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

Indinavir, a HIV-1 protease inhibitor, showed 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 indinavir bioavailability. A liquid formulation of indinavir was developed from indinavir capsules in order to study indinavir pharmacokinetics in healthy volunteers. Compartmental and noncompartmental analysis of indinavir plasma concentrations showed high inter-individual variability in terms of area under the curve (AUC) and maximal plasma concentration (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). Apparent clearance (CL/[F × weight]) and volume of distribution (VD/[F × weight]) showed a positive correlation with P-gp activity. Conversely, 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.