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Antimicrobial Agents and Chemotherapy, November 2002, p. 3456-3462, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3456-3462.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Direct Evidence that Saquinavir Is Transported by Multidrug Resistance-Associated Protein (MRP1) and Canalicular Multispecific Organic Anion Transporter (MRP2)

Gregory C. Williams,1 Angela Liu,2 Gregory Knipp,1 and Patrick J. Sinko1*

Department of Pharmaceutics, School of Pharmacy, Rutgers University,1 Department of Pharmacology, Robert Wood Johnson Medical School, Piscataway, New Jersey 088542

Received 26 March 2002/ Returned for modification 3 June 2002/ Accepted 16 August 2002

To determine if saquinavir mesylate (saquinavir) is a substrate of human multidrug resistance-associated protein 1 (hMRP1 [ABCC1]) or hMRP2 (cMOAT, or ABCC2), MDCKII cells that overexpress either hMRP1 (MDCKII-MRP1) or hMRP2 (MDCKII-MRP2) were used to investigate saquinavir's cytotoxicity and transport in comparison with those of control MDCKII wild-type (MDCKII/wt) cells. Cytotoxicity was assessed with the mitochondrial marker MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium], and saquinavir transport was measured directly through the cell monolayers. GF120918 (an inhibitor of P glycoprotein, but not of the MRP family) and MK-571 (an MRP family inhibitor) were used to delineate the specific contributions of these transporters to saquinavir cytotoxicity and transport. In the presence of GF120918 and increasing saquinavir concentrations, the MDCKII-MRP1 (50% lethal dose [LD50] = 10.5 µM) and MDCKII-MRP2 (LD50 = 27.1 µM) cell lines exhibited statistically greater viability than the MDCKII/wt cells (LD50 = 7.8 µM). Saquinavir efflux was directional, not saturable, and was inhibited by MK-571 (35 and 75 µM) in all cell lines. The ratios of saquinavir (3 µM) basolateral to apical permeability (i.e., efflux ratios) for the MDCKII/wt, MDCKII-MRP1, and MDCKII-MRP2 cell monolayers were 2.6, 1.8, and 6.8, respectively. The MDCKII-MRP1 cells have a significantly reduced saquinavir efflux ratio relative to MDCKII/wt cells, due to basolaterally directed transport by hMRP1 competing with endogenous, apically directed canine MRP2. The MDCKII-MRP2 cells have a significantly increased saquinavir efflux ratio relative to MDCKII/wt cells, due to the additive effects of the apically directed transport by hMRP2 and endogenous MRP2. Collectively, the cytotoxicity and transport results provide direct evidence that saquinavir is transported by MRP1 and MRP2.

* Corresponding author. Mailing address: Department of Pharmaceutics, School of Pharmacy, Rutgers University, 160 Frelinghuysen Rd., Piscataway, NJ 08854. Phone: (732) 445-3839/2256. Fax: (732) 445-4271. E-mail: sinko{at}rci.rutgers.edu.

Antimicrobial Agents and Chemotherapy, November 2002, p. 3456-3462, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3456-3462.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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