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Background/Objectives: Using a combination of analgesics allows for the use of lower doses of each, therefore, lowering risk of side effects. The study aims to estimate the bioavailability (pharmacokinetics of enantiomers and metabolites, as well as linearity and sex-related effects) of fixed doses combinations of Ibuprofen/Tramadol via an intravenous (IV) vs. oral route, and it is interesting to bridge the gap of equipotent doses by different routes. Methods: This was a randomized, open-label, crossover, five-period pharmacokinetics clinical trial, in which a single dose of each formulation [four different strengths of Ibuprofen 400 mg/Tramadol HCl (30, 31.5, 33, 37.5 mg), intravenous; Ibuprofen/Tramadol HCl 400 mg/37.5 mg, granules for oral solution], were administered to healthy volunteers. Enantiomers of Ibuprofen, of Tramadol, and of its main active metabolite O-desmethyl-Tramadol (M1) were measured, and pharmacokinetic parameters (maximal concentration (Cmax) and area under the concentration curve (AUC)) were estimated. Given the exploratory nature of the study, the sample size was small to provide sufficient power for comparisons of differences across all subgroups. The study was registered at Spanish register of clinical trials (REec), EudraCT code: 2017-001303-77. Results: Twelve subjects were recruited. Different patterns of rate and amount of the studied analytes are shown for oral and the several strengths of IV drugs tested. Ibuprofen, with an absolute oral bioavailability of 91%, showed an equivalent AUC of oral and IV administration. Tramadol showed an absolute oral bioavailability of 80%. Conclusions: Intravenous administration of Tramadol produces higher bioavailability (Cmax and AUClast) of the parent drug and lower of M1, than oral route. Dose normalized Cmax and AUClast of Tramadol and M1 were into the bioequivalence interval. Upon our pharmacokinetics study results, the intravenous dose of Tramadol should not be reduced when switching from oral dosing. No significant differences attributable to sex, once corrected by weight, were found. Full article