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Vicriviroc, A Novel CCR5 Inhibitor, is NOT A p-glycoprotein Substrate In Vitro

The CCR5 chemokine receptor is a promising target for antiretroviral therapy because of its role as a coreceptor for HIV entry and propagation of infection. Vicriviroc, a small molecule CCR5 inhibitor being studied in clinical trials, is well absorbed in rats and monkeys; in vitro studies were performed with caco-2 cells to determine its bi-directional permeability and potential as a p-glycoprotein (pGp) efflux substrate.

Caco-2 cells (passage 60 to 61) were grown for 3 weeks to confluency and the integrity of the monolayer was confirmed by TEER measurements in the presence of vicriviroc (50 to 400 mM). For bi-directional permeability studies, vicriviroc was placed on either the apical (A) or basolateral (B) compartment at a concentration of 40 mM and permeability (n = 3) was determined over 2 hrs with an LC/MS/MS assay. Total recovery exceeded 85% in all studies. The passive permeability (A to B) performance of the caco-2 cell monolayers were confirmed with atenolol (Pc = 3 ± 1.7 nm/s) and pindolol (Pc = 200 ± 9 nm/s). Functional expression of pGp was confirmed with the standard pGp substrate digoxin (bi-directional efflux ratios: 4- to 10-fold).

Vicriviroc showed high A to B permeability (Pc = 400 ± 4 nm/s) consistent with its high in vivo oral absorption. The bi-directional efflux ratio of vicriviroc was only 0.6 indicating that it is not a pGp substrate in vitro. These data suggested that pGp is unlikely to affect the oral absorption of vicriviroc and that co-administration of vicriviroc with a pGp inhibitor is unlikely to cause significant drug-drug interactions.

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Correspondence to Cheng Li.

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Li, C., Keung, A., Morrison, R.A. et al. Vicriviroc, A Novel CCR5 Inhibitor, is NOT A p-glycoprotein Substrate In Vitro. Retrovirology 2, P158 (2005).

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  • Atenolol
  • Pindolol
  • CCR5 Chemokine Receptor
  • Passive Permeability
  • CCR5 Chemokine