Montelukast is a potent and durable inhibitor of multidrug resistance protein 2-mediated efflux of taxol and saquinavir.
The ATP binding cassette (ABC)-transporters are energy dependent efflux pumps which regulate the pharmacokinetics of both anti-cancer chemotherapeutic agents, e.g. taxol, and of human immunodeficiency virus-1 (HIV-1) protease inhibitors (HPIs), e.g. saquinavir. Increased expression of several ABC-transporters, especially P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2), are observed in multidrug resistant (MDR) tumor cells and on HIV-1 infected lymphocytes. In addition, due to their apical expression on vascular endothelial barriers, both P-gp and MRP2 are of crucial importance towards dictating drug access into sequestered tissues. However, although a number of P-gp inhibitors are currently in clinical trials, possible inhibitors of MRP2 are not being thoroughly investigated. The experimental leukotriene receptor antagonist (LTRA), MK-571 is known to be a potent inhibitor of MRP transporters. Using the MRP2 over-expressing Madin-Darby canine kidney cell line, MDCKII-MRP2, we evaluated whether the clinically approved LTRAs, e.g. montelukast (Singulair) and zafirlukast (Accolate), can similarly suppress MRP2-mediated efflux. We compared the efficacy of increasing concentrations (20-100 microM) of MK-571, montelukast, and zafirlukast, in suppressing the efflux of calcein-AM, a fluorescent MRP substrate, and the radiolabeled [(3)H-] drugs, taxol and saquinavir. Montelukast was the most potent inhibitor (p<0.01) of MRP2-mediated efflux of all three substrates. Montelukast also increased (p<0.01) the duration of intracellular retention of both taxol and saquinavir. More than 50% of the drugs were retained in cells even after 90 min post removal of montelukast from the medium. Our findings implicate that montelukast, a relatively safe anti-asthmatic agent, may be used as an adjunct therapy to suppress the efflux of taxol and saquinavir from MRP2 overexpressing cells.
Roy
Upal
U
Department of Pharmacology, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Chakravarty
Geetika
G
Honer Zu Bentrup
Kerstin
K
Mondal
Debasis
D
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D017024:Chemotherapy, Adjuvant; D003521:Cyclopropanes; D004285:Dogs; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D024882:Drug Resistance, Viral / Q000187:drug effects; D005452:Fluoresceins / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007211:Indoles; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000627:therapeutic use; D048448:Phenylcarbamates; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D019258:Saquinavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013440:Sulfides; D013449:Sulfonamides; D013997:Time Factors; D014105:Tosyl Compounds / Q000494:pharmacology
D000085:Acetates; D018927:Anti-Asthmatic Agents; D000972:Antineoplastic Agents, Phytogenic; D003521:Cyclopropanes; D005452:Fluoresceins; D017320:HIV Protease Inhibitors; D007211:Indoles; D020024:Leukotriene Antagonists; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D048448:Phenylcarbamates; D011422:Propionates; D011804:Quinolines; D019258:Saquinavir; D013440:Sulfides; D013449:Sulfonamides; D014105:Tosyl Compounds; C085925:calcein AM; C059141:verlukast; C093875:montelukast; C062735:zafirlukast