中国精神分裂症患者多剂量喹硫平及其代谢产物的药代动力学

Multiple Dose Pharmacokinetics of Quetiapine and its Metabolites in Chinese Suffering From Schizophrenia

目的:研究多剂量喹硫平及其代谢产物在中国精神分裂症患者体内的药代动力学。方法:21名精神分裂症患者给予口服喹硫平,以50mgdd开始,第4d达200mgd次,2次dd,再连续给药4d。第8d采血,用HPCL-MS测定喹硫平及其代谢产物。结果:喹硫平、7-羟基-氮-去烷基-喹硫平、硫氧化喹硫平和7-羟基-喹硫平的主要多剂量药代动力学参数分别为:Tmax(h):2.0(0.3～5.0),4.0(1.5～6.0),3.0(0.5～5.0)和3.0(0.5～5.0);T1d2(h):7±3,9±3,7±3和8±5;Cmsasx(μgdL):678±325,19±5,451±216和58±22;AUC0s～s∞(μg·h·L-1):5534±4198,287±107,3858±2012和529±262。喹硫平的CLdF和VdF分别为(67±25)Ldh和(672±394)L。以固定剂量给药48h内,喹硫平及其代谢产物达稳态。在不同性别间喹硫平及其代谢产物的药代动力学参数无显著性差异。结论:喹硫平在体内吸收快、分布广、主要代谢为硫氧化喹硫平。喹硫平及其三个代谢产物清除速率相似,性别不影响他们的药代动力学。临床治疗剂量不造成体内药物蓄积。

Objective: To study the multiple dose pharmacokinetics of quetiapine and its sulfoxide- , 7- hydroxy- , 7- hydroxy-N- dealkyl- metabolites in Chinese suffering from schizophrenia.Methods: 21 patients ( 11females and 10 males) were givenquetiapine twice a day to control the symptoms.After reach steady state of 200mg twice a day, blood were collected.The plasmaconcentrations of quetiapine and its metabolites were determined by HPLC- MS.Results: The main pharmacokinetic parametersof quetiapine, 7- hydroxy- N- dealkyl- quetiapine, Quetiapine sulfoxide, and 7- hydroxy- quetiapine were as follows: Tmax( h) were2.0 ( 0.3～5.0) , 4.0 ( 1.5～6.0) , 3.0 ( 0.5～5.0) , and 3.0 ( 0.5～5.0) respectively; T1R2 ( h) were 7±3, 9±3, 7±3, and 8±5respectively; C msasx ( μgRL) were 678±325, 19±5, 451±216, and 58±22 respectively;( μgRL) were 51±68, 3±2, 35±36, and 5±4respectively;( μgRL) were 295±144, 13±4, 209±71, and 28±9 respectively;( μg·hRL) were 3 538±1 728, 153±44, 2 512±854,and 335±104 respectively;( μg·hRL) were 5 534±4 198, 287±107, 3 858±2 012, and 529±262 respectively; Ke ( h- 1) were0.11±0.03, 0.08±0.02, 0.11±0.03, and 0.10±0.03 respectively; The CLRF and VRF of quetiapine were( 67±25) LRh and( 672±394)L respectively.The plasma concentrations of the four compounds reached steady state within 48 hours at the dose of 200mginitiation.There were no significant difference between the male and female pharmacokinetic parameters.Conclusion: Quetiapinewas absorbed quickly, distributed widely, and its main metabdite was quetiapine sulfoxide.The elimination speeds of quetiapineand its three metabolites were similar.Gender had no effect on the pharmacokinetics of quetiapine and its metabolites.Therewere no drug accumulation at clinical dosage.