwell plate. The amount of transportation of Ziprasidone was detected with UPLC-MS/MS and the apparent permerbility coefficient (Papp) was obtained. Consequently, the transportation of Ziprasidone across Caco-2 monolayer model was estimated.CONCLUSIONS1. We obtained the pharmacokinetics parameters of ZIP for Chineseschizophrenic firstly. The results of this pharmacokinetic study and the comparison with previous obtained other studies indicated that oral ziprasidone had a predictable pharmacokinetic profile, characterized by the AUC and Cmax increased dose-proportionally, and t1/2 depended on dose level; meanwhile, the value of t1/2 and AUC of our study were littler than the reported date. Accordingly, these results supported the use of ziprasidone in the treatment of schizophrenia in Chinese patients, and the dosage adjustment and dose interval should be considered.2. The clinical efficacy of ZIP was correlative with the plasma concentration of it in schizophrenic. It could obtain better results when the steady state trough concentration of ZIP was above 110.0 ng·mL-1. Overall, plasma concentration monitor for ZIP is necessary to optimize ZIP therapy.3. It was the first time to study the interaction between ZIP and P-glycoprotein (P-gp). There was no difference between ziprasidone groups of the three concentration of 0.1,1,10μmol/L and negative control group in the intracellular fluorescence (P>0.05), but the intracellular fluorescence of verapamil group was significantly higher than those of drug-groups (P<0.05). As a result, ZIP had no effect on the function of P-gp.4. It was the first time to study the effect of P-gp on the transportation of ZIP using Caco-2 cell monolayer model. The Papp decreased with the increased concentration of ZIP. The P-gp inhibitor (veravamil) could influence the transportation of ZIP significantly (P<0.05).When ZIP was used in conjunction with the inhibitors of P-gp clinically, drug interaction should be observed.
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