effect of oral co-administration of frozen-dried grapefruit juice on pharmacokinetics of tramadol in dogs

tramadol is a centrally acting analgesic drug extensively metabolized in animal species. its clinicalresponse is mainly due to the m1 metabolite, poorly produced in dogs. grapefruit-juice can inhibit themetabolism of different drugs in animals and humans. the aim of the present study was to evaluate thepharmacokinetics of tramadol and its major metabolites after co-administration of tramadol and frozen-dried grapefruit-juice. a balanced cross-over study was used involving six male beagle dogs. they were administered with tramadol alone (5 mg/kg) or with tramadol (5 mg/kg) plus frozen-dried grapefruit-juice (10 g). the plasma concentration vs time curves showed significant differences during the first 4 h following drug administration. tmax was at 1.33 and 1.70 h following tramadol and tramadol plus frozen-dried grapefruit-juice treatment, respectively. significant differences were also shown in cmax (490 vs 270 ng/ml) and auc (11,610 vs 5,890 h·h·ng/ml). significant differences between the treatments were shown in all the m1 parameters reported. m2 and m5 did not show significant differences after both administrations. in conclusion, the frozen-dried grapefruit-juice was shown to affect the plasma concentrations of m1, despite them being well below those reported in humans.