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Enantioselective an...
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Jansson, Rasmus,1979Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology
(författare)
Enantioselective and nonlinear intestinal absorption of eflornithine in the rat.
- Artikel/kapitelEngelska2008
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LIBRIS-ID:oai:gup.ub.gu.se/76919
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https://gup.ub.gu.se/publication/76919URI
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https://doi.org/10.1128/AAC.00050-08DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:du-17663URI
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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 M for 300 l 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 M for 50 l 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.
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Malm, MikaelaHögskolan Dalarna,Kemiteknik(Swepub:du)mml
(författare)
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Roth, ChristinaGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology
(författare)
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Ashton, Michael,1955Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology(Swepub:gu)xashmi
(författare)
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Göteborgs universitetInstitutionen för neurovetenskap och fysiologi, sektionen för farmakologi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Antimicrobial Agents and Chemotherapy52:8, s. 2842-80066-48041098-6596
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