Document Detail


MDR1 G1199A polymorphism alters permeability of HIV protease inhibitors across P-glycoprotein-expressing epithelial cells.
MedLine Citation:
PMID:  16184031     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: To evaluate the impact of the human multidrug resistance gene (MDR1) G1199A polymorphism (amino acid change Ser400Asn) on P-glycoprotein (P-gp)-dependent transepithelial permeability and uptake kinetics of HIV protease inhibitors (PI), by using recombinant epithelial cells expressing wild-type MDR1 (MDR1wt) or the G1199A variant (MDR1(1199A)). METHODS: Using a recombinant expression system developed previously, the transepithelial permeability and uptake kinetic parameters of five PI, amprenavir, indinavir, lopinavir, ritonavir, and saquinavir were estimated across polarized epithelial cells. RESULTS: For all PI, the transepithelial permeability ratio (basolateral-to-apical transport divided by apical-to-basolateral transport) was significantly greater in MDR1(1199A) cells than MDR1wt cells: amprenavir (1.7-fold), indinavir (1.8-fold), lopinavir (1.5-fold), ritonavir (2.8-fold), and saquinavir (2.1-fold). However, the impact of G1199A on P-gp activity appeared to primarily influence drug permeability in the apical-to-basolateral direction. Kinetic analysis of ritonavir and saquinavir uptake by MDR1wt- and MDR1(1199A)-expressing cells showed that Vmax was similar, while uptake Km was significantly higher in cells expressing the G1199A variant suggesting that alterations in P-gp-dependent efflux mediated by G1199A were due to changes in transporter affinity. CONCLUSIONS: Alterations in transepithelial permeability of HIV PI due to the G1199A polymorphism may impact oral bioavailability of PI and penetration into cells and tissues of the lymphoid and central nervous systems.
Authors:
Erica L Woodahl; Ziping Yang; Tot Bui; Danny D Shen; Rodney J Y Ho
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  AIDS (London, England)     Volume:  19     ISSN:  0269-9370     ISO Abbreviation:  AIDS     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-09-26     Completed Date:  2006-05-03     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8710219     Medline TA:  AIDS     Country:  England    
Other Details:
Languages:  eng     Pagination:  1617-25     Citation Subset:  IM; X    
Affiliation:
Department of Pharmaceutics, University of Washington, Seattle, Washington 98195-7610, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biological Transport / genetics
Cells, Cultured
Epithelial Cells / metabolism*
Genes, MDR / genetics*,  physiology
HIV Protease Inhibitors / pharmacokinetics*
P-Glycoprotein / metabolism*
Permeability
Polymorphism, Genetic*
Swine
Grant Support
ID/Acronym/Agency:
AI31854/AI/NIAID NIH HHS; AI52663/AI/NIAID NIH HHS; ES07033/ES/NIEHS NIH HHS; GM07750/GM/NIGMS NIH HHS; GM62883/GM/NIGMS NIH HHS; HL56548/HL/NHLBI NIH HHS; NS39178/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/HIV Protease Inhibitors; 0/P-Glycoprotein

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