This study aimed to investigate if the absorption of the human
African trypanosomiasis agent
eflornithine was stereospecific and dose dependent after
oral administration. Male Sprague-Dawley rats were administered single doses of racemic
eflornithine hydrochloride as an oral
solution (750, 1,500, 2,000, or 3,000 mg/kg of
body weight) or intravenously (375 or 1,000 mg/kg of
body weight). Sparse blood samples were obtained for determination of
eflornithine enantiomers by liquid chromatography with evaporative light-scattering detection (lower limit of quantification [LLOQ], 83 microM for 300 microl plasma). The full plasma concentration-time profile of racemic
eflornithine following frequent sampling was determined for another group of rats, using a high-performance liquid chromatography-UV method (LLOQ, 5 microM for 50 microl plasma). Pharmacokinetic data were analyzed in NONMEM for the combined racemic and enantiomeric concentrations. Upon
intravenous administration, the plasma concentration-time profile of
eflornithine was biphasic, with marginal differences in enantiomer kinetics (mean clearances of 14.5 and 12.6 ml/min/kg for L- and D-
eflornithine, respectively). The complex absorption kinetics were modeled with a number of transit compartments to account for delayed absorption, transferring the
drug into an absorption compartment from which the rate of influx was saturable. The mean bioavailabilities for L- and D-
eflornithine were 41% and 62%, respectively, in the dose range of 750 to 2,000 mg/kg of
body weight, with suggested increases to 47% and 83%, respectively, after a dose of 3,000 mg/kg of
body weight.
Eflornithine exhibited enantioselective absorption, with the more potent L-isomer being less favored, a finding which may help to explain why clinical attempts to develop an oral treatment have hitherto failed. The mechanistic explanation for the stereoselective absorption remains unclear.