Cyp1a2‐knockout increases the systemic exposure of a serotonin and norepinephrine reuptake inhibitor duloxetine in mice

Abstract

Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor for the treatment of major depressive disorder, mainly metabolized by CYP1A2 and CYP2D6 in human. Despite DLX has a good tolerance, serious adverse events (e.g., liver injury) have been reported in rare cases. The role of DLX metabolism in its toxicity remains unclear. Here, we evaluated the effects of systemic Cyp1a2 loss‐of‐function on the pharmacokinetics of DLX using Cyp1a2‐knockout (Cyp1a2‐KO) and counterpart wild‐type (WT) mice. At the clinically relevant dose (12 mg/kg, p.o.), the AUC and Cmax of DLX in Cyp1a2‐KO mice increased by 56% and 106% compared to those in WT mice, which is in line with the clinical observation: Co‐administration of CYP1A2 inhibitor increases the AUC and Cmax of DLX in human subjects. Meanwhile, the AUC of one major circulating metabolite, glucuronide of hydroxylated DLX, decreased by 23% in Cyp1a2‐KO mice, in which CYP1A2 mediates the hydroxylated DLX formation. Unexpectedly, the hepatic level of DLX in Cyp1a2‐KO mice was 21% lower than that in WT mice. But the excretion of DLX in Cyp1a2‐KO mouse feces increased by 78.9%. At subtoxic dose (50 mg/kg, p.o.), the Cmax of DLX increased over 5‐fold and AUC over 10‐fold compared to those at the dose of 12 mg/kg in both WT and Cyp1a2‐KO mice. However, the Cmax and AUC of DLX shown the similar levels in WT and Cyp1a2‐KO, but the hepatic level of DLX in Cyp1a2‐KO mice slightly increased by 12%. In summary, the findings indicated that the loss of Cyp1a2 activity increased DLX systemic exposure at clinical dose and different DLX and metabolite pharmacokinetic profiles were observed in WT and Cyp1a2‐KO mice. The liver toxicity of DLX in Cyp1a2‐KO mice will be pursued in the future studies to determine the role of Cyp1a2‐mediated metabolism in DLX hepatoxicity.