Relationship between P-glycoprotein activity measured in peripheral blood mononuclear cells and indinavir bioavalability in healthy volunteers

BRAMUGLIA G., CORTADA C., CURRAS V., HÖCHT C.,BUONTEMPO F., MATO G., NISELMAN V.,RUBIO M., CARBALLO M.

JOURNAL OF PHARMACEUTICAL SCIENCES

John Wiley & Sons

Año: 2009 vol. 98 p. 327 - 336

0022-3549

Indinavir is a HIV-1 protease inhibitor that showed a large inter-individual pharmacokinetic variability. It has been proposed as a substrate of, P-glycoprotein (P-gp) an efflux transporter that may contribute to limit their bioavailability. A liquid formulation of indinavir was developed from indinavir capsules in order to study indinavir pharmacokinetics in healthy volunteers. Compartmental and non compartmental analysis showed a high inter-individual variability in terms of AUC and Cmax. A significant negative association between AUC normalized to body weight (AUC*weight) and lymphocyte P-gp activity, using Rh123 efflux assay, was observed (p=0.008; r = -0.75). AUC normalized to elimination rate constant (AUC*beta) also showed a significant negative relationship with lymphocyte P-gp activity (p=0.03, r =  -0.64). Clearance and distribution volume apparent values estimates CL/[F*weight] and VD/[F*weight] showed a positive correlation with P-gp activity. Elimination rate constant did not correlate with P-gp activity. Although there is not enough evidence of a correlation between lymphocitary and intestinal function of P-gp, our results suggest a relationship between a P-gp phenotype marker, Rh123 efflux assay in lymphocytes, and indinavir bioavailability.