Investigations on the Oral and Brain Uptake Mechanisms of D‐ and L‐eflornithine in the Rat

Abstract

Eflornithine is a recommended treatment of the otherwise fatal disease late stage Gambian human African trypanosomiasis (HAT). Whereas racemic eflornithine is today administered intravenously, an oral eflornithine treatment option would increase accessibility for patients in affected areas in sub-Saharan Africa. Oral absorption of eflornithine is stereoselective when dosed as a racemic mixture with the more potent L-enantiomer disfavoured [1, 2]. In late stage Gambian HAT, the brain is the primary site of pharmacological action. Knowledge on whether stereoselective passage also occurs across the blood-brain barrier is limited. This study aimed to investigate the rate, extent and potential stereoselectivity of brain uptake of D- and L-eflornithine using in vivo microdialysis in the rat. Microdialysis probes were inserted in the third brain ventricle with simultaneous catheterizing of the jugular vein for blood sampling in Sprague-Dawley rats (n=16). Racemic eflornithine was dosed (1200 mg/kg) by oral gavage. Plasma and microdialysis samples were collected up to nine hours after dosing. Stereoselective eflornithine concentrations were determined by high performance liquid chromatography [3]. Plasma data was complemented with data from a prior study [1]. Areas under the curve (AUC) were determined using pharmacokinetic modelling with naïve pooled data analysis as implemented in Phoenix (Version 8.3, Certara, Princeton, NJ, USA). Pharmacokinetics of D- and L-eflornithine were best described by a two-compartment drug disposition model. Transit compartments were used to model the delay in oral absorption. Observed AUCs in plasma and brain dialysate for D-eflornithine were 160 min•mM and 1.0 min•mM, respectively. For L-eflornithine, AUCs were 60 min•mM and 0.38 min•mM in plasma and brain dialysate, respectively. Oral uptake of D- and L-eflornithine was, as expected, stereoselective whereas the uptake to the third ventricle in the rat brain was not stereoselective since the dialysate/plasma AUC ratio was similar for the enantiomers. Overall, results suggested a brain efflux of both D- and L-eflornithine to a similar extent. The findings will be used in future translational investigations to model the feasibility of an oral eflornithine based therapy against late stage Gambian HAT.