![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts-New England Medical Center, Boston, Massachusetts (E.S.P., S.X.D., D.J.G., L.L.v.M.); and Center for HIV Care and Research, Section of Infectious Disease, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts (P.R.S.)
The effect of atazanavir on P-glycoprotein (P-gp) expression and activity, as well as its inhibitory potency against CYP3A activity, was evaluated in vitro. Induction of P-gp activity and expression was studied using LS180V cells. P-gp inhibition was studied using both LS180V cells and Caco-2 cells. P-gp activity was assessed by measuring P-gp-mediated rhodamine 123 (Rh123) transport, and P-gp expression was determined using SDS-polyacrylamide gel electrophoresis/Western blot analysis. CYP3A inhibition was tested using triazolam hydroxylation in human liver microsomes (HLM). Extended (3-day) exposure of LS180V cells to 30 µM atazanavir caused a 2.5-fold increase in immunoreactive P-gp expression as well as a concentration-dependent decrease of intracellular Rh123 to a mean 45% (S.D. 5.2%) of control. Acute exposure (2 h) of LS180V cells to atazanavir increased intracellular Rh123 concentrations up to 300% of control at 100 µM atazanavir. At 30 µM and above, acute atazanavir exposure reversed P-gp induction caused by 3-day pretreatment with 10 µM ritonavir. P-gp inhibition was also observed in Caco-2 cells, causing an effect comparable to that observed for the known P-gp inhibitor verapamil (50% of control). In HLM, atazanavir was an inhibitor of triazolam hydroxylation, with inhibitory potency greatly increased by preincubation. IC50 values with and without preincubation were 0.31 µM (S.D. 0.13) and 5.7 µM (S.D. 4.1), respectively. Thus, atazanavir is an inhibitor and inducer of P-gp as well as a potent inhibitor of CYP3A in vitro, suggesting a potential for atazanavir to cause drug-drug interactions in vivo.
This article has been cited by other articles:
|
|
 |
|
  L. Dickinson, M. Boffito, D. Back, L. Waters, L. Else, G. Davies, S. Khoo, A. Pozniak, and L. Aarons Population pharmacokinetics of ritonavir-boosted atazanavir in HIV-infected patients and healthy volunteers J. Antimicrob. Chemother., June 1, 2009; 63(6): 1233 - 1243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Rhee and D. J. Greenblatt Pharmacologic Consideration for the Use of Antiretroviral Agents in the Elderly J. Clin. Pharmacol., October 1, 2008; 48(10): 1212 - 1225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Zhang and L.-Y. Lim Effects of Spice Constituents on P-Glycoprotein-Mediated Transport and CYP3A4-Mediated Metabolism in Vitro Drug Metab. Dispos., July 1, 2008; 36(7): 1283 - 1290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Tong, T. K. Phan, K. L. Robinson, D. Babusis, R. Strab, S. Bhoopathy, I. J. Hidalgo, G. R. Rhodes, and A. S. Ray Effects of Human Immunodeficiency Virus Protease Inhibitors on the Intestinal Absorption of Tenofovir Disoproxil Fumarate In Vitro Antimicrob. Agents Chemother., October 1, 2007; 51(10): 3498 - 3504. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. Weiss, D. Theile, N. Ketabi-Kiyanvash, H. Lindenmaier, and W. E. Haefeli Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by Nucleoside, Nucleotide, and Non-Nucleoside Reverse Transcriptase Inhibitors Drug Metab. Dispos., March 1, 2007; 35(3): 340 - 344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Roucairol, S. Azoulay, M.-C. Nevers, C. Creminon, T. Lavrut, R. Garraffo, J. Grassi, A. Burger, and D. Duval Quantitative Immunoassay To Measure Plasma and Intracellular Atazanavir Levels: Analysis of Drug Accumulation in Cultured T Cells Antimicrob. Agents Chemother., February 1, 2007; 51(2): 405 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Weiss, J. Rose, C. H. Storch, N. Ketabi-Kiyanvash, A. Sauer, W. E. Haefeli, and T. Efferth Modulation of human BCRP (ABCG2) activity by anti-HIV drugs J. Antimicrob. Chemother., February 1, 2007; 59(2): 238 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Colombo, T. Buclin, M. Cavassini, L. A. Decosterd, A. Telenti, J. Biollaz, and C. Csajka Population Pharmacokinetics of Atazanavir in Patients with Human Immunodeficiency Virus Infection Antimicrob. Agents Chemother., November 1, 2006; 50(11): 3801 - 3808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Burger, S. Agarwala, M. Child, A. Been-Tiktak, Y. Wang, and R. Bertz Effect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Antimicrob. Agents Chemother., October 1, 2006; 50(10): 3336 - 3342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Greenblatt, R. A. Leigh-Pemberton, and L. L. von Moltke In Vitro Interactions of Water-Soluble Garlic Components with Human Cytochromes P450 J. Nutr., March 1, 2006; 136(3): 806S - 809S. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
