Effect of Organic Anion Transporting Polypeptide 1B1 on Plasma Concentration Dynamics of Clozapine in Patients with Treatment-Resistant Schizophrenia

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Dec 17

PMID 39684938

Authors

Toshihiro Sato

Takeshi Kawabata

Masaki Kumondai

Nagomi Hayashi

Hiroshi Komatsu

Yuki Kikuchi

Go Onoguchi

Yu Sato

Kei Nanatani

Masahiro Hiratsuka

Masamitsu Maekawa

Hiroaki Yamaguchi

Takaaki Abe

Hiroaki Tomita

Nariyasu Mano

Affiliations

Soon will be listed here.

Abstract

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.

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