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 (C(max)). A significant negative association between AUC normalized to body weight (AUC x 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 x beta) also showed a significant negative relationship with lymphocyte P-gp activity (p = 0.03, r = -0.64). Apparent clearance (CL/[F x weight]) and volume of distribution (VD/[F x 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.
Bramuglia
Guillermo F
GF
Cátedra de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 5to piso (C1113AAD), Buenos Aires, Argentina. gbram@ffyb.uba.ar
Cortada
Catalina M
CM
Curras
Verónica
V
Höcht
Christian
C
Buontempo
Fabián
F
Mato
Gabriel
G
Niselman
Viviana
V
Rubio
Modesto
M
Carballo
Marta
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood / Q000378:metabolism*; D000328:Adult; D001682:Biological Availability; D005260:Female; D006801:Humans; D019469:Indinavir / Q000097:blood / Q000493:pharmacokinetics*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019469:Indinavir