title: HIV-1 integrase inhibitors are substrates for the multidrug transporter MDR1-P-glycoprotein.
abstract: BACKGROUND
  The discovery of diketoacid-containing derivatives as inhibitors of HIV-1 Integrase (IN) (IN inhibitors, IINs) has played a major role in validating this enzyme as an important target for antiretroviral therapy. Since the in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether the IINs are recognized by the multidrug transporter MDR1-P-glycoprotein (P-gp) thereby reducing their intracellular accumulation. To address the effect of IINs on drug transport, nine quinolonyl diketo acid (DKA) derivatives active on the HIV-1 IN strand transfer (ST) step and with EC50 ranging from 1.83 to >50 mum in cell-based assays were tested for their in vitro interaction with P-gp in the CEM-MDR cell system. IINs were investigated for the inhibition and induction of the P-gp function and expression as well as for multidrug resistance (MDR) reversing ability.
  
  
  RESULTS
  The HIV-1 IINs act as genuine P-gp substrates by inhibiting doxorubicin efflux and inducing P-gp functional conformation changes as evaluated by the modulation of UIC2 mAb epitope. Further, IINs chemosensitize MDR cells to vinblastine and induce P-gp expression in drug sensitive revertants of CEM-MDR cells.
  
  
  CONCLUSIONS
  To our knowledge, this is the first demonstration that HIV-1 IINs are P-gp substrates. This biological property may influence the absorption, distribution and elimination of these novels anti HIV-1 compounds.
authors.affiliation: Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. maurizio.cianfriglia@iss.it
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cianfriglia
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Dupuis
authors.forename: Agnese
authors.initials: A
authors.lastname: Molinari
authors.forename: Antonio
authors.initials: A
authors.lastname: Verdoliva
authors.forename: Roberta
authors.initials: R
authors.lastname: Costi
authors.forename: Clementina Maria
authors.initials: CM
authors.lastname: Galluzzo
authors.forename: Mauro
authors.initials: M
authors.lastname: Andreotti
authors.forename: Andrea
authors.initials: A
authors.lastname: Cara
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Santo
authors.forename: Lucia
authors.initials: L
authors.lastname: Palmisano
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology*; D024921:Drug Resistance, Multiple, Viral; D005434:Flow Cytometry; D019428:HIV Integrase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D018613:Microscopy, Confocal; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000821:virology; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019428:HIV Integrase Inhibitors; D004317:Doxorubicin; D014700:Verapamil