Sattar Haseeb, Jadoon Sarmad Sheraz, Yang Ni, Li Shihong, Xu Mingzhen, Han Yong, Ramzan Adil, Li Weiyong
Department of Clinical Pharmacy, Wuhan Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pharmacology, Hubei University of Traditional Chinese Medicine, Wuhan, China.
Saudi J Med Med Sci. 2020 Sep-Dec;8(3):196-200. doi: 10.4103/sjmms.sjmms_441_19. Epub 2020 Aug 20.
Uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes play a significant role in the metabolism of quetiapine, and coadministration with a UGT inhibitor/inducer drug may change its pharmacokinetic profile.
The objective of this study was to assess the impact of probenecid, a UGT enzyme inhibitor, on the pharmacokinetic profile of quetiapine.
Twelve treatment-naïve, 7-week-old male Sprague-Dawley rats (weighting 161 ± 22 g) were randomly and equally divided into control, quetiapine-alone and quetiapine plus probenecid groups. The quetiapine plus probenecid group received a single oral dose of probenecid (50 mg/kg) followed by 50 mg/kg of quetiapine; the quetiapine-alone group only received 50 mg/kg of quetiapine. Blood samples (0.2 ml) were collected from all rats after 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24 h of the drug administration in heparinized tubes. The pre-established liquid chromatography-mass spectrometry method was utilized to ascertain the plasma concentration of quetiapine and the control group was used to prepare the controlled standard.
Significant pharmacokinetic differences were observed between the quetiapine-alone and quetiapine plus probenecid groups in terms of C (392 ± 209 vs. 1323 ± 343 ug/L, respectively, = 0.004), AUC ( = 0.04) and T ( = 0.004). Further, in the combined drug group, there was a decrease in drug clearance (CL/F) (from 27 ± 11 to 16 ± 3 L/h/kg; = 0.005) and an increase in the volume of distribution (Vd) ( = 0.01), but there was no significant difference between both groups in terms of half-lives ( = 0.27). No significant within-group variability of pharmacokinetic parameters was observed ( = 0.25).
The results of this animal study suggest that glucuronidation by UGT enzyme system may also play an important role in quetiapine metabolism, which, if proven in future human studies, would imply that the bioavailability and pharmacokinetic parameters of quetiapine may require alterations when co-administered with probenecid to avoid development of quetiapine toxicity.
尿苷5'-二磷酸葡萄糖醛酸基转移酶（UGT）在喹硫平的代谢中起重要作用，与UGT抑制剂/诱导剂药物合用可能会改变其药代动力学特征。
本研究旨在评估UGT酶抑制剂丙磺舒对喹硫平药代动力学特征的影响。
将12只未经治疗的7周龄雄性Sprague-Dawley大鼠（体重161±22 g）随机等分为对照组、单用喹硫平组和喹硫平加丙磺舒组。喹硫平加丙磺舒组先口服单剂量丙磺舒（50 mg/kg），随后给予50 mg/kg喹硫平；单用喹硫平组仅给予50 mg/kg喹硫平。给药后0、0.25、0.5、1、2、4、6、8、10、12和24小时，从所有大鼠的肝素化管中采集血样（0.2 ml）。采用预先建立的液相色谱-质谱法测定喹硫平的血浆浓度，并以对照组制备对照标准品。
单用喹硫平组和喹硫平加丙磺舒组在C（分别为392±209 vs. 1323±343 ug/L，P = 0.004）、AUC（P = 0.04）和T（P = 0.004）方面存在显著的药代动力学差异。此外，在联合用药组中，药物清除率（CL/F）降低（从27±11降至16±3 L/h/kg；P = 0.005），分布容积（Vd）增加（P = 0.01），但两组在半衰期方面无显著差异（P = 0.27）。未观察到药代动力学参数在组内有显著差异（P = 0.25）。
该动物研究结果表明，UGT酶系统的葡萄糖醛酸化在喹硫平代谢中可能也起重要作用，如果在未来的人体研究中得到证实，这意味着与丙磺舒合用时，喹硫平的生物利用度和药代动力学参数可能需要改变，以避免喹硫平毒性的发生。
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