Pharmacokinetic and Pharmacodynamic Studies of Tapentadol and its Enhanced Antinociceptive Effect by Flupirtine

Tapentadol (TAP) is a novel centrally acting analgesic that combines two different mechanisms of action, MOR agonist and NE reuptake inhibition. TAP showed lower side effects in humans, as compared to classic opioids. The aim of this study are: i) to assess the pharmacokinetics of tapentadol (TAP) after IV, IM and SC injection in healthy cats; ii) to assess the pharmacokinetics of TAP after IV and IM injection in healthy goats; iii) to evaluate the pharmacokinetic/pharmacodynamics (PK/PD) relationship in turtles, after a single IM injection of TAP; iv) to determine the antinociceptive effect of TAP and flupirtine (FLP) in rats when administered separately or in combination, as well as their synergistic interaction. The dose rate used was 5 mg/kg and the concentrations of TAP in plasma were evaluated using high-performance liquid chromatography. For PD study in turtles, an infrared thermal stimuli was applied to the plantar surface of the turtles’ hind limbs to evaluate the thermal withdrawal latency (TWL). For drug interaction study, the orofacial formalin test was used to assess the synergism between TAP and FLP. The bioavailabilities in cats (IM, 94%; SC, 90%) and goats (IM, 88%) were relatively high. There were large interspecies variations in its half-lives and Tmax between mammals (cats, goats) and reptiles (turtles). TAP showed longer half-life and Tmax in turtles as compared to cats and goats. TAP produced excellent thermal antinociception in turtles. The thermal antinociceptive effect occurred rapidly and lasted as long as 10 hours. A linear relationship (r2 = 0.99) between TAP plasma concentration and effect was found. The combination of TAP and FLP resulted in a synergistic antinociceptive effect. Therefore, this co-administration is considered to enhance the antinociceptive effect of both drugs.