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

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.