Population pharmacokinetic modeling and deconvolution of enantioselective absorption of eflornithine in the rat.
Journal article, 2013

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.

pharmacokinetics

Animals

Cell Line

Caco-2 Cells

Biological Availability

Absorption

Eflornithine

Stereoisomerism

Male

Models

Tumor

Sprague-Dawley

pharmacokinetics

Rats

Metabolic Clearance Rate

Humans

Rats

Biological

Enzyme Inhibitors

Author

Carl-Christer Johansson

University of Gothenburg

Peter Gennemark

Per Artursson

Angela Abelö

University of Gothenburg

Michael Ashton

University of Gothenburg

Rasmus Jansson Löfmark

University of Gothenburg

Journal of Pharmacokinetics and Pharmacodynamics

1567-567X (ISSN) 1573-8744 (eISSN)

Vol. 40 1 117-28

Subject Categories

Pharmaceutical Sciences

DOI

10.1007/s10928-012-9293-x

PubMed

23307171

More information

Created

10/10/2017