Influence of a polymeric formulation of ketoprofen on its diffusion into cerebrospinal fluid in rats

Abstract

Poly( d,l)lactide nanocapsules (NCs) have been proposed as an alternative carrier for many drugs. We investigated the influence of this formulation on the pharmacokinetics of ketoprofen in the plasma and cerebrospinal fluid (CSF). Male Wistar rats were given intraperitoneal dose of ketoprofen (5 mg/kg) in a suspension of NCs or in a carboxymethylcellulose (CMC) solution (reference preparation). Blood and CSF samples were collected at different times up to 24 h after dosing. The unbound fraction of ketoprofen in plasma ( f u) was determined using ultrafiltration. The total ( C T) and free ( C F) concentrations of ketoprofen in plasma and the simultaneous CSF concentrations ( C CSF) were measured by a HPLC method and the areas under the curve (AUC T, AUC F, AUC CSF) were calculated. AUC T of ketoprofen-loaded NCs in plasma was similar to that of the reference solution, while AUC F of the former (5.41 mg/l×h) was higher than that produced by the latter (4.03 mg/l×h). Accordingly, the unbound fraction ( f u) was higher after administration of NCs than that of the solution (2.5 and 1.8%, respectively). Finally, AUC CSF were identical for both formulations. These findings suggest that the binding of ketoprofen to plasma proteins is not the major factor that governs its blood-to-CSF exchanges.