title: Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIV-infected patients.
abstract: OBJECTIVE
  The protease inhibitor indinavir is characterized by an important interindividual pharmacokinetic variability, which results from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A and the multidrug efflux pump P-glycoprotein (P-gp), encoded by MDR1. Using a population pharmacokinetic approach, we investigated the effect of several MDR1 and CYP3A5 polymorphisms on the pharmacokinetic parameters of indinavir in HIV-infected patients.
  
  
  METHODS
  Twenty-eight patients receiving indinavir alone or together with ritonavir were included. Indinavir pharmacokinetics were studied over a 12 h interval. Genetic polymorphisms were assessed by real-time PCR assays and direct sequencing for MDR1 and by PCR-SSCP analysis for CYP3A5.
  
  
  RESULTS
  The pharmacokinetics of indinavir were best described by a one-compartment model with first-order absorption. In the final model, the MDR1 C3435T genotype and ritonavir were identified as statistically significant covariates (P </= 0.001) for the absorption rate constant (95% confidence interval on the difference between CC and CT genotype 0.37, 5.53) and for clearance (95% confidence interval on the difference 5.8, 26.2), respectively. Patients with the CYP3A5*3/*3 genotype receiving indinavir alone had a 31% decrease in the indinavir clearance rate compared with patients carrying the CYP3A5*1/*3 genotype.
  
  
  CONCLUSIONS
  The MDR1 C3435T genotype affects the absorption constant of indinavir suggesting that P-gp may be implicated in its pharmacokinetic variability. Through its inhibition of CYP3A and P-gp, ritonavir could attenuate the pharmacokinetic variability linked to genetic differences, reducing significantly the interindividual variability of indinavir. However, genotyping MDR1 and/or CYP3A5 to optimize protease inhibitor boosted regimens does not seem clinically relevant.
authors.affiliation: Fédération de Pharmacologie, AP-HM Hôpital La Timone, and Unité FRE-CNRS 2737, Faculté de Pharmacie, AP-HM Hôpital de la Conception, Marseille, France. caroline.solas@ap-hm.fr
authors.forename: Caroline
authors.initials: C
authors.lastname: Solas
authors.forename: Nicolas
authors.initials: N
authors.lastname: Simon
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Drogoul
authors.forename: Sylvie
authors.initials: S
authors.lastname: Quaranta
authors.forename: Véronique
authors.initials: V
authors.lastname: Frixon-Marin
authors.forename: Véronique
authors.initials: V
authors.lastname: Bourgarel-Rey
authors.forename: Corinne
authors.initials: C
authors.lastname: Brunet
authors.forename: Jean-Albert
authors.initials: JA
authors.lastname: Gastaut
authors.forename: Alain
authors.initials: A
authors.lastname: Durand
authors.forename: Bruno
authors.initials: B
authors.lastname: Lacarelle
authors.forename: Isabelle
authors.initials: I
authors.lastname: Poizot-Martin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D019469:Indinavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D019438:Ritonavir / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D019469:Indinavir; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D019438:Ritonavir