Pharmacokinetics and Pharmacodynamics Evaluation of Tramadol In Thermoreversibles Gels

Abstract

In this study, new drug delivery formulations of tramadol (TR) in thermoreversible gels were studied with regard to the pre-clinical pharmacokinetics (PK) and pharmacodynamics (PD). The poloxamer (PL)-TR systems were prepared by direct dispersion of the drug (20 mg.mL-1) in solutions with PL 407 and PL 188. The formulations used in this study were: F1- TR 2% in aqueous solution; F2- PL 407 (20%) + PL 188 (10%) + TR 2%; F3- PL 407 (25%) + PL 188 (5%) + TR 2% and F4 - PL 407 (20%) + TR 2%. New Zealand white rabbits were divided in four groups (n=6) and treated by subcutaneous route with F1, F2, F3 or F4 (10 μg.kg-1). Blood samples (1 mL) from an ear vein were collected pre dose (0 min) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420 and 480 minutes after the injection of formulations. TR and its main metabolite (M1) plasma levels were determinate using a triple stage quadrupole mass spectrometer. PD evaluation was performed with the measurement of both pupils’ diameters using callipers in the same periods of blood collection. F2 showed higher TR plasma concentration than all other formulations after 180 minutes and presented lower M1 concentrations at almost all evaluated periods (P<0.05). Areas under the curve and cleareance of TR in F2 presented differences compared to F1 (P<0.05). F2 presented significant Pearson correlation between the enhancement of TR / M1 concentrations and miosis (P<0.05). Thus, the association of PL407 (20%) and PL188 (10%) in F2 altered pharmacokinetics and pharmacodynamics of TR, since this formulation was effective to enhance the bioavailability and this effect was correlated with a more intense biologic effect.