Pharmacokinetic Evaluation of Metabolic Drug Interactions between Repaglinide and Celecoxib by a Bioanalytical HPLC Method for Their Simultaneous Determination with Fluorescence Detection

Abstract

Since diabetes mellitus and osteoarthritis are highly prevalent diseases, combinations of antidiabetic agents like repaglinide (REP) and non-steroidal anti-inflammatory drugs (NSAID) like celecoxib (CEL) could be commonly used in clinical practice. In this study, a simple and sensitive bioanalytical HPLC method combined with fluorescence detector (HPLC-FL) was developed and fully validated for simultaneous quantification of REP and CEL. A simple protein precipitation procedure and reversed C18 column with an isocratic mobile phase (mixture of ACN and pH 6.0 phosphate buffer) were employed for sample preparation and chromatographic separation. The fluorescence detector was set at a single excitation/emission wavelength pair of 240 nm/380 nm. The linearity (10–2000 ng/mL), accuracy, precision, extraction recovery, matrix effect, and stability for this method were validated as per the current FDA guidance. The bioanalytical method was applied to study pharmacokinetic interactions between REP and CEL in vivo, successfully showing that concurrent administration with oral REP significantly altered the pharmacokinetics of oral CEL. Furthermore, an in vitro metabolism and protein binding study using human materials highlighted the possibility of metabolism-based interactions between CEL and REP in clinical settings.

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

“…The in vivo intravenous and oral doses of RPG and QCT were selected based on previous rat pharmacokinetic studies [ 43 , 44 , 45 , 46 ]. In our present rat study, the urinary and fecal excretion of RPG administered intravenously was negligible (≤1.60% of the dose) [ 36 ], suggesting that RPG is primarily eliminated via metabolic routes. Assuming that RPG is metabolized exclusively by the liver, the hepatic clearance (CL H ) of RPG becomes equivalent to its blood clearance (calculated as CL/R B = 9.11 mL/min/kg).…”

“…The concentrations of RPG and QCT in the buffer, microsomes, and (diluted) plasma samples were determined as reported previously [ 36 , 37 ], with slight modifications. For RPG, 50 μL of the sample (or 120 μL of the plasma sample obtained from the in vivo pharmacokinetic study) was deproteinized with 300 μL of acetonitrile that contain ketoconazole (internal standard; 100 ng/mL).…”

A Review of Analytical Methods for Determination of Type- Ii Antidiabetic Drugs in Pharmaceuticals and Biological Matrices

“…The bioanalytical method was applied to the study of pharmacokinetic interactions between repaglinide and Celecoxib in vivo study. Furthermore, an in vitro metabolism and protein binding study using human [plasma/urine]materials highlighted the possibility of metabolism-based interactions between Celecoxib and repaglinide in a study of clinical settings [60].…”

In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole

“…The peaks of the analytes at the LLOQ should be discrete, identifiable, and reproducible with acceptable precision (<20%) and accuracy (within 80-120%). The extraction recovery, matrix effect, dilution integrity, and stability (under bench-top, freeze-thaw, post-preparative, and long-term conditions) in addition to the intra-assay (five different samples) and inter-assay (five different runs) precision and accuracy for each analyte were determined at the LLOQ and three different QC levels as described in the US FDA guidelines and in previous studies [11,[17][18][19]].…”

“…As shown in Figure 2, the fluorescence emission profiles of the two compounds were similar, exhibiting the maximum fluorescence intensity at excitation and emission wavelengths of 280 and 323 nm, respectively. The wavelength pair for the internal standard was set at 240 nm/380 nm (excitation/emission), which was optimized in our previous study [18]. The composition of mobile phase was optimized with respect to the pH and ACN content.…”