Linked Life Data

15858856

Source:http://linkedlifedata.com/resource/pubmed/id/15858856

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2005-5-3
pubmed:abstractText
Insufficient concentrations of protease inhibitors such as nelfinavir may reduce the effectiveness of HIV dementia treatment. The efflux transporter mdr1 product P-glycoprotein (P-gp) has been demonstrated to play a role in limiting nelfinavir brain levels. The goal of this study was to compare the effect of GF120918 (10 mg/kg, IV), a P-gp inhibitor, on intravenous nelfinavir (10 mg/kg) in vivo disposition and tissue penetration in P-gp-competent mdr1a/1b (+/+) mice versus P-gp double knockout mdr1a/1b (-/-) mice. Intravenous administration with the P-gp inhibitor GF120918 to mdr1a/1b (+/+) mice increased nelfinavir concentrations over a range of 2.3- to 27-fold, whereas nelfinavir distribution in mdr1a/1b (-/-) mice was 2- to 16-fold higher than that in their wild counterparts. Nelfinavir levels after GF120918 coadministration were higher in the heart, liver, and kidneys than those detected with mdr1a/1b knockout mice. In contrast, mdr1a/1b knockout mice exhibited higher nelfinavir levels in the brain (16.1-fold vs. 8.9-fold increase) and spleen (4.1-fold vs. 2.3-fold increase) compared to pharmacological inhibition with GF120918 in wild mice. Most notably, GF120918 provided tissue-specific effects in mdr1a/1b knockout mice with enhanced (p < 0.05) drug accumulation in the brain ( approximately 21-fold) and heart (3.3-fold). Our results suggest mdr1a/1b-independant mechanisms may also contribute to nelfinavir tissue distribution in mice.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-3549
pubmed:author
pubmed:copyrightInfo
(c) 2005 Wiley-Liss, Inc.
pubmed:issnType
Print
pubmed:volume
94
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1216-25
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
The impact of pharmacologic and genetic knockout of P-glycoprotein on nelfinavir levels in the brain and other tissues in mice.
pubmed:affiliation
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural