ArticleBritish journal of clinical pharmacology2007
Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIV-infected patients.
Article in British journal of clinical pharmacology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 38 citations in OpenAlex.
- Discordant associations between SLCO1B1 521T→C and plasma levels of ritonavir-boosted protease inhibitors in AIDS clinical trials group study A5146.Therapeutic drug monitoring · 2013Trial
- Population pharmacokinetic-pharmacogenetic study of nevirapine in HIV-infected Cambodian patients.Antimicrobial agents and chemotherapy · 2010Trial
- A marijuana-drug interaction primer: Precipitants, pharmacology, and pharmacokinetics.Pharmacology & therapeutics · 2019Review
- Pharmacogenetics of unboosted atazanavir in HIV-infected individuals in resource-limited settings: a sub-study of the AIDS Clinical Trials Group (ACTG) PEARLS study (NWCS 342).The Journal of antimicrobial chemotherapy · 2016Article
- Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature.Clinical pharmacokinetics · 2015Review
- Analysis of single-nucleotide polymorphisms (SNPs) in human CYP3A4 and CYP3A5 genes: potential implications for the metabolism of HIV drugs.BMC medical genetics · 2014Article
- CYP3A5, ABCB1, and SLCO1B1 polymorphisms and pharmacokinetics and virologic outcome of lopinavir/ritonavir in HIV-infected children.Therapeutic drug monitoring · 2011Article
- Atazanavir pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors.The Journal of antimicrobial chemotherapy · 2009Article
- The role of transporters in the pharmacokinetics of orally administered drugs.Pharmaceutical research · 2009Review
- Pharmacogenetics and population pharmacokinetics: impact of the design on three tests using the SAEM algorithm.Journal of pharmacokinetics and pharmacodynamics · 2009Article
- Role of placental ATP-binding cassette (ABC) transporters in antiretroviral therapy during pregnancy.Journal of pharmaceutical sciences · 2009Review
- Influence of pharmacogenetics on indinavir disposition and short-term response in HIV patients initiating HAART.European journal of clinical pharmacology · 2009Article
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsThe 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.
methodsTwenty-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.
resultsThe 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.
conclusionsThe 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.
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