Enantioselective and Nonlinear Intestinal Absorption of Eflornithine in the Rat

Abstract

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 M for 300 l 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 M for 50 l 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.

6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

“…In rat liver, L-eflornithine (L-difluoromethylornithine) was more effective in irreversibly inhibiting ornithine decarboxylase than D-eflornithine (D-difluoromethylornithine) (128). The mean bioavailability of L-and D-eflornithine in rats was 41% and 62%, respectively, indicating that eflornithine exhibits enantioselective absorption, the more potent L-isomer being less favoured (129).…”

“…Conflict and sociopolitical instability are associated with the persistence and resurgence of infection (62). There is some evidence that people develop immunity to T. b. gambiense (129), and it has been suggested that the inter-epidemic intervals observed in the twentieth century occurred while the population of susceptible individuals was increasing to a size that could support another epidemic.…”

“…Additional studies on the performance, cost-effectiveness and ease of implementation of these rapid diagnostic tests are being conducted (26,128) to better understand their optimal implementation in different settings. In order to further avoid nonspecific reactions and to standardize and facilitate the test production process, the possibility of replacing the native proteins used as antigens in these tests by recombinant proteins or synthetic peptides is being investigated (24,129). The development of the LAMP assay represents important progress and, if the format is simplified further, could bring molecular diagnostics closer to the district or reference hospital level (13,130).…”

Chemotherapy against human African trypanosomiasis: Is there a road to success?

“…Since 2007 the WHO, with funding from the sanofi-aventis programme, has provided eflornithine in kits including all necessary ancillary materials (Priotto et al 2008), but considerable logistic constraints remain as the kit for two patients has a volume of about 1 m 3 . An oral formulation was thought to solve many of the treatment related difficulties, but was abandoned after discouraging results of a pharmacokinetic trial (Na-Bangchang et al 2004;Jansson et al 2008).…”

Determination of eflornithine enantiomers in plasma, by solid-phase extraction and liquid chromatography with evaporative light-scattering detection

“…d/l-DFMO was intravenously administered to a rat with a dosage of 375 mg/kg body weight (Sprague-Dawley rat, male, weighing approximately 300 g) [31]. The administered dose corresponds to a human dose of approximately 75 mg/kg.…”