Bioavailability of tramadol after i.m. injection in comparison to i.v. infusion

Objectives and methods: The bioavailability of tramadol after i.m. injectio n of tramadol-HCl was determined from serum concentration data in a balance d two-period crossover study with 12 healthy male subjects in comparison to the 30-min i.v. infusion. Additionally, the tramadol concentrations in sal iva and urine samples were measured. The subjects received single doses of 50 mg after an overnight fast, the washout period was one week. Serum, sali va and urine concentrations of tramadol were analyzed by gas chromatography , and pharmacokinetic (PK) evaluation was carried out model-independently D escriptive statistical evaluation was performed by calculating geometric me ans with standard deviations ((X) over bar(g) (SDg)) or medians with ranges ((x) over tilde (min, max)) and the extent of systemic availability (F) wa s tested for bioequivalence using the ANOVA(log)-based 90% confidence inter val(CI). Results: Retrospective sparteine phenotyping revealed two of the s ubjects as poor metabolizers (PM). Nevertheless, all subjects were consider ed on statistical evaluation since the PM results were within the range of the extensive metabolizers (EM). The 90% CI of F = AUC(i.m)./AUC(i.v). was 92.9 105.4% ((x) over bar(g) = 99.0%) and was thus within the range of 80 - 125% generally accepted for a positive bioequivalence decision. After i.m. injection the serum concentration peaks were reached after t(max) = 0.75 ( 0.25, 1.50) h and amounted to c(max) = 166 (1.24) ng/ml; the corresponding results after i.v. infusion were t(max) = 0.50 (0.33, 1.50) h and c(max) = 293 (1.35) ng/ml. Thus, the results reflect the different invasion kinetics of the two modes of administration. However, the observed difference is no t therapeutically relevant since in both cases minimal effective serum conc entrations are already reached after a few minutes and are maintained for 9 - 10 h on the average. The i.v. results for all PK parameters agreed well with those of previous studies. Tramadol concentrations in saliva and urine were considerably higher than in serum. Therefore, saliva and urine sample s are very suitable for the qualitative proof of tramadol intake in therape utic drug monitoring and forensic toxicology. Conclusions: Tramadol is rapi dly and almost completely absorbed after i.m. injection. The i.m. injection and the 30-min i.v. infusion are bioequivalent with respect to the extent of systemic availability. The differences in the times of onset and duratio n of action to be expected due to a slightly slower invasion after i.m. inj ection are small and probably therapeutically irrelevant.