HIV-1 integrase inhibitors are substrates for the multidrug transporter MDR1-P-glycoprotein.
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.
Cianfriglia
Maurizio
M
Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. maurizio.cianfriglia@iss.it
Dupuis
Maria Luisa
ML
Molinari
Agnese
A
Verdoliva
Antonio
A
Costi
Roberta
R
Galluzzo
Clementina Maria
CM
Andreotti
Mauro
M
Cara
Andrea
A
Di Santo
Roberto
R
Palmisano
Lucia
L
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*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019428:HIV Integrase Inhibitors; D004317:Doxorubicin; D014700:Verapamil