Flupirtine: pharmacokinetics and disposition in the horse

NTRODUCTION Flupirtine (FLU) is a non-opioid analgesic drug with no antipyretic or antiphlogistic effects, it is used in the treatment of a wide range of pain states in human beings. It does not induce the side effects associated with the classical drugs used as pain relievers. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after IV and PO administration in healthy horses. MATERIALS AND METHODS Six mixed breed adult mares (aged 9 to 13 years and weighing 480 to 590 kg) were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, paired, cross-over design (2 9 2 Latin-square). The Animal Welfare Committee of the University of Pisa, approved the study. Group 1 (n = 3) received a single dose of 1 mg kg 1 of FLU injected IV into the jugular vein. Group 2 (n = 3) received FLU (5 mg kg 1) via nasogastric tube. The wash out period was 1-week. Blood samples (5 ml) were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 24, 36 and 48 h and plasma was then analysed by a validated HPLC method. Pharmacokinetic curves were fit according to a compartmental analysis by Win- Nonlin (V5.3.1). RESULTS AND CONCLUSIONS Some mild and transient adverse effects (that spontaneously resolved within 5 min) were observed in 2 out of 6 animals after IV administration. No adverse effects were noticed in the PO administration group. A bi-compartmental model best fitted the plasma concentrations after IV and PO administrations in all the six horses. After IV and PO administrations, FLU was detectable in plasma for up to 36 h. The mean elimination half-life was longer after PO (10.27 h) than after IV (3.02 h) administration. The oral bioavailability was about 70%. This higher than that reported in cats [1] and dogs [2]. After in silico pharmacokinetic simulation/modelling, an oral dose of 2.6 mg kg 1 in horses has been calculated to give Cmax and AUC values similar to those reported in humans after a clinical dose administration [3] with a theoretical FLU effective plasma concentration of 187 ng ml 1. The average oral pharmacokinetic profile indicated that this value is exceeded for over 9 and 15 h following administration of 2.6 and 5 mg kg 1 of FLU, respectively. This study could pave the road for further study about the use of this active ingredient in equine medicine.

INTRODUCTION Flupirtine (FLU) is a non-opioid analgesic drug with no antipyretic or antiphlogistic effects, it is used in the treatment of a wide range of pain states in human beings. It does not induce the side effects associated with the classical drugs used as pain relievers. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after IV and PO administration in healthy horses. MATERIALS AND METHODS Six mixed breed adult mares (aged 9 to 13 years and weighing 480 to 590 kg) were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, paired, cross-over design (2 9 2 Latin-square). The Animal Welfare Committee of the University of Pisa, approved the study. Group 1 (n = 3) received a single dose of 1 mg kg 1 of FLU injected IV into the jugular vein. Group 2 (n = 3) received FLU (5 mg kg 1) via nasogastric tube. The wash out period was 1-week. Blood samples (5 ml) were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 24, 36 and 48 h and plasma was then analysed by a validated HPLC method. Pharmacokinetic curves were fit according to a compartmental analysis by Win- Nonlin (V5.3.1). RESULTS AND CONCLUSIONS Some mild and transient adverse effects (that spontaneously resolved within 5 min) were observed in 2 out of 6 animals after IV administration. No adverse effects were noticed in the PO administration group. A bi-compartmental model best fitted the plasma concentrations after IV and PO administrations in all the six horses. After IV and PO administrations, FLU was detectable in plasma for up to 36 h. The mean elimination half-life was longer after PO (10.27 h) than after IV (3.02 h) administration. The oral bioavailability was about 70%. This higher than that reported in cats [1] and dogs [2]. After in silico pharmacokinetic simulation/modelling, an oral dose of 2.6 mg kg 1 in horses has been calculated to give Cmax and AUC values similar to those reported in humans after a clinical dose administration [3] with a theoretical FLU effective plasma concentration of 187 ng ml 1. The average oral pharmacokinetic profile indicated that this value is exceeded for over 9 and 15 h following administration of 2.6 and 5 mg kg 1 of FLU, respectively. This study could pave the road for further study about the use of this active ingredient in equine medicine.