Linked Life Data

11988394

Source:http://linkedlifedata.com/resource/pubmed/id/11988394

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2002-5-3
pubmed:abstractText
The solubility enhancing effects of various excipients, including their compatibility with in vitro permeability (P(app)) systems, was investigated using drugs representative of Biopharmaceutics Classification System (BCS) classes I-IV. Turbidimetric solubility determination using nephelometry and transport experiments using MDCK Strain I cell monolayers were employed. The highest usable concentration of each excipient [dimethyl sulfoxide (DMSO), ethanol, hydroxypropyl-beta-cyclodextrin (HPCD), and sodium taurocholate] was determined by monitoring apical (AP) to basolateral (BL) [14C]mannitol apparent permeability (P(app)) and the transepithelial electrical resistance (TEER) in transport experiments done at pH 6.0 and 7.4. The excipients were used in conjunction with compounds demonstrating relatively low aqueous solubility (amphotericin B, danazol, mefenamic acid, and phenytoin) in order to obtain a drug concentration >50 microM in the donor compartment. The addition of at least one of the selected excipients enhanced the solubility of the inherently poorly soluble compounds to >50 microM as determined via turbidimetric evaluation at pH 6.0 and 7.4. Ethanol and DMSO were found to be generally disruptive to the MDCK monolayer and were not nearly as useful as HPCD and sodium taurocholate. Sodium taurocholate (5 mM) was compatible with MDCK monolayers under all conditions investigated. Additionally, a novel in vitro system aimed at more accurately simulating in vivo conditions, i.e., a pH gradient (6.0 AP/7.4 BL), sodium taurocholate (5 mM, AP), and bovine serum albumin (0.25%, BL), was shown to generate more reliable P(app) values for compounds that are poorly soluble and/or highly protein bound.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0928-0987
pubmed:author
pubmed:issnType
Print
pubmed:volume
15
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
331-40
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
Optimized conditions for MDCK permeability and turbidimetric solubility studies using compounds representative of BCS classes I-IV.
pubmed:affiliation
Novo Nordisk A/S, Department of Drug Metabolism, Novo Nordisk Park, DK-2760 Maaloev, Denmark. mtaub@rdg.boehringer-ingelheim.com
pubmed:publicationType
Journal Article