ABSTRACT
OBJECTIVE: 1) To determine the pharmacokinetics of tramadol hydrochloride and its active metabolite, O-desmethyltramadol (M1), after administration through different routes in female and male C57Bl/6 mice; 2) to evaluate the stability of tramadol solutions; and 3) to identify a suitable dose regimen for prospective clinical analgesia in B6 mice. STUDY DESIGN: Prospective, randomized, blinded, parallel design. ANIMALS: A total of 18 male and 18 female C57Bl/6 mice (20-30 g). METHODS: Mice were administered 25 mg kg-1 tramadol as a bolus [intravenously (IV), intraperitoneally (IP), subcutaneously (SQ), orally per gavage (OSgavage)] over 25 hours [orally in drinking water (OSwater) or Syrspend SF (OSSyrsp)]. Venous blood was sampled at six predetermined time points over 4 to 31 hours, depending on administration route, to determine tramadol and M1 plasma concentrations (liquid chromatography and tandem mass spectrometry detection). Pharmacokinetic parameters were described using a noncompartmental model. The stability of tramadol in water (acidified and untreated) and Syrspend SF (0.20 mg mL-1) at ambient conditions for 1 week was evaluated. RESULTS: After all administration routes, Cmax was >100 ng mL-1 for tramadol and >40 ng mL-1 for M1 (reported analgesic ranges in man) followed by short half-lives (2-6 hours). The mean tramadol plasma concentration after self-administration remained >100 ng mL-1 throughout consumption time. M1 was found in the OSSyrs group only at 7 hours, whereas it was detectable in OSwater throughout administration. Tramadol had low oral bioavailability (26%). Short-lasting side effects were observed only after IV administration. Water and Syrspend SF solutions were stable for 1 week. CONCLUSIONS AND CLINICAL RELEVANCE: 1) At the dose administered, high plasma concentrations of tramadol and M1 were obtained, with half-life depending on the administration route. 2) Plasma levels were stable over self-consumption time. 3) Solutions were stable for 1 week at ambient conditions.