Simultaneous quantification of volitinib and gefitinib in rat plasma by HPLC-MS/MS for application to a pharmacokinetic study in rats.

A rapid, simple, and accurate procedure was developed and validated for the simultaneous quantification of two anticancer agents, volitinib and gefitinib in rat plasma by high-performance liquid chromatography with tandem mass spectrometry. The samples were separated by gradient elution from a cyano column within five minutes, using 0.1% formic acid in acetonitrile and 10 mM ammonium formate solution (pH 3.0) as mobile phase. When plasma samples were deproteinated by adding methanol, the analytes in the extract were detected in the positive ionization mode with the tracer ion mass of 346.1 → 145.1 for volitinib and 446.8 → 128.1 for gefitinib. The assay was determined to be valid in the concentration ranges of 2 to 1000 ng/mL for volitinib, and of 1 to 500 ng/mL for gefitinib. Intra- and interday accuracies ranged from 88.0 to 104.7% for volitinib and from 90.3 to 101%, for gefitinib. The precision of the assay ranged from 2.1 to 9.71% for volitinib and 2.31 to 12.1% for gefitinib. This method was successfully applied to a pharmacokinetic study of volitinib and gefitinib after the administration of an intravenous or oral dose, indicating that the developed assay can be used to simultaneously determine the concentrations of volitinib and gefitinib in rat plasma.

Kinetics of the Absorption, Distribution, Metabolism, and Excretion of Lobeglitazone, a Novel Activator of Peroxisome Proliferator-Activated Receptor Gamma in Rats.

This study was performed to determine biopharmaceutical properties of lobeglitazone (LB), a novel thiazolidinedione-based activator of peroxisome proliferator-activated receptor gamma, in rats. In parallel artificial membrane permeability assay and Madin-Darby canine kidney (MDCK) cell permeability assays of LB, the activator was found to interact with multidrug-resistance protein 1 (MDR1) and OATP1B1. The concentration resulting in 50% inhibition value for LB in MDR1 expressing MDCK cells was approximately 12.5 ± 3.61 µM. LB had adequate stability (i.e., 56% remaining at 0.5 h) in rat liver microsomes. A cytochrome P450 (CYP) inhibitory potency study indicated that LB is primarily interacted with CYP1A2, 2C9, and 2C19. In rats, LB appeared to be readily absorbed after an oral administration (an absolute bioavailability of ∼95%). Following intravenous administration, LB exhibited linear pharmacokinetics in the dose range of 0.5-2 mg/kg. The primary distribution site was the liver but it was also distributed to heart, lungs, and fat tissue. The excretion of LB to the urine, bile, feces, and intestine was insignificant (i.e., <10% of the dose) in rats. These observations suggest that, despite the fact that it interacts with some drug transporters and metabolizing enzymes, the pharmacokinetics of LB were linear with a high oral bioavailability.