Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats
Abstract Background Despite the wide spread use of lumefantrine, there is no study reporting the detailed preclinical pharmacokinetics of lumefantrine. For the development of newer anti-malarial combination(s) and selection of better partner drugs, it is long felt need to understand the detailed pre...
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ftdoajarticles:oai:doaj.org/article:f93ff1febb8942a48b64416817b0e8fd 2023-05-15T15:16:50+02:00 Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats Wahajuddin Singh Sheelendra P Raju Kanumuri SR Nafis Asad Puri Sunil K Jain Girish K 2011-10-01T00:00:00Z https://doi.org/10.1186/1475-2875-10-293 https://doaj.org/article/f93ff1febb8942a48b64416817b0e8fd EN eng BMC http://www.malariajournal.com/content/10/1/293 https://doaj.org/toc/1475-2875 doi:10.1186/1475-2875-10-293 1475-2875 https://doaj.org/article/f93ff1febb8942a48b64416817b0e8fd Malaria Journal, Vol 10, Iss 1, p 293 (2011) Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2011 ftdoajarticles https://doi.org/10.1186/1475-2875-10-293 2022-12-31T03:20:21Z Abstract Background Despite the wide spread use of lumefantrine, there is no study reporting the detailed preclinical pharmacokinetics of lumefantrine. For the development of newer anti-malarial combination(s) and selection of better partner drugs, it is long felt need to understand the detailed preclinical pharmacokinetics of lumefantrine in preclinical experimental animal species. The focus of present study is to report bioavailability, pharmacokinetics, dose linearity and permeability of lumefantrine in rats. Methods A single dose of 10, 20 or 40 mg/kg of lumefantrine was given orally to male rats (N = 5 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of lumefantrine was given to rats (N = 4) at 0.5 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of lumefantrine and its metabolite desbutyl-lumefantrine in plasma were determined by partially validated LC-MS/MS method. In-situ permeability study was carried in anaesthetized rats. The concentration of lumefantrine in permeability samples was determined using RP-HPLC. Results For nominal doses increasing in a 1:2:4 proportion, the C max and AUC 0-∞ values increased in the proportions of 1:0.6:1.5 and 1:0.8:1.8, respectively. For lumefantrine nominal doses increasing in a 1:2:4 proportion, the C max and the AUC 0-t values for desbutyl-lumefantrine increased in the proportions of 1:1.45:2.57 and 1:1.08:1.87, respectively. After intravenous administration the clearance (Cl) and volume of distribution (Vd) of lumefantrine in rats were 0.03 (± 0.02) L/h/kg and 2.40 (± 0.67) L/kg, respectively. Absolute oral bioavailability of lumefantrine across the tested doses ranged between 4.97% and 11.98%. Lumefantrine showed high permeability (4.37 × 10 -5 cm/s) in permeability study. Conclusions The pharmacokinetic parameters of lumefantrine and its ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 10 1 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
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Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
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Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 Wahajuddin Singh Sheelendra P Raju Kanumuri SR Nafis Asad Puri Sunil K Jain Girish K Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
Abstract Background Despite the wide spread use of lumefantrine, there is no study reporting the detailed preclinical pharmacokinetics of lumefantrine. For the development of newer anti-malarial combination(s) and selection of better partner drugs, it is long felt need to understand the detailed preclinical pharmacokinetics of lumefantrine in preclinical experimental animal species. The focus of present study is to report bioavailability, pharmacokinetics, dose linearity and permeability of lumefantrine in rats. Methods A single dose of 10, 20 or 40 mg/kg of lumefantrine was given orally to male rats (N = 5 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of lumefantrine was given to rats (N = 4) at 0.5 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of lumefantrine and its metabolite desbutyl-lumefantrine in plasma were determined by partially validated LC-MS/MS method. In-situ permeability study was carried in anaesthetized rats. The concentration of lumefantrine in permeability samples was determined using RP-HPLC. Results For nominal doses increasing in a 1:2:4 proportion, the C max and AUC 0-∞ values increased in the proportions of 1:0.6:1.5 and 1:0.8:1.8, respectively. For lumefantrine nominal doses increasing in a 1:2:4 proportion, the C max and the AUC 0-t values for desbutyl-lumefantrine increased in the proportions of 1:1.45:2.57 and 1:1.08:1.87, respectively. After intravenous administration the clearance (Cl) and volume of distribution (Vd) of lumefantrine in rats were 0.03 (± 0.02) L/h/kg and 2.40 (± 0.67) L/kg, respectively. Absolute oral bioavailability of lumefantrine across the tested doses ranged between 4.97% and 11.98%. Lumefantrine showed high permeability (4.37 × 10 -5 cm/s) in permeability study. Conclusions The pharmacokinetic parameters of lumefantrine and its ... |
format |
Article in Journal/Newspaper |
author |
Wahajuddin Singh Sheelendra P Raju Kanumuri SR Nafis Asad Puri Sunil K Jain Girish K |
author_facet |
Wahajuddin Singh Sheelendra P Raju Kanumuri SR Nafis Asad Puri Sunil K Jain Girish K |
author_sort |
Wahajuddin |
title |
Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats |
title_short |
Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats |
title_full |
Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats |
title_fullStr |
Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats |
title_full_unstemmed |
Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats |
title_sort |
intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats |
publisher |
BMC |
publishDate |
2011 |
url |
https://doi.org/10.1186/1475-2875-10-293 https://doaj.org/article/f93ff1febb8942a48b64416817b0e8fd |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 10, Iss 1, p 293 (2011) |
op_relation |
http://www.malariajournal.com/content/10/1/293 https://doaj.org/toc/1475-2875 doi:10.1186/1475-2875-10-293 1475-2875 https://doaj.org/article/f93ff1febb8942a48b64416817b0e8fd |
op_doi |
https://doi.org/10.1186/1475-2875-10-293 |
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Malaria Journal |
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10 |
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1 |
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1766347131544666112 |