School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China.
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China.
Toxicol Appl Pharmacol. 2021 Jul 1;422:115560. doi: 10.1016/j.taap.2021.115560. Epub 2021 May 3.
Antipsychotic polypharmacy (APP), as one maintenance treatment strategy in patients with schizophrenia, has gained popularity in real-world clinical settings. Risperidone (RIS) and clozapine (CLZ) are the most commonly prescribed second-generation antipsychotics, and they are often used in combination as APP. In this study, the pharmacokinetics of RIS and CLZ in rats were examined after co-administration to explore the reliability and rationality of co-medication with RIS and CLZ. In addition, the effects of CLZ on RIS metabolism and transport in vitro were investigated. The results illustrated that in the 7-day continuous administration test in rats, when co-administered with CLZ, the area under curve and peak concentrations of RIS were increased by 2.2- and 3.1-fold at the first dose, respectively, increased by 3.4- and 6.2-fold at the last dose, respectively. The metabolite-to-parent ratio of RIS was approximately 22% and 33% lower than those of RIS alone group at the first and last doses, respectively. Moreover, CLZ significantly increased RIS concentrations in the brain (3.0-4.8 folds) and cerebrospinal fluid (2.1-3.5 folds) in rats, which was slightly lower than the impact of verapamil on RIS after co-medication. Experiments in vitro indicated that CLZ competitively inhibited the conversion of RIS to 9-hydroxy-RIS with the inhibition constants of 1.36 and 3.0 μM in rat and human liver microsomes, respectively. Furthermore, the efflux ratio of RIS in Caco-2 monolayers was significantly reduced by CLZ at 1 μM. Hence, CLZ may affect the exposure of RIS by inhibiting its metabolism and P-glycoprotein-mediated transport. These findings highlighted that APP with RIS and CLZ might increase the plasma concentrations of RIS and 9-hydroxy-RIS beyond the safety ranges and cause toxic side effects.
抗精神病药联合治疗（APP）作为精神分裂症患者的一种维持治疗策略，在真实临床环境中得到了广泛应用。利培酮（RIS）和氯氮平（CLZ）是最常用的第二代抗精神病药，常联合用于 APP。在这项研究中，考察了 RIS 和 CLZ 联合用药后在大鼠体内的药代动力学，以探讨联合用药的可靠性和合理性。此外，还研究了 CLZ 对 RIS 体外代谢和转运的影响。结果表明，在大鼠 7 天连续给药试验中，与 CLZ 合用时，RIS 的 AUC 和 Cmax 分别在第 1 次剂量时增加了 2.2 倍和 3.1 倍，在最后 1 次剂量时增加了 3.4 倍和 6.2 倍。RIS 的代谢产物与母体的比值在第 1 次和最后 1 次剂量时分别比 RIS 单药组低约 22%和 33%。此外，CLZ 可显著增加 RIS 在大鼠脑（3.0-4.8 倍）和脑脊液（2.1-3.5 倍）中的浓度，略低于与维拉帕米合用时对 RIS 的影响。体外实验表明，CLZ 分别以 1.36 和 3.0 μM 的抑制常数在大鼠和人肝微粒体中竞争性抑制 RIS 转化为 9-羟基-RIS。此外，CLZ 在 1 μM 时可显著降低 RIS 在 Caco-2 单层细胞中的外排率。因此，CLZ 可能通过抑制 RIS 的代谢和 P-糖蛋白介导的转运来影响 RIS 的暴露。这些发现表明，RIS 和 CLZ 的 APP 可能会使 RIS 和 9-羟基-RIS 的血药浓度超过安全范围，导致毒性副作用。
