Bridging Pharmacokinetics between Laboratory/Veterinary animal Species and Man by Allometry : A Case Study of intravenous Tramadol

Tramadol, an important non-narcotic analgesic agent, has found clinical utility in several veterinary species in addition to its well accepted human use. The availability of published data on clearance and volume of distribution of Tramadol in veterinary/laboratory animal species rendered the applicability of allometry. The results of the interspecies scaling for both clearance (2.036353W;R = 0.781829) and volume of distribution (2.526827W;R =0.943264) suggested that simple allometry could help in formulating an effective dosing strategy of Tramadol in a new veterinary species. For instance, the predicted clearance for Tramadol was within 2-fold of the observed value in camels (predicted: 1.08 L/h; observed: 1.94 L/h); while, the predicted steady state volume of distribution value was in close proximity to the observed value in camels (predicted: 2.67 L; observed: 2.58 L). Also, simple allometry performed by the use of laboratory animal (rat, rabbit, dog) and human data predicted clearance and volume parameters in cat, goat, horse and camel within 4-fold and 2-fold, respectively. In summary, interspecies allometry scaling inclusive human data can be potentially used as a tool for dosing strategy when a new veterinary species is chosen. Tramadol, known for its analgesic activity, has purported mechanism of action through variety of centrally acting receptors such as adrenergic and serotonin with relatively low affinity towards opioid receptors [1, 2, 3]. Tramadol is well absorbed after oral doses and undergoes extensive metabolism in both preclinical species and human subjects [4, 5]. One of the metabolites of Tramadol, namely OdesmethylTramadol formed via an oxidative deaklyation process has been shown to be active [6]. However, it should be noted that studies involving [C]-Tramadol are limited in many veterinary species for an unambiguous determination of routes of elimination of Tramadol. On the basis of the information gathered in human subjects, Tramadol undergoes extensive metabolism (both Phase I and Phase II reactions are implicated) and many of the metabolites are excreted in the urine either intact and/or sulphate/glucuronide conjugates [4]. Both hepatic impairment and renal insufficiency can alter the pharmacokinetics of Tramadol suggesting the important roles of metabolism and urinary elimination pathways in the disposition of Tramadol [7]. The work of Mastocinque and Fantoni (2003) suggested that Tramadol produced beneficial effects comparable to morphine in reducing post-operative pain following ovariohysterectomy after pyometra in dogs [8]. On a similar note, Tramadol was shown to exhibit good analgesic activity following intravenous and epidural administration to horses [9, 10]. The pharmacokinetic disposition of Tramadol and its active metabolite, O-desmethyltranadol, has been well documented in a number of animal species and human subjects [11, 12, 13, 14, 15, 16, 17, 18, 19]. Since the use of Tramadol is gaining popularity across various animal species and human subjects, the aim of this work was to apply simple allometric principles to scale the derived pharmacokinetic parameters of Tramadol. The allometric equations generated separately for parameters such as clearance and volume of distribution at steady state for Tramadol could be applied to generate equivalent values in new animal species hitherto not tested and/or enable an optimised dose design in the new animal species. In the allometric scaling work attempted in this exercise, the active metabolite of O-desmethylTramadol was not considered for the following reasons: 1) the formation of OdesmethylTramadol is highly variable across species owing to a number of factors including presence of gentic polymorphism; 2) it was felt that incorporation of O-desmethylTramadol may not help guide the dosing strategy of Tramadol since “f” would be confounding across species; 3) OdesmethylTramadol formation is likely to happen in the various species contributing for the purported activity and lack of consideration of the active metabolite may not pose a big risk in the dosing strategy of Tramadol. As tabulated in Table 1, the intravenous pharmacokinetics of Tramadol have been generated in number of species over the last decade. A quick examination of the numerical values of both clearance and volume terms in relation to the body Nuggehally R SRinivas /J. Pharm. Sci. & Res. Vol.3(8), 2011,1368-1372