title: Population pharmacokinetic modeling and deconvolution of enantioselective absorption of eflornithine in the rat.
abstract: Enantioselective pharmacokinetics and absorption of eflornithine in the rat was investigated using population pharmacokinetic modeling and a modified deconvolution method. Bidirectional permeability of L- and D-eflornithine was investigated in Caco-2 cells. The rat was administered racemic eflornithine hydrochloride as a single oral dose [40-3,000 mg/kg bodyweight (BW)] or intravenously (IV) (100-2,700 mg/kg BW infused over 60-400 min). Serial arterial blood samples were collected and L- and D-eflornithine were quantitated with a previously published chiral bioanalysis method. The D:L concentration ratio was determined in rat faeces. Intravenous L-and D-eflornithine plasma concentration-time data was analyzed using population pharmacokinetic modeling and described with a 3-compartment pharmacokinetic model with saturable binding to one of the peripheral compartments. Oral plasma concentration-time data was analyzed using a modified deconvolution method accounting for nonlinearities in the eflornithine pharmacokinetics. Clearance was similar for both enantiomers (3.36 and 3.09 mL/min). Oral bioavailability was estimated by deconvolution at 30 and 59% for L- and D-eflornithine. The D:L concentration ratio in feces was 0.49 and the Caco-2 cell permeability was similar for both enantiomers (6-10 × 10(-8) cm/s) with no evident involvement of active transport or efflux. The results presented here suggest that the difference in the bioavailability between eflornithine enantiomers is caused by a stereoselective difference in extent rather than rate of absorption. The presented modified deconvolution method made it possible to account for the non-linear component in the suggested three-compartment pharmacokinetic model thus rapidly estimating eflornithine oral bioavailability.
authors.affiliation: Unit for Pharmacokinetics and Drug Metabolism, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden. c-c.johansson@telia.com
authors.forename: Carl-Christer
authors.initials: CC
authors.lastname: Johansson
authors.forename: Peter
authors.initials: P
authors.lastname: Gennemark
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
authors.forename: Angela
authors.initials: A
authors.lastname: Äbelö
authors.forename: Michael
authors.initials: M
authors.lastname: Ashton
authors.forename: Rasmus
authors.initials: R
authors.lastname: Jansson-Löfmark
mesh_terms: D000042:Absorption; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D000518:Eflornithine / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: D004791:Enzyme Inhibitors; D000518:Eflornithine