ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir

Lubomirov, Rubin; Iulio, Julia di; Fayet, Aurélie; Colombo, Sara; Martínez, Raquel; Marzolini, Catia; Furrer, Hansjakob; Vernazza, Pietro; Calmy, Alexandra; Cavassini, Matthias; Ledergerber, Bruno; Rentsch, Katharina; Descombes, Patrick; Buclin, Thierry; Décosterd, Laurent A.; Csajka, Chantal; Telenti, Amalio

doi:10.1097/fpc.0b013e328336eee4

Cited by 106 publications

(106 citation statements)

References 54 publications

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“…Genotyping revealed polymorphisms for ABCC2 at the following sites: 1846AϾT(Y39F; rs927344), 21214GϾA(V417I; rs2273697), Ϫ24CϾT (rs717620), 36351TϾG(L849R; rs45494393), 53395TϾA(V1188E; rs17222723), 61606CϾT(I1324I; rs3740066), 64260GϾT(V1430V; rs1137968), 67932CϾT(H1496H; rs8187707), and 68693GϾA(C1515Y; rs8187710) in the promoter, coding and noncoding regions. Among these, two SNPs (i.e., Ϫ24CϾT and 68693GϾA) have been associated with decreased MRP2 activity, activity that was assessed indirectly (Wojnowski et al, 2005;Sookoian et al, 2009;Lubomirov et al, 2010;Franke et al, 2011). Here, we report the comparison of MRP2 expression in human livers harboring those SNPs reported to cause change in activity.…”

Section: Resultsmentioning

confidence: 99%

Interindividual Variability in Hepatic Expression of the Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2): Quantification by Liquid Chromatography/Tandem Mass Spectrometry

Deo¹,

Prasad²,

Balogh³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Multidrug-associated protein 2 (MRP2) is an efflux transporter that is expressed at the bile canalicular membrane. To allow in vitro to in vivo extrapolation of the contribution of MRP2 toward hepatic disposition of its substrates, data on the interindividual variability of hepatic MRP2 protein expression are required. Therefore, we quantified the expression of MRP2 in the University of Washington (UW) human liver bank (n ‫؍‬ 51) using a modified version of a previously validated liquid chromatography/ tandem mass spectrometry assay. An unlabeled (LTIIPQDPILFSGSLR) and stable isotope-labeled (LTIIPQDPILFSGSL[ Quality control samples created by spiking human serum albumin or pooled human liver (n ‫؍‬ 51) matrix with three different MRP2 synthetic peptide concentrations generated error and precision values of less than 15%. As determined by the surrogate peptide, the average MRP2 expression in the UW liver bank samples was 1.54 ؎ 0.64 fmol/g liver membrane protein and was found to be independent of age (7-63 years) or sex. A single nucleotide polymorphism in the promoter region (rs717620), previously thought to affect MRP2 expression, did not influence hepatic expression of MRP2. In contrast, the single nucleotide polymorphism 21214G>A (V417I; rs2273697) was associated with significantly higher hepatic MRP2 expression.

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Section: Resultsmentioning

confidence: 99%

Interindividual Variability in Hepatic Expression of the Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2): Quantification by Liquid Chromatography/Tandem Mass Spectrometry

Deo¹,

Prasad²,

Balogh³

et al. 2012

Drug Metab Dispos

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“…20 Furthermore, it has been shown that the single nucleotide polymorphism 521T>C in SLCO1B1 is associated with significantly increased plasma concentrations of lopinavir. 20,21 In contrast, a recent publication showed that the hepatic uptake of nelfinavir, lopinavir and ritonavir is primarily mediated by passive diffusion in sandwichcultured human hepatocytes. 22 Additionally, they suggested an unidentified sinusoidal uptake transporter for amprenavir.…”

Section: Introductionmentioning

confidence: 94%

Clearance Prediction of HIV Protease Inhibitors in Man: Role of Hepatic Uptake

Bruyn

Stieger

Augustijns

et al. 2016

Journal of Pharmaceutical Sciences

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The aim of this work was to explore the contribution of the organic anion transporting polypeptide-1B (OATP1B) drug transporters in the hepatic clearance (Cl) of all marketed HIV protease inhibitors (PI) in humans. HIV PI uptake rates in OATP1B1/1B3-transfected Chinese hamster ovary cells were converted to uptake Cl values in human hepatocytes via a relative activity factor, which was determined by comparing uptake of known substrates between OATP1B1/3-transfected cells and human hepatocytes. Metabolic Cl values were determined in human liver microsomes. In vivo hepatic Cl values were calculated either by combining drug uptake and metabolism or based on one of these individual Cl processes and compared with published in vivo hepatic Cl values. Excellent in vitro-in vivo correlation (R(2) = 0.85) was observed when only uptake Cl values were used, but not when only metabolic Cl was used (R(2) = 0.40). The correlation did not improve when both processes were taken into account (R(2) = 0.85). PBPK models confirmed the remarkable sensitivity of predicted exposure to hepatic drug uptake, indicating a key role for OATP1B1/3 in hepatic disposition of several HIV PI in man. This may contribute to the interindividual variability in systemic and hepatic exposure to these drugs in the clinic.

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“…3642 customized SNPs covering pharmacokinetic genes were added in the Cardiometabochip (Lubomirov, Csajka, & Telenti, 2007;Lubomirov et al, 2010), among which 8 SNPs from the CYP2A6 gene (rs5031016, rs8192730, rs1809810, rs1801272, rs28399453, rs28399454, rs28399433, rs2892625). Four SNPs were excluded from analysis due to a very low minor allele frequencies (MAF<0.005) as reported in European population (rs5031016, rs8192730, rs1809810, rs28399454) (Flicek et al, 2014).…”

Section: Genotypingmentioning

confidence: 99%

Association of nicotine metabolism and sex with relapse following varenicline and nicotine replacement therapy.

Glatard¹,

Dobrinas²,

Gholam‐Rezaee³

et al. 2017

Experimental and Clinical Psychopharmacology

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Nicotine is metabolized into cotinine and then into trans-3'-hydroxycotinine, mainly by cytochrome P450 2A6. Recent studies reported better effectiveness of varenicline in women and in nicotine normal metabolizers phenotypically determined by nicotine-metabolite ratio. Our objective was to study the influence of nicotine-metabolite ratio, CYP2A6 genotype and sex on the response to nicotine replacement therapy and varenicline. Data were extracted from a longitudinal study which included smokers participating in a smoking cessation program. Response to treatment was defined by the absence of relapse when a set threshold of reduction in cigarettes per day relative to the week before the study was no more reached. The analysis considered total and partial reduction defined by a diminution of 100% and of 90% in cigarettes per day, respectively. The hazard ratio of relapsing was estimated in multivariate Cox regression models including the sex and the nicotine metabolism determined by the phenotype or by CYP2A6 genotyping (rs1801272 and rs28399433). In the normal metabolizers determined by phenotyping and in women, the hazard ratio for relapsing was significantly Public Significance StatementsThis study confirms that varenicline has better effectiveness than nicotine replacement therapy in nicotine normal metabolizers determined by the nicotine-metabolite ratio, and in women. The nicotine normal metabolizers determined by CYP2A6 rs1801272 genotyping also have greater response to varenicline than to nicotine replacement therapy. The choice of the smoking cessation pharmacological treatment should take into account nicotine metabolism and sex to obtain better abstinence rate in smokers.

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ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir

Abstract: The two-stage strategy successfully identified genetic variants affecting LPV/r pharmacokinetics. Such a general approach of ADME pharmacogenetics should be generalized to other drugs.

Cited by 106 publications

References 54 publications

Interindividual Variability in Hepatic Expression of the Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2): Quantification by Liquid Chromatography/Tandem Mass Spectrometry

Interindividual Variability in Hepatic Expression of the Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2): Quantification by Liquid Chromatography/Tandem Mass Spectrometry

Clearance Prediction of HIV Protease Inhibitors in Man: Role of Hepatic Uptake

Association of nicotine metabolism and sex with relapse following varenicline and nicotine replacement therapy.

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