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

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Abstract

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.

Section snippets

INTRODUCTION

The small intestine represents the principal site of absorption for any ingested compound, whether dietary, therapeutic, or toxic. Oral administration is the most popular route for drug administration since dosing is convenient and noninvasive and most drugs are well absorbed by the gastrointestinal tract. As well as degrading and absorbing nutrients and solutes from the intestinal lumen, intestinal enterocytes form a selective barrier to drugs and xenobiotics. This barrier function largely

Sample Collection

Eleven healthy volunteers, enrolled previously in a collaborative P-gp activity clinical study that consented to participate in the pharmacokinetic assay were included. The study was approved by the Faculty of Pharmacy and Biochemistry, University of Buenos Aires Ethics Committee. For the pharmacokinetic study a liquid formulation of IDV was developed from IDV capsules containing 400 mg of IDV. The powder was dissolved in distillated water (final concentration 20 mg/mL) at 40°C. The solution was

RESULTS

Demographic data of the volunteers included in the study are shown in Table 1. Age ranged from 24 to 58 years. Inter-individual coefficient of variation of body weight was 16%. The volunteers did not show any hepatic or renal disfunction previously or at the moment of the study. P-gp activity of the volunteers is shown in Table 2. The intra-day coefficient of variation of the efflux assay was 12.7%.

The temporal course of IDV plasma levels after the administration of the oral solution are shown

DISCUSSION

The results of the pharmacokinetics analysis of IDV in the volunteers were in agreement with previously reported population data. Mean CL/F and V/F estimated were similar than those reported by Di Cenzo et al.26 using a two compartment open model and first-order absorption (median clearance: 98.4 L/h; median volume of distribution: 103.4 L). In spite of the variability observed in the estimates of CL/F or V/F, our estimates fell within the wide range of values found in previous studies.27,28

Acknowledgements

This study was supported by Agencia Nacional de Promoción Científica y Tecnológica (PICT 05-12097), and Universidad de Buenos Aires (UBACYT, Urgencia Social, B707), Argentina.

REFERENCES (43)

  • V.D. Makhey et al.

    Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells

    Pharm Res

    (1998)
  • C. Cordon-Cardo et al.

    Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissue

    J Histochem Cytochem

    (1990)
  • F. Thiebaut et al.

    Immunohistochemical localization in normal tissue of different epitopes in the multidrug transport protein p170: Evidence for localization in brain capillaries and crossreactivity of one antibody with muscle protein

    J Histochem Cytochem

    (1989)
  • M.F. Herbert

    Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery

    Adv Drug Deliv Rev

    (1997)
  • K. Arimori et al.

    Drug exsorption from blood into the gastrointestinal tract

    Pharm Res

    (1998)
  • K.S. Lown et al.

    Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine

    Clin Pharmacol Ther

    (1997)
  • L.M.S. Chana et al.

    The ABCs of drug transport in intestine and liver: Efflux proteins limiting drug absorption and bioavailability

    Eur J Pharm Sci

    (2004)
  • J.H. Hochman et al.

    Influence of P-glycoprotein on the transport and metabolismof indinavir in Caco-2 cells expressing cytochrome P-450 3 A4

    J Pharmacol Exp Ther

    (2000)
  • C.B. Washington et al.

    The disposition of saquinavir in normal and p-glycoprotein deficient mice, rats, and in cultured cells

    Drug Metab Dispos

    (2000)
  • R.B. Kim et al.

    The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors

    J Clin Invest

    (1998)
  • J. Van Asperen et al.

    The role of mdr1a P-glycoprotein in the biliary and intestinal secretion of doxorubicin and vinblastine in mice

    Drug Metab Dispos

    (2000)

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