| PURPOSEA sensitive and rapid LC–MS/MS method has been developed for simultaneousdeterminationof iloperidone and its two major metabolites in human plasma. Theplasma concentrations of ILP, P88, P95in Chinese healthy volunteers weredetermined by the assay. The pharmacokinetic parameters were calculated and theconcentration-time curves of three analytes are drawed. The assay investigated thepharmacokinetic characteristics in vivo and provided data support for the ILP listing.METHODThe simultaneous quantitative analytical assay of iloperidone and its two mainmetabolites was developed by LC-MS/MS. The plasma samples were extracted withsolid-phase extraction method using acetonitrile as the eluent. Three analytes wereseparated on a SUPELCO Ascentis-C18column (50mm×4.6mm I.D.，5μm) usinggradient elution, the mobile phase was consisted of methanol:10mM ammoniumacetate containing0.1%formic acid. The ESI source was operated in positive ionmode using multiple-reaction monitoring (MRM). Iloperidone, P88, P95and IS weremonitored using the transitions fo the protonated molecular ion at m/z427.3→m/z261.0,m/z429.3→m/z261.0,m/z429.3→m/z261.0and m/z256.3→m/z167.1,respectively. The method was fully validated based on FDA guidance,containingprecision and accuracy, specificity, linear, LLOQ, recovery, matrix effectsand stability.In accordance with the Declaration of Helsinki and The Drug AdministrationLaw of the PRC, sixteen healthy Chinese volunteers were orally administrated1mgand3mg iloperridone. Blood samples were collected after oral administration and, the concentrations of ILP and its two main metabolites were determined byLC-MS/MS. The pharmacokinetic parameters were calculated using Drug andstatistics3.0and analyzed by SPSS software in order to evaluate the pharmacokineticcharacteristics of ILP in human.RESULTSThe LC-MS/MS method of simultaneous determination of iloperidone and itstwo main metabolites in human plasma was developed, and there were no interferencepeaks at the retention time of the analytes and IS. The linear ranges of iloperidone andits two main metabolites were all5-1500pg/mL. Intra-and inter day precision andaccuracy of low, middle and high concentrations of quality control samples were allwithin±15%. The recoveries of ILP and its two main metabolites P88, P95were85.89±4.08%,95.17±6.93%,86.07±1.07%;97.98±5.29%,92.29±2.58%,84.04±0.34%and110.96±2.81%,97.00±7.68%,102.04±1.49%, respectively. Thematrix effects of ILP, P88and P95were81.96±5.10%,85.55±9.09%,95.86±1.97%;88.20±2.68%,91.18±10.05%,97.51±1.75%and91.27±5.04%,84.18±3.80%,98.39±2.02%respectively, indicating that no significant interfering from theco-eluting compound from plasma could impact the determination of ILP, P88andP95. The stability of untreated and treated plasma samples was investigated undervarious conditions and, the relative error were all within±15%. The plasma sampleswere extracted after diluted10-fold, the calculated precision and accuracywere within±15%. The developed method of simultaneous determinationof iloperidone and itstwo mainmetabolites was sensitive, selective, rapid, reproducible and has goodprecision and accuracy, and was successfully applied to a clinical pharmacokineticstudy of ILP.After oral administration of1mg and3mg ILP tablets to sixteen healty Chinesevolunteers, the concentrations of three analytes were detected, the concentration-timecurves were drawed. The pharmacokinetic parameters were calculated using DAS3.0software, and analyzed with SPSS, the result shows that the pharmacokinetic processof ILP in human was non-linear kinetics. The pharmacokinetic processes of P88and P95were unable to discern. |
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