Effects of loganin on the pharmacokinetics of voriconazole in rats with acetaminophen-induced hepatotoxicity

Abstract

Voriconazole, an antifungal agent belonging to the triazole class, is effective against mold infections. Fungal infections are common in patients with immune diseases. In this experiment, acetaminophen induces liver toxicity in mice, confirming changes in the pharmacokinetics of voriconazole. It also investigates changes in liver protection when affected by loganin and its effect on the pharmacokinetics of voriconazole. Pharmacokinetic studies involved the administration of voriconazole via both intravenous and oral routes to rats. Tests were performed to evaluate the drug's plasma levels through both intravenous (at 10 mg/kg) and oral (at 20 mg/kg) administration of voriconazole. To verify metabolism within liver microsomes, calculations were made for the maximum velocity (Vmax), Michaelis-Menten constant (Km), and intrinsic clearance (CLint) for metabolic processes occurring in both liver and intestinal microsomes. After intravenous or oral administration of voriconazole, the total area under the plasma concentration time curve (AUC) of the APAP rats, which is a hepatotoxic model, was significantly larger than that of the AL rats administered with loganin, which is a protective substance. In addition, there was also a decrease in the time mean gap (CL). In an in vitro metabolic study, the APAP rats showed reduced levels of CYP2C19 and CYP3A4 in the liver, and subsequently recovered from the AL rats. In vitro metabolic studies, in liver microsomes, the APAP rats reduced Vmax and CLint. In conclusion, in the APAP rats, there was an absence of voriconazole metabolism and excretion, leading to an AUC increase due to reduced CL. It was confirmed that the AUC recovered compared to the APAP rats when loganin (AL rats) was administered, alongside restored CYP expression and enzyme activity. The restoration of voriconazole metabolism and AUC was confirmed upon concurrent administration of loganin. Key words: voriconazole, acetaminophen, loganin, CYP3A1/2, CYP 2C19