Evaluation of linearity of anticonvulsant drug GIZh-298 pharmacokinetics in rats

BACKGROUND: A key step in drug pharmacokinetic analysis is testing the linearity hypothesis, as it allows one to judge how predictably the concentration of a substance changes when its dose is corrected. AIM: To evaluate the linearity of the pharmacokinetics of the compound GIZh-298 (4-benzoylpyridine O-(2-morpholinoethyl) oxime oxalate) in blood plasma of rats after a single intragastric administration at doses of 60, 90 and 120 mg/kg. METHODS: The study was performed on outbred, sexually mature male white rats. The test compound was administered intragastrically once at doses of 60, 90, and 120 mg/kg. Plasma GIZh-298 concentrations were determined by high-performance liquid chromatography with mass spectrometric detection. Dose proportionality was assessed by normalizing the area under the drug concentration-time curve (AUC) and the maximum plasma drug concentration after extravascular administration (Cmax) to the drug dose. RESULTS: The pharmacokinetics of GIZh-298 in rats in the dose range of 60–120 mg/kg is nonlinear, as evidenced by the calculated proportionality constant (b), which is significantly greater than unity. The interception points of the function described by the linear regression equation, with the abscissa (a) of the linear regression equations was close to zero (-0.32 for AUC0→∞ and 0.34 for Cmax), meaning the regression lines originated almost from the reference center and thus demonstrated a linear portion of the curve that included the 60 and 90 mg/kg points. In the portion from the minimum detectable dose to 90 mg/kg, the dose dependence of AUC and Cmax was linear. A sharp deviation from proportionality was observed upon transition to a dose of 120 mg/kg, leading to an overestimated mean b value when analyzing all the three points. CONCLUSION: The pharmacokinetics of GIZh-298 in rats is linear over a dose range of up to 90 mg/kg. A further increase in the dose to 120 mg/kg resulted in a disruption of linear proportionality, which may be due to saturation of absorption or elimination processes.