Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs.
BACKGROUND
Various drug transporters of the ATP-binding cassette (ABC) family restrict the oral bioavailability and cellular, brain, testis, cerebrospinal fluid and fetal penetration of substrate drugs. MDRI P-glycoprotein (P-gp) has been demonstrated to transport most HIV protease inhibitors (HPI) and to reduce their oral bioavailability and lymphocyte, brain, testis and fetal penetration, possibly resulting in major limiting effects on the therapeutic efficacy of these drugs.


OBJECTIVE
To investigate whether the ABC transporters MRP1, MRP2, MRP3, MRP5 and breast cancer resistance protein 1 (Bcrp1) are efficient transporters of the HPI saquinavir, ritonavir and indinavir.


METHODS
Polarized epithelial non-human (canine) cell lines transduced with human or murine complementary DNA (cDNA) for each of the transporters were used to study transepithelial transport of the HPI.


RESULTS
MRP2 efficiently transported saquinavir, ritonavir and indinavir and this transport could be enhanced by probenecid. Sulfinpyrazone was also able to enhance MRP2-mediated saquinavir transport. In contrast, MRP1, MRP3, MRP5, or Bcrp1 did not efficiently transport the HPI tested.


CONCLUSIONS
Human MRP2 actively transports several HPI and could, based on its known and assumed tissue distribution, therefore reduce HPI oral bioavailability. It may also limit brain and fetal penetration of these drugs and increase their hepatobiliary, intestinal and renal clearance. MRP2 function and enhancement of its activity could adversely affect the therapeutic efficacy, including the pharmacological sanctuary penetration, of HPI. In vivo inhibition of MRP2 function might, therefore, improve HIV/AIDS therapy.
Huisman
Maarten T
MT
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Smit
Johan W
JW
Crommentuyn
Kristel M L
KM
Zelcer
Noam
N
Wiltshire
Hugh R
HR
Beijnen
Jos H
JH
Schinkel
Alfred H
AH
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D004285:Dogs; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D004847:Epithelial Cells / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D019469:Indinavir / Q000493:pharmacokinetics; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000494:pharmacology*; D009363:Neoplasm Proteins; D019438:Ritonavir / Q000493:pharmacokinetics; D019258:Saquinavir / Q000493:pharmacokinetics; D014161:Transduction, Genetic
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D017320:HIV Protease Inhibitors; D019469:Indinavir; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D019438:Ritonavir; D019258:Saquinavir; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1