This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jansson, R.
Right arrow Articles by Ashton, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jansson, R.
Right arrow Articles by Ashton, M.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, August 2008, p. 2842-2848, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00050-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Enantioselective and Nonlinear Intestinal Absorption of Eflornithine in the Rat{triangledown}

R. Jansson,1 M. Malm,2,3 C. Roth,1 and M. Ashton1*

Sahlgrenska Academy at Göteborg University, Unit for Pharmacokinetics and Drug Metabolism, Göteborg, Sweden,1 Dalarna University College, Borlänge, Sweden,2 Department of Physical and Analytical Chemistry, Uppsala University, Uppsala, Sweden3

Received 14 January 2008/ Returned for modification 22 March 2008/ Accepted 26 May 2008

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 µM for 300 µl 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 µM for 50 µl 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.

* Corresponding author. Mailing address: Sahlgrenska Academy at Göteborg University, Unit for Pharmacokinetics and Drug Metabolism, Medicinaregatan 13, 41390 Göteborg, Sweden. Phone: 46 31 786 3412. Fax: 46 31 786 3164. E-mail: Michael.Ashton{at}pharm.gu.se

{triangledown} Published ahead of print on 2 June 2008.

Antimicrobial Agents and Chemotherapy, August 2008, p. 2842-2848, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00050-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»