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Göteborgs universitets publikationer

Population pharmacokinetic modeling and deconvolution of enantioselective absorption of eflornithine in the rat.

Författare och institution:
Carl-Christer Johansson (Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi); Peter Gennemark (-); Per Artursson (-); Angela Abelö (Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi); Michael Ashton (Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi); Rasmus Jansson Löfmark (Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi)
Publicerad i:
Journal of pharmacokinetics and pharmacodynamics, 40 ( 1 ) s. 117-28
ISSN:
1573-8744
Publikationstyp:
Artikel, refereegranskad vetenskaplig
Publiceringsår:
2013
Språk:
engelska
Fulltextlänk:
Sammanfattning (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.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
MEDICIN OCH HÄLSOVETENSKAP ->
Medicinska grundvetenskaper ->
Farmaceutisk vetenskap ->
Biofarmaci
Nyckelord:
Absorption, Animals, Biological Availability, Caco-2 Cells, Cell Line, Tumor, Eflornithine, pharmacokinetics, Enzyme Inhibitors, pharmacokinetics, Humans, Male, Metabolic Clearance Rate, Models, Biological, Rats, Rats, Sprague-Dawley, Stereoisomerism
Postens nummer:
186693
Posten skapad:
2013-11-14 13:28
Posten ändrad:
2016-08-24 15:21

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