普萘洛尔对精神分裂症患者体内氯氮平药动学的影响研究

目的：研究精神分裂症患者体内普萘洛尔对氯氮平血药浓度及药动学的影响。方法：选取24位精神分裂症患者，进行氯氮平片试验制剂和参比制剂的随机、开放、2周期交叉的空腹生物等效性试验，其中15人早晚服用氯氮平片100 mg，另外9人服用氯氮平片+普萘洛尔，每周期在固定的时间点进行血样采集，应用高效液相色谱-串联质谱法检测血样中氯氮平的浓度，使用WinNonlin 7.0软件计算参比制剂组氯氮平的药动学参数。结果：与单用氯氮平相比，合并使用普萘洛尔后，氯氮平的平均AUC_0-12、C_min，ss及C_av，ss均显著增高（P=0.043，P=0.017和P=0.042）；合用普萘洛尔组的氯氮平C_max，ss均值也较单用氯氮平组高（854.11±286.47） ng·mL^-1 vs.（671.14±160.98） ng·mL^-1]，但差异无统计学意义；合用普萘洛尔组氯氮平的平均t_1/2显著长于单用氯氮平组（P=0.001）。结论：合并使用普萘洛尔可显著增加氯氮平的系统暴露量，在临床上需注意普萘洛尔对氯氮平的影响。

Effect of propranolol on pharmacokinetics of clozapine in schizophrenics

OBJECTIVE To explore the effect of propranolol on steady-state concentration and pharmacokinetics of clozapine in schizophrenics.METHODS For this randomized, open, two-period, crossover bioequivalence study, generic and brand-name clozapines were assessed under fasting conditions in 15 patients on clozapine monotherapy and 9 patients receiving clozapine plus propranolol. Blood samples were collected at regular intervals during each treatment period and plasma concentration of clozapine was determined by high performance liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters of brand-name clozapine were calculated by WinNonlin 7.0.RESULTS Mean AUC _0-12, C_min,ss and C_av,ss of clozapine were all signicantly higher for clozapine plus propranolol than clozapine alone (P=0.043, P=0.017 and P=0.042). The average value of C_max,ss for clozapine was higher in the presence than that in the absence of propranolol(854.11±286.47) vs. (671.14±160.98) ng·mL^-1]. However, there was no statistically significant difference between them (P=0.074). Mean t_1/2 of clozapine was significantly longer in the presence than that in the absence of propranolol (P=0.001).CONCLUSION Combined use of propranolol may significantly boost systemic exposure of clozapine and such an interaction should be considered for prescribing decisions.