Pharmacokinetics of tramadol and its major metabolites in alpacas following intravenous and oral administration

Edmondson, M. A., Duran, S. H., Boothe, D. M., Stewart, A. J., Ravis, W. R. Pharmacokinetics of tramadol and its major metabolites in alpacas following intravenous and oral administration. J. vet. Pharmacol. Therap. 35, 389-396. Tramadol, a centrally acting opioid analgesic with monamine reuptake inhibition, was administered to six alpacas (4371 kg) randomly assigned to two treatment groups, using an open, single-dose, two-period, randomized cross-over design at a dose of 3.44.4 mg/kg intravenously (IV) and, after a washout period, 11 mg/kg orally. Serum samples were collected and stored at -80 degrees C until assayed by HPLC. Pharmacokinetic parameters were calculated. The mean half-lives (t1/2) IV were 0.85 +/- 0.463 and 0.520 +/- 0.256 h orally. The Cp(0) IV was 2467 +/- 540 ng/mL, and the Cmax was 1202 +/- 1319 ng/mL orally. Tmax occurred at 0.111 +/- 0.068 h orally. The area under the curve (AUC0-8) IV was 895 +/- 189 and 373 +/- 217 ng*h/mL orally. The volume of distribution (Vd[area]) IV was 5.50 +/- 2.66 L/kg. Total body clearance (Cl) IV was 4.62 +/- 1.09 h; Cl/F for oral administration was 39.5 +/- 23 L/h/kg. The IV mean residence time (MRT) was 0.720 +/- 0.264. Oral adsorption (F) was low (5.919.1%) at almost three times the IV dosage with a large inter-subject variation. This may be due to binding with the rumen contents or enzymatic destruction. Assuming linear nonsaturable pharmacokinetics and absorption processes, a dosage of 6.7 times orally would be needed to achieve the same IV serum concentration of tramadol. The t1/2 of all three metabolites was longer than the parent drug; however, O-DMT, N-DMT, and Di-DMT metabolites were not detectable in all of the alpacas. Because of the poor bioavailability and adverse effects noted in this study, the oral administration of tramadol in alpacas cannot be recommended without further research.