Pregabalin is a structural analogue of inhibitory neurotransmitter γ-aminobutyric acid (GABA) and acts on the central nervous system. It is used for the additional treatment of epilepsy, for the treatment of neuropathic pain and anxiety disorders. Within the range of recommended daily doses it has a linear pharmacokinetics and predictable relationship between the dose and effect. Secretion takes place mostly in the kidneys, so with the patients who have a decreased renal function the adaption of the dose is needed. The aim of the master’s dissertation was to determine plasma pregabalin concentrations after the oral administration of the medicine under fasting conditions and, on the basis of the measured concentrations, calculate individual pharmacokinetic parameters. Plasma pregabalin concentrations of 12 healthy male volunteers were determined. We used a high performance fluid chromatography method and fluorescence detector. Samples were prepared using solid phase extraction method. Since pregabalin does not absorb visible and ultraviolet light, the extracted samples were derivatized with 7-chloro-4-nitrobenzofurazan (NBD-Cl), which forms a fluorescent derivative with the amino group of pregabalin. The results were partially validated according to the US Food and Drug Administration’s guidelines for bioanalytical methods. The method was linear within the range of 0.375-30 μg/mL, accurate (100.4-107.9 %) and precise (0.60-5.17 %). With the model-independent approach and directly from the graph showing the dependence of plasma concentration and time, we have calculated the basic pharmacokinetic parameters for the measured pregabalin concentrations in plasma samples, such as maximum concentration of pregabalin in plasma (8.25 μg/mL), time in which this concentration is reached (0.875 h), elimination rate constant (0.1102 h-1) and the area under the plasma curve extrapolated to infinite time (43.27 μg×h/mL). Using pharmacokinetic modelling, we determined that pregabalin follows a two-compartment pharmacokinetic model. A typical value of the pregabalin absorption rate constant is 0.247 h-1, of the apparent volume of distribution 36.9 L and of clearance 126,7 mL/min. The latter and the creatinine clearance, which clinical practice uses for the estimation of glomerular filtration rate, are directly mutually interdependent. In straight line equation y = 0.72x – 0.23, representing the connection between pregabalin clearance and creatinine clearance, the y-axis intercept near value 0 indicates that systemic metabolism of pregabalin is negligible and fully dependent on renal function.
|
