title: MDR1 G1199A polymorphism alters permeability of HIV protease inhibitors across P-glycoprotein-expressing epithelial cells.
abstract: 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.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington 98195-7610, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Woodahl
authors.forename: Ziping
authors.initials: Z
authors.lastname: Yang
authors.forename: Tot
authors.initials: T
authors.lastname: Bui
authors.forename: Danny D
authors.initials: DD
authors.lastname: Shen
authors.forename: Rodney J Y
authors.initials: RJ
authors.lastname: Ho
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D019450:Genes, MDR / Q000235:genetics* / Q000502:physiology; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D010539:Permeability; D011110:Polymorphism, Genetic; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors