| MDR1 G1199A polymorphism alters permeability of HIV protease inhibitors across P-glycoprotein-expressing epithelial cells. | |
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MedLine Citation:
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PMID: 16184031 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Erica L Woodahl; Ziping Yang; Tot Bui; Danny D Shen; Rodney J Y Ho |
Publication Detail:
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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:
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Title: AIDS (London, England) Volume: 19 ISSN: 0269-9370 ISO Abbreviation: AIDS Publication Date: 2005 Oct |
Date Detail:
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Created Date: 2005-09-26 Completed Date: 2006-05-03 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 8710219 Medline TA: AIDS Country: England |
Other Details:
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Languages: eng Pagination: 1617-25 Citation Subset: IM; X |
Affiliation:
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Department of Pharmaceutics, University of Washington, Seattle, Washington 98195-7610, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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:
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0/HIV Protease Inhibitors; 0/P-Glycoprotein |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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