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Enantioselective and dose dependent intestinal absorption of eflornithine in the rat
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
2008 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, Vol. 52, no 8, 2842-2848 p.Article in journal (Refereed) Published
Abstract [en]

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 microM for 300 microl 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 microM for 50 microl 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.

Place, publisher, year, edition, pages
2008. Vol. 52, no 8, 2842-2848 p.
National Category
Chemical Sciences
URN: urn:nbn:se:uu:diva-96864DOI: 10.1128/AAC.00050-08ISI: 000258365800021PubMedID: 18519728OAI: oai:DiVA.org:uu-96864DiVA: diva2:171588
Available from: 2008-03-19 Created: 2008-03-19 Last updated: 2010-01-07Bibliographically approved
In thesis
1. Drug Analysis: Bioanalytical Method Development and Validation
Open this publication in new window or tab >>Drug Analysis: Bioanalytical Method Development and Validation
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes bioanalytical methods for drug determination in biological matrixes, with drugs in focus used against diseases largely affecting low-income countries.

Solid-phase extraction is used for sample cleanup, and processed samples are analyzed by liquid chromatography. Developed bioanalytical methods are validated according to international guidelines.

Eflornithine (DFMO) is a chiral drug, used for treating human African trypanosomiasis. A bioanalytical method for determination of DFMO enantiomers in plasma is presented. The enantiomers are detected by evaporative light-scattering detection. The method has been applied to determination of D-DFMO and L-DFMO in rats, after intravenous and oral administration of racemic DFMO. It is concluded that DFMO exhibits enantioselective absorption, with the more potent enantiomer L-DFMO being less favored.

Sulfadoxine (SD) and sulfamethoxazole (SM) are sulfa-drugs used for malaria and pneumonia respectively. Two methods are described for simultaneous determination of SD and SM in capillary blood sampled on filter paper. The former method allows direct injection of extracts from dried blood spots (DBS), while for the latter method solid-phase extraction is added. Pre-analytical factors contributing to measurement uncertainty is also discussed, and it is concluded that it is of high importance that homogeneity in type of sampling paper and sampling volume is assured.

Piperaquine (PQ) is an antimalarial, increasingly used in artemisinin combination therapy. A method for determination of piperaquine in DBS is presented. By using a monolithic LC column, a very short LC analysis of two minutes per sample is achieved.

A method for simultaneous determination of three antiretroviral drugs i.e. lamivudine (3TC), zidovudine (AZT) and nevirapine (NVP), in DBS samples is described. The method is applied to drug determination in two subjects after receiving standard antiretroviral treatment. Conclusion is that the method is suitable for determination of 3TC and NVP, and to some extent for AZT.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 59 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 406
Analytical chemistry, African trypanosomiasis, calibration model, chiral chromatography, dried blood spots, eflornithine, evaporative light-scattering detection, HIV/AIDS, lamivudine, liquid chromatography, malaria, nevirapine, piperaquine, pneumonia, solid-phase extraction, sulfadoxine, sulfamethoxazole, validation, zidovudine, Analytisk kemi
urn:nbn:se:uu:diva-8547 (URN)978-91-554-7125-5 (ISBN)
Public defence
2008-04-18, Clas Ohlson room, Tenoren, Högskolan Dalarna, Borlänge, 13:00 (English)
Available from: 2008-03-19 Created: 2008-03-19 Last updated: 2009-03-24Bibliographically approved

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