Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Abstract

Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC50 of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0–18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53–5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a Ki of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and Cmax) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

Effect of Myricetin on CYP2C8 Inhibition to Assess the Likelihood of Drug Interaction Using In Silico, In Vitro, and In Vivo Approaches

“…Similar observation during CYP-mediated delay in the metabolism of drugs, including amodiaquine, has been reported in the literature. , Quercetin is reported to enhance the oral exposure of repaglinide by 1.8-fold in a rat model . Although amodiaquine has been used as a model drug in the present study, an alteration in the metabolism of such a drug can cause augmentation in oral exposure due to drug interaction, leading to precipitation of dose-dependent severe side effects like hepatotoxicity or agranulocytosis.…”

“… 47 , 48 Quercetin is reported to enhance the oral exposure of repaglinide by 1.8-fold in a rat model. 49 Although amodiaquine has been used as a model drug in the present study, an alteration in the metabolism of such a drug can cause augmentation in oral exposure due to drug interaction, leading to precipitation of dose-dependent severe side effects like hepatotoxicity or agranulocytosis. To achieve the inhibitory effect of myricetin on the activity of hepatic CYP2C8 in rats, the dose of myricetin was given through intravenous route.…”

Factors determining the oral absorption and systemic disposition of zeaxanthin in rats: in vitro , in situ , and in vivo evaluations

“…The hepatic clearance (CL H ) of zeaxanthin can be estimated to be 31.2–49.8 mL/kg from the observed E H of 0.623 and reported hepatic blood flow rate of 50–80 mL/kg (Kim et al. 2021 ). By comparing the CL H and blood CL (calculated as plasma CL/R B ) of zeaxanthin, it can be inferred that the liver is the major eliminating organ of zeaxanthin, accounting for 53.5–90.1% of the total clearance process.…”

Differential effects of ketoconazole, fluconazole, and itraconazole on the pharmacokinetics of pyrotinib in vitro and in vivo

“…This inhibition resulted from a mixed mechanism, incorporating uncompetitive and non-competitive inhibition. For the in vitro parameters, the apparent Ki values exhibited the dissociation constant for the interaction between the inhibitor and the enzyme, The parameter α was indicative of the inhibition type ( Kim et al, 2019 ; Kim et al, 2021 ). When Ki = αKi, namely α = 1, it demonstrated noncompetitive inhibition.…”