| OBJECTIVESTo study the multiple dose pharmacokinetics, metabolic methanism and the relationships beween plasma concentration and efficacy and side effect.METHODS1. Dose administrationDuring the first period (day 1-8), multiple and rising doses of Q were given to the subjects twice daily (b.i.d). The dosage started at 25mg b.i.d, reached 200mg b.i.d by d 4 and remained at 200mg b.i.d on day 57. On day 8, only 200mg Q in the morning and 7.5mg M in the evening were given. During the second period (day 9-12), fixed doses of Q (200mg, b.i.d) and erythromycin (500mg, three times daily) were co-administered to the subjects. On day 12, a final combination dose of Q (200mg) and erythromycin (SOOmg) in the morning and 7.5mg M in the evening was given. From d 13 on, fixed doses of Q (200mg, b.i.d) were given alone.2. Blood samples collectionSamples for determination of Q and its metabolites were collected before and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24h after the morning doses of Q. Samples for determination of M and OM were collected at Ih after M administration. Plasma was separated by centrifuging and then stored at -80癈.3. Sample analysisVI3.1 Q and its three metabolites were determined by HPLC-MS.3.2 M and OM were determined by HPLC-DAD4. Efficacy and side effect assessment4.1 The efficacy was assessed by BPRS, SANS and SAPS before and after 1, 2 and 3 weeks of therapy.4.2 Side effect was assessed by TESS after 1, 2 and 3 weeks of therapy.RESULTS1. Determine Q and its metabolitesThe calibration curves were linear in the ranges of 102000ug'L' for Q and QS, and l200p.g-L"1 forQO and QN. The average extraction recoveries for all the four compounds were above 85%. The methodology recoveries were much higher than 95%. The intra-day and inter-day RSD were less than 15%.2. Pharmacokinetics of Q and its metabolitesQ: W 2.0(0.35.0)h, t,/2: (7.1?.2)h, C^: (678.0 + 324.5)(ig-I/1, Qn: (50.5 ?68.4)ug-l/1, C" :(294.9 ?144.0)ng-L'1, AUC^, :(3538 ?1728)ug-h-L'', AUC^:(5534? 198)ug-h-L:', CL/F: (66.9?5.2) L-h'1 ^n V/F (671.9 + 393.9) L,Ke:0.111+0.033h'1.QN: tmax: 4.0 (1.5-6.0) h, t1/2: (9.4 + 2.7) h, C?(18.7 + 5.4)^-^, Cn: (3.3 + 1.6)ug-L-1, C: (12.8?.6)ug-L-', AUCl,2: (153+44)jig-h-L-', AUCl.: (287 + 107)ug-h-L'', Ke: (0.079 + 0.019) h'1.QS: w. 3.0 (0.5-5.0) h , t,/2: (7.0 + 3.2) h, c^: (451.2 + 216.1 ^g-L'1, Cin: (34.7?6.4)ng-L'1, c;: (209.4 + 71.2)ug-L'', AUC?12: (2 512?54)ug-L"', AUC^:(3 858 + 2 012)ug-h-L'', Kc: (0.112?.032) h'1.QO: tmax: 3.0 (0.5-5.0)h; t,,2: (7.8 + 5.\)h, C^ : (58.3 +22.4)ug-L-', C,;,,: (4.7?.1)ug-L'', c;: (27.9^8.7)ug-L-', AUC?[2: (335?104)ug-h-L'', Al'Ct,: (529?62)pig-h-L'1, Ke: (0.103 + 0.028)^'.viiThese parameters were not statistically different between genders.3 . The inhibit effect of Erythroraycin en Q metabolismIn the presence of erythromycin:For midazolam. plasma concentration ratio of l'-hydroxy- midazolam to midazoam (OM/M) decreased (P<0.05)For quetiapine. the mean C^, AUC^X , AUC^ and t,/2 elevated (PO.05), the mean CL/F and Ke decreased (PO.05), the mean V/F showed no statistical change. The variation of AUC^24 was significantly negative correlated to that of OM/M and the variation of CL/F was significantly positive correlated to that of OM/M.For quetiapine sulfoxide, the meai C^and Ke decreased (P<0.05), the mean ti/2 elevated (P<0.05), the mean AUC"U and AUC"^ displayed no statistical change, and the variation of ty2was significantly positive correlated to that of OM/M.For 7-hydroxy-quetiapine, the mean Ke decreased (PO.05), the mean t1/2 elevated (PO.05). The variations of pharmacokinetic parameters were not correlated to that of OM/M.For 7-hydroxy-N-desalkyl-quetiapine, the mean C^ , AUC^ and AUC "-? decreased (PO.05), the mean Kg and t]/2 showed no statistical change. The variation of AUC^ was significantly positive correlated to that of OM/M.4. The relationship of efficacy and plasma concentrations of Q and its metabolitesA... |
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