QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.076216v1 312/3/1249    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Park, S. Articles by Sinko, P. J. Search for Related Content PubMed PubMed Citation Articles by Park, S. Articles by Sinko, P. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ACRIDINE

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

P-Glycoprotein and Mutlidrug Resistance-Associated Proteins Limit the Brain Uptake of Saquinavir in Mice

Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey

Efflux transporters such as P-glycoprotein (P-gp) and multidrug resistance-associated proteins (Mrps) and their contributions to saquinavir (SQV) brain uptake were characterized. Cerebral flow rate was estimated from diazepam uptake and brain vascular volume was assessed using inulin. Mice brains were perfused with buffer containing SQV alone or coperfused with different concentrations of GF120918, a P-gp inhibitor or MK571, a specific Mrp family inhibitor. Inulin, a nonabsorbable marker, was also coperfused in all studies to assess whether the inhibitors altered the physical integrity of the blood-brain barrier (BBB). The estimated cerebral flow rate using diazepam was 250 ml·100g^-1·min^-1. The brain vascular volume, estimated using inulin, was almost constant (0.94 ± 0.03 ml·100 g^-1, n = 12) during the perfusion study. SQV uptake kinetics was linear during the sampling period. Inclusion of 10 µM GF120918 in the perfusate resulted in a more than 7-fold increase in the brain distributional volume (i.e., uptake) of SQV. Inclusion of 100 µM MK571 in the perfusate increased SQV apparent brain uptake by more than 4.4-fold, suggesting, for the first time, that Mrp transporters may play an important role in the brain uptake and retention of SQV. Neither GF120918 nor MK571 altered the integrity of the BBB during the time course of the study. Although the current results reaffirm that SQV is a P-gp substrate, this is the first report implicating the Mrp transporter family in the limited brain uptake and retention of SQV in vivo in mice.

Address correspondence to: Dr. Patrick J. Sinko, Rutgers University, Ernest Mario School of Pharmacy, 160 Frelinghuysen Rd., Piscataway, NJ 08854. E-mail: sinko{at}rci.rutgers.edu

This article has been cited by other articles:

				M. Eilers, U. Roy, and D. Mondal MRP (ABCC) Transporters-Mediated Efflux of Anti-HIV Drugs, Saquinavir and Zidovudine, from Human Endothelial Cells Experimental Biology and Medicine, September 1, 2008; 233(9): 1149 - 1160. [Abstract] [Full Text] [PDF]

				L. W. Chinn, J. M. Gow, M. M. Tse, S. L. Becker, and D. L. Kroetz Interindividual variability in the effect of atazanavir and saquinavir on the expression of lymphocyte P-glycoprotein J. Antimicrob. Chemother., July 1, 2007; 60(1): 61 - 67. [Abstract] [Full Text] [PDF]

				G. Pan, N. Giri, and W. F. Elmquist Abcg2/Bcrp1 Mediates the Polarized Transport of Antiretroviral Nucleosides Abacavir and Zidovudine Drug Metab. Dispos., July 1, 2007; 35(7): 1165 - 1173. [Abstract] [Full Text] [PDF]

				N. von Hentig, A. Muller, C. Rottmann, T. Wolf, T. Lutz, S. Klauke, M. Kurowski, B. Oertel, B. Dauer, S. Harder, et al. Pharmacokinetics of Saquinavir, Atazanavir, and Ritonavir in a Twice-Daily Boosted Double-Protease Inhibitor Regimen Antimicrob. Agents Chemother., April 1, 2007; 51(4): 1431 - 1439. [Abstract] [Full Text] [PDF]

				S. Dallas, D. S. Miller, and R. Bendayan Multidrug resistance-associated proteins: expression and function in the central nervous system. Pharmacol. Rev., June 1, 2006; 58(2): 140 - 161. [Abstract] [Full Text] [PDF]

				S. Park and P. J. Sinko THE BLOOD-BRAIN BARRIER SODIUM-DEPENDENT MULTIVITAMIN TRANSPORTER: A MOLECULAR FUNCTIONAL IN VITRO-IN SITU CORRELATION Drug Metab. Dispos., October 1, 2005; 33(10): 1547 - 1554. [Abstract] [Full Text] [PDF]