Sato Toshihiro, Kawabata Takeshi, Kumondai Masaki, Hayashi Nagomi, Komatsu Hiroshi, Kikuchi Yuki, Onoguchi Go, Sato Yu, Nanatani Kei, Hiratsuka Masahiro, Maekawa Masamitsu, Yamaguchi Hiroaki, Abe Takaaki, Tomita Hiroaki, Mano Nariyasu
Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan.
Graduate School of Information Sciences, Tohoku University, Sendai 980-8578, Japan.
Int J Mol Sci. 2024 Dec 9;25(23):13228. doi: 10.3390/ijms252313228.
The involvement of drug-metabolizing enzymes and transporters in plasma clozapine (CLZ) dynamics has not been well examined in Japanese patients with treatment-resistant schizophrenia (TRS). Therefore, this clinical study investigated the relationship between single nucleotide polymorphisms (SNPs) of various pharmacokinetic factors (drug-metabolizing enzymes and transporters) and dynamic changes in CLZ. Additionally, we aimed to determine whether CLZ acts as a substrate for pharmacokinetic factors using in vitro assays and molecular docking calculations. We found that 6 out of 10 patients with TRS and with multiple organic anion transporting polypeptide (OATP) variants (OATP1B1: , ; OATP1B3: 334T>G, 699G>A; and OATP2B1: , 935G>A, 601G>A, 76_84del) seemed to be highly exposed to CLZ and/or -desmethyl CLZ. A CLZ uptake study using OATP-expressing HEK293 cells showed that CLZ was a substrate of OATP1B1 with and values of 38.9 µM and 2752 pmol/mg protein/10 min, respectively. The results of molecular docking calculations supported the differences in CLZ uptake among OATP molecules and the weak inhibitory effect of cyclosporine A, which is a strong inhibitor of OATPs, on CLZ uptake via OATP1B1. This is the first study to show that CLZ is an OATP1B1 substrate and that the presence of SNPs in OATPs potentially alters CLZ pharmacokinetic parameters.
在日本难治性精神分裂症（TRS）患者中，药物代谢酶和转运体对血浆氯氮平（CLZ）代谢动态的影响尚未得到充分研究。因此，本临床研究调查了各种药代动力学因素（药物代谢酶和转运体）的单核苷酸多态性（SNP）与CLZ代谢动态变化之间的关系。此外，我们旨在通过体外试验和分子对接计算来确定CLZ是否为药代动力学因素的底物。我们发现，10例TRS且存在多种有机阴离子转运多肽（OATP）变体（OATP1B1： ， ；OATP1B3：334T>G，699G>A；以及OATP2B1： ，935G>A，601G>A，76_84del）的患者中，有6例似乎对CLZ和/或去甲基CLZ高度暴露。使用表达OATP的HEK293细胞进行的CLZ摄取研究表明，CLZ是OATP1B1的底物，其Km和Vmax值分别为38.9 μM和2752 pmol/mg蛋白/10分钟。分子对接计算结果支持了OATP分子之间CLZ摄取的差异以及环孢素A（一种OATP的强抑制剂）对通过OATP1B1摄取CLZ的弱抑制作用。这是第一项表明CLZ是OATP1B1底物且OATP中SNP的存在可能改变CLZ药代动力学参数的研究。
