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Clozapine impaired the hypoglycemic effect of metformin by inhibiting hepatic organic cation transporter 1 (OCT1)

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

Atypical antipsychotics often cause hyperglycemia, with clozapine showing the highest risk. Metformin is a first-line medication for managing diabetes or prediabetes and is often used to control clozapine-induced hyperglycemia. Clinical studies, however, have reported metformin resistance in some clozapine-treated patients, but the underlying mechanism remains unclear. In this study, we investigated the mechanism by which clozapine impaired the hypoglycemic effect of metformin and developed a mechanism-based semi-PBPK-PD model to predict the effect of clozapine on the pharmacokinetics and hypoglycemic effect of metformin in rats. Rats received clozapine (50 mg·kg−1·d−1, i.g.) for 7 days. The rats received metformin (200 mg/kg, i.g.) at 0.5 h after the last dose on D7. IPGTT or pharmacokinetics study was performed at 0.5 h after the administration of metformin. We showed that clozapine impaired the hypoglycemic effect of metformin during the glucose tolerance test without altering the plasma exposure of metformin in the rats. The liver is the main target for the hypoglycemic effect of metformin. We showed that clozapine significantly reduced the hepatic distribution of metformin, inhibited metformin uptake in rat livers and rat primary hepatocytes, and inhibited the glucose consumption enhanced by metformin in rat primary hepatocytes. OCT1 mediates the hepatic uptake of metformin. We demonstrated that clozapine dose-dependently inhibited metformin uptake in HEK293-OCT1 cells with the IC50 value of 8.9 μM. Silencing OCT1 in rat primary hepatocytes impaired metformin uptake and attenuated the enhanced glucose consumption by metformin, suggesting that clozapine impaired the hypoglycemic effect of metformin by inhibiting OCT1-mediated hepatic uptake. Subsequently, a semi-PBPK-PD model was constructed based on this mechanism. The model well predicted the decreased hepatic exposure and hypoglycemic effect of metformin in the rat co-administered with clozapine.

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Fig. 1: Schematic diagram of the semi-PBPK-PD model illustrating the pharmacokinetics and hypoglycemic effect of metformin during IPGTT.
Fig. 2: Effects of clozapine on the pharmacodynamics and pharmacokinetics of metformin in rats.
Fig. 3: Effects of clozapine on the intestinal absorption and renal excretion of metformin.
Fig. 4: Effects of clozapine on the distribution of metformin in liver, intestine, pancreas, muscle, and adipose in rats.
Fig. 5: Clozapine inhibited the stimulation of glucose consumption by metformin partly by inhibiting OCT1-mediated hepatic metformin uptake.
Fig. 6: The development of the semi-PBPK-PD model characterizing the DDI between metformin and clozapine in rats.
Fig. 7: Sensitive analysis of the semi-PBPK-PD model.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82173884).

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Authors and Affiliations

  1. Department of Pharmacy, Nanjing Drum Tower Hospital, China Pharmaceutical University, Nanjing, 210008, China

    Wen-han Wu

  2. Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

    Wen-han Wu, Yi-dong Dai, Wen-ke Feng, Hao-ran Chen, Xin-yue Zhu, Ling Jiang, Xiao-dong Liu & Li Liu

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Contributions

WHW was responsible for conceptualization, methodology, investigation, formal analysis, validation, and writing-original draft. LL and XDL were responsible for conceptualization, methodology, writing-reviewing, editing, supervision, and funding acquisition. LJ was responsible for methodology, writing-reviewing, and editing. YDD was responsible for investigation, validation, and data curation. WKF, HRC, and XYZ were responsible for investigation.

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Correspondence to Ling Jiang, Xiao-dong Liu or Li Liu.

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Wu, Wh., Dai, Yd., Feng, Wk. et al. Clozapine impaired the hypoglycemic effect of metformin by inhibiting hepatic organic cation transporter 1 (OCT1). Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01707-3

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