Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?

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Fältnamn	Indikatorer	Metadata
000		04654naa a2200433 4500
001		oai:DiVA.org:uu-366566
003		SwePub
008		181121s2019 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3665662 URI
024	7	a https://doi.org/10.1016/j.jconrel.2019.04.0382 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Alskär, Linda C.u Uppsala universitet,Institutionen för farmaci4 aut0 (Swepub:uu)linpe249
245	1 0	a Effect of lipids on absorption of carvedilol in dogs :b Is coadministration of lipids as efficient as a lipid-based formulation?
264	1	b Elsevier BV,c 2019
338		a electronic2 rdacarrier
520		a Lipid-based formulations (LBFs) is a formulation strategy for enabling oral delivery of poorly water-soluble drugs. However, current use of this strategy is limited to a few percent of the marketed products. Reasons for that are linked to the complexity of LBFs, chemical instability of pre-dissolved drug and a limited understanding of the influence of LBF intestinal digestion on drug absorption. The aim of this study was to explore intestinal drug solubilization from a long-chain LBF, and evaluate whether coadministration of LBF is as efficient as a lipidbased drug formulation containing the pre-dissolved model drug carvedilol. Thus, solubility studies of this weak base were performed in simulated intestinal fluid (SIF) and aspirated dog intestinal fluid (DIF). DIF was collected from duodenal stomas after dosing of water and two levels (1 g and 2 g) of LBF. Similarly, the in vitro SIF solubility studies were conducted prior to, and after addition of, undigested or digested LBF. The DIF fluid was further characterized for lipid digestion products (free fatty acids) and bile salts. Subsequently, carvedilol was orally administered to dogs in a lipid-based drug formulation and coadministered with LBF, and drug plasma exposure was assessed. In addition to these studies, in vitro drug absorption from the different formulation approaches were evaluated in a lipolysis-permeation device, and the obtained data was used to evaluate the in vitro in vivo correlation. The results showed elevated concentrations of free fatty acids and bile salts in the DIF when 2 g of LBF was administered, compared to only water. As expected, the SIF and DIF solubility data revealed that carvedilol solubilization increased by the presence of lipids and lipid digestion products. Moreover, coadministration of LBF and drug demonstrated equal plasma exposure to the lipid-based drug formulation. Furthermore, evaluation of in vitro absorption resulted in the same rank order for the LBFs as in the in vivo dog study. In conclusion, this study demonstrated increased intestinal solubilization from a small amount of LBF, caused by lipid digestion products and bile secretion. The outcomes also support the use of coadministration of LBF as a potential dosing regimen in cases where it is beneficial to have the drug in the solid form, e.g. due to chemical instability in the lipid vehicle. LBFs.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng
653		a Intestinal digestion
653		a in vivo dog study
653		a lipid-based formulation
653		a coadministration
653		a absorption
653		a in vitro in vivo correlation (IVIVC)
700	1	a Parrow, Albinu Uppsala universitet,Institutionen för farmaci4 aut0 (Swepub:uu)albpa780
700	1	a Keemink, Jannekeu Uppsala universitet,Institutionen för farmaci4 aut0 (Swepub:uu)janke374
700	1	a Pernilla, Johanssonu AstraZeneca R&D, Gothenburg, Sweden4 aut
700	1	a Abrahamsson, Bertilu AstraZeneca R&D, Gothenburg, Sweden4 aut
700	1	a Bergström, Christel A. S.,d 1973-u Uppsala universitet,Institutionen för farmaci4 aut0 (Swepub:uu)cjo29958
710	2	a Uppsala universitetb Institutionen för farmaci4 org
773	0	t Journal of Controlled Released : Elsevier BVg 304, s. 90-100q 304<90-100x 0168-3659x 1873-4995
856	4	u https://uu.diva-portal.org/smash/get/diva2:1264933/FULLTEXT01.pdfx primaryx Raw objecty fulltext:postprint
856	4	u http://uu.diva-portal.org/smash/get/diva2:1264933/FULLTEXT01
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-366566
856	4 8	u https://doi.org/10.1016/j.jconrel.2019.04.038

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