Céline Verstuyft

Assistance Publique – Hôpitaux de Paris, Lutetia Parisorum, Île-de-France, France

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Publications (85)412.28 Total impact

  • La Revue de Médecine Interne 12/2014; 35. · 1.32 Impact Factor
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    ABSTRACT: An association between serotonin 2A receptor (5-HT2AR), encoded by HTR2A gene, and major depressive disorder (MDD) has been suggested. Here, we combined preclinical and ecological clinical approaches to explore the impact of impaired 5-HT2AR-mediated transmission on MDD or anxio-depressive-like phenotype in mice. Htr2a knock-out mice (Htr2a-/- ) and wild-type mice were compared for the ability of chronic corticosterone to elicit some anxio-depressive-like phenotype in three behavioral paradigms (elevated plus maze, tail suspension test and splash test). Accordingly, two single nucleotide polymorphisms of the HTR2A gene (rs6314 ie His452Tyr and rs6313 ie 102C/T), which specific allelic variants may decrease 5-HT2AR-mediated transmission (as in Htr2a-/-mice), were studied in a sample of 485 Caucasian patients with MDD. In response to chronic corticosterone exposure, Htr2a-/- mice displayed more pronounced anxiodepressive-like phenotype than wild-type mice, as shown by a significant higher “emotionality score” (p < 0.01). In patients, the C allele of rs6313 was more frequent in depressed patients (p = 0.019) and was also associated with a more severe major depressive episode (p = 0.03). This translational and ecological study involving constitutive Htr2a-/- knock-out mice and related SNPs in depressed patients suggests that a lower neurotransmission at the 5-HT2AR may favor the susceptibility and severity of MDE. It also suggests that specific allelic variants of the rs6313 and rs6314 may reduce 5-HT2AR-mediated transmission.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 10/2014; 54:76–82. · 4.03 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the association between the functional polymorphic region of the serotonin transporter gene (5-HTTLPR) and antidepressant efficacy in menopausal and non-menopausal women. Since serotonergic system has been shown to be linked to estrogens, menopausal status of women may explain previous contradictory results on antidepressant efficacy in major depressive episode related to 5-HTTLPR in women. Seventy-four women (43 non-menopausal and 31 menopausal) and 29 men with a major depressive episode were genotyped for the 5-HTTLPR and assessed prospectively for antidepressant efficacy after 4 weeks of treatment. Non-menopausal women with at least one copy of the long allele had better antidepressant efficacy than those who were homozygous for the short allele, whereas no difference was found in menopausal women. Furthermore, antidepressant response was correlated with an interaction between the 5-HTTLPR polymorphism and age in women, but not in men. This finding suggested that the differences in antidepressant response were not linked to age but, rather, to menopausal status of women. Further research on a bigger sample is needed with steroids measurements to determine how menopausal status and 5-HTTLPR polymorphism influence antidepressant response.
    Archives of Women s Mental Health 09/2014; · 1.96 Impact Factor
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    ABSTRACT: Co-administration of methotrexate (MTX) and proton pump inhibitors (PPIs) can cause a pharmacokinetic interaction that result in delayed MTX elimination and a subsequent increase in MTX blood concentrations. Human organic anion transporters (OATs) are responsible for renal tubular secretion of MTX, and are thought to be involved in this drug interaction. The aim of this study was to evaluate the inhibitory potencies of PPIs on hOAT1 and hOAT3, the two isoforms of OATs predominantly expressed in kidney proximal tubules. Using stably transfected cell systems expressing the uptake transporters HEK-hOAT1 and HEK-hOAT3, we analyzed the inhibitory potencies of omeprazole, lansoprazole and pantoprazole, on OAT-mediated [(3)H]ES, [(3)H]PAH and [(3)H]MTX uptake in vitro. hOAT3 is a high affinity transporter for MTX (Km = 21.17 ± 5.65 μM). Omeprazole, lansoprazole and pantoprazole inhibited [(3)H]MTX uptake in HEK-hOAT3 cells with IC50 of 6.8 ± 1.16 μM, 1.14 ± 0.26 μM and 4.45 ± 1.62 μM respectively and [(3)H]ES uptake in HEK-hOAT3 cells with IC50 of 20.59 ± 4.07 μM, 3.96 ± 0.96 μM and 7.89 ± 2.31 μM respectively. Furthermore, omeprazole, lansoprazole and pantoprazole exhibited concentration-dependent inhibition of PAH uptake on hOAT1 (IC50 = 4.32 ± 1.26 μM, 7.58 ± 1.06 μM and 63.21 ± 4.74 μM respectively). These in vitro results suggest that inhibition of [(3)H]MTX transport by PPIs via hOAT3 inhibition, probably explains the drug-drug interactions between MTX and PPIs and should be considered for others OATs substrates.
    Drug metabolism and disposition: the biological fate of chemicals 09/2014; · 3.74 Impact Factor
  • American Journal of Psychiatry 08/2014; 171(8):890. · 13.56 Impact Factor
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    ABSTRACT: The cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of most antidepressants. Comedication with a potent CYP2D6 inhibitor can convert patients with extensive metabolizer (EM) or ultra-rapid metabolizer (UM) genotypes into poor metabolizer (PM) phenotypes. Since comedication is frequent in depressed patients treated with antidepressants, we investigated the effect of the CYP2D6 composite phenotype on antidepressant efficacy, taking into account both the CYP2D6 genotype and comedication with CYP2D6 inhibitors. 87 Caucasian in patients with a major depressive episode were prospectively treated with flexible doses of antidepressant monotherapy as well as comedications and genotyped for the major CYP2D6 alleles (CYP2D6*3 rs35742686, *4 rs3892097, *5 del, *6 rs5030655, and *2xN). They were classified for CYP2D6 composite phenotype and assessed for antidepressant response after 4 weeks. In terms of genotypes (g), 6 subjects were UMg, 6 PMg, and 75 EMg. Ten patients were coprescribed a CYP2D6 inhibitor, resulting in the following composite phenotypes (cp): 5 UMcp, 16 PMcp, and 66 EMcp. Whereas none of the CYP2D6 genotypes were significantly associated with antidepressant response, UMcp had a lower antidepressant response than PMcp or EMcp (respectively: 39.0 ± 17.9, 50.0 ± 26.0, and 61.6 ± 23.4, p = 0.02). Despite small sample size, this study suggests that a CYP2D6 composite phenotype, taking into account both genotype and comedications with CYP2D6 inhibitors, could predict CYP2D6 substrate antidepressants response. Thus, to optimize antidepressant response, CYP2D6 genotype could be performed and comedications with CYP2D6 inhibitors should be avoided, when prescribing CYP2D6 substrate antidepressants.
    Journal of Neural Transmission 07/2014; · 2.87 Impact Factor
  • European Neuropsychopharmacology 03/2014; 24:S59-S60. · 5.40 Impact Factor
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    ABSTRACT: Tacrolimus, an immunosuppressant drug, presents a narrow therapeutic window and a large pharmacokinetic variability with poor correlation between drug dosing regimen and blood concentration. The objective was to identify predictive factors influencing tacrolimus trough concentrations (C0) using a bottom-up approach. A physiologically based pharmacokinetic (PBPK) model of tacrolimus was proposed, taking into account the body weight, the proportion of fat (P fat), hematocrit, lipid fraction of organs, typical intrinsic clearance (CLityp), CYP3A5 genotype of liver donor, plasma unbound fraction of tacrolimus (fup), and concomitant drugs (CYP3A4 inhibitors). For the evaluation of the PBPK model, mean C0 and concentrations 2 h after oral dose of tacrolimus were compared with those from 66 liver transplant recipients included in a multicentric pharmacokinetic study and were found very close. Tacrolimus concentration profiles were simulated in a virtual population defined by a set of covariate values similar to those from the real population. The sensitivity of tacrolimus C0 with respect to each covariate has been tested to identify the most influential ones. With the range of covariate values tested, the impact of each covariate on tacrolimus C0 may be ranked as follows: fup, CLityp, bioavailability, body weight, hematocrit, CYP3A5 polymorphism, P fat, and CYP3A4 inhibitory drug-drug interactions. Values for initial dosing regimen of tacrolimus in order to reach a C0 of 10 ng/ml at day 5 (assuming a constant dosing schedule) as a function of CYP3A5 donor genotype and patient's hematocrit and body weight are proposed.
    The AAPS Journal 02/2014; · 3.91 Impact Factor
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    ABSTRACT: We investigated the population pharmacokinetics and pharmacogenetics of efavirenz in 307 patients coinfected with human immunodeficiency virus and tuberculosis and included in the Cambodian Early vs Late Initiation of Antiretrovirals trial (CAMELIA) in Cambodia. Efavirenz (600 mg/d) and stavudine plus lamivudine were ad-ministered in addition to standard antituberculosis treatment, including rifampicin and isoniazid. Blood samples were obtained a mean of 14 hours after efavirenz intake at weeks 2 and 6 after initiation of efavirenz and weeks 22 (efavirenz plus antituberculosis drugs) and 50 (efavirenz alone) after initiation of antituberculosis treatment. Ten patients participated in an extensive pharmacokinetic study after week 50. CYP2B6 G516T and C485-18T polymorphisms were the most significant covariates, with weight showing a significant minor effect. Change in efavirenz apparent clearance in patients taking both efavirenz and antituberculosis treatment was highly dependent on NAT2 polymorphism, as a possible surrogate of isoniazid exposure. Patients carrying the CYP2B6 516 TT genotype and slow-acetylation NAT2 phenotype had the lowest efavirenz apparent clearance. These data suggest that the inducing effect of rifampicin is counterbalanced by a concentration-dependant in-hibitory effect of isoniazid on efavirenz clearance. Efavirenz is a nonnucleoside reverse-transcriptase inhib-itor of human immunodeficiency virus (HIV) type 1 and one of the preferred components of the first-line an-tiretroviral treatment (ART) regimen of HIV infection worldwide. Current guidelines recommend efavirenz at a dosage of 600 mg/d combined with 2 nucleoside (or nucleotide) analogues as one of the preferred options for first-line therapy in developed as well as resource-limited countries [1]. Furthermore, it was demonstrated that efavirenz can be coadministered safely with stan-dard antituberculosis therapy that includes rifampicin, a potent drug enzyme inducer, and isoniazid for 6 months and ethambutol plus pyrazinamide for the first 2 months. Earlier studies recommended increasing the efavirenz dosage to 800 mg/d in patients receiving efa-virenz and rifampicin concomitantly [2, 3]. Later studies demonstrated the efficacy of efavirenz at a dosage of 600 mg/d along with antituberculosis drugs [4]; recently, it has been suggested that the efavirenz dosage be in-creased to 800 mg/d in patients weighing >50 kg [5]. Efavirenz is metabolized mainly through CYP2B6 [6], which has been demonstrated to be inducible
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    ABSTRACT: The SLCO1B1 c.521T>C polymorphism is associated with statin plasma levels and simvastatin-induced adverse drug reactions. We studied whether the c.521T>C polymorphism is associated with dose decreases or switches to other cholesterol-lowering drugs during simvastatin and atorvastatin therapy, because these events are indicators of adverse drug reactions. We identified 1939 incident simvastatin and atorvastatin users in the Rotterdam Study, a population-based cohort study. Associations were studied using Cox proportional hazards analysis. Meta-analysis was performed with data from the Utrecht Cardiovascular Pharmacogenetics study. Simvastatin users with the c.521 CC genotype had a significantly higher risk of a dose decrease or switch than users with the TT genotype [hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.05-2.88]. Female sex, age below 70 years, and low starting dose were risk factors. In atorvastatin users with starting dose of more than 20 mg, the risk of a dose decrease or switch was higher in users carrying a C allele than in users with the TT genotype (HR 3.26, 95% CI 1.47-7.25). In the meta-analysis the association in simvastatin users remained, with a significantly higher risk of a dose decrease or switch in simvastatin users with two minor alleles (HR 1.69, 95% CI 1.05-2.73). For atorvastatin users no significant association was found. In simvastatin users in the Rotterdam Study, we demonstrated an association between the c.521T>C polymorphism and dose decrease or switching, as indicators of adverse drug reactions, and provided risk factors for this association. For atorvastatin, an association was found in users with a starting dose of more than 20 mg.
    Pharmacogenetics and Genomics 11/2013; · 3.45 Impact Factor
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    ABSTRACT: SSRIs are commonly prescribed for the treatment of major depressive episodes (MDE). However, 50% of patients do not respond to these medications. Although evidence incriminates the overactivation of 5-HT1A autoreceptor in both (MDE) and poor antidepressant response, others serotonergic receptors could be recruited. This study first examined the effects of 5-HT2A receptor (5-HT2AR) inactivation on the electrophysiological activity of 5-HT neurons in mice. Second, it evaluated the impact of two putatively functional SNPs of the 5-HT2AR gene (T102C and His452Tyr) on the severity of depression in a sample of 485 Caucasians patients with MDE. Correlations between 5-HT1AR and 5-HT2AR activity was also investigated. In 5-HT1AR+/+ mice, acute administration of SSRIs decreased the firing rate of dorsal raphe (DR) 5-HT neurons, while 5-HT1AR antagonism reversed this effect. Remarkably, such an inhibitory response persisted in mice displaying a pharmacological or genetic inactivation of 5-HT1AR. These results along with the observation that 5-HT2AR antagonism also reversed escitalopram-induced decrease in DR 5-HT neuronal activity suggest that the simultaneous blockade of 5-HT1AR and 5-HT2AR is required to prevent the inhibitory effects of SSRIs. Interestingly, although long-term SSRIs treatment was associated with a recovery to normal of DR 5-HT activity, this response was blunted in 5-HT2AR-/- mice due to 5-HT1A autoreceptor hypersensitization. In patients, the C allele of T102C and the rare TT variant of His452Tyr were associated with a more severe depression. This study demonstrates a role of 5-HT2AR in chronic antidepressant drugs response that needs to be further investigated in patients with MDE.
    European Neuropsychopharmacology 10/2013; 23(Supplement 2):131S. · 5.40 Impact Factor
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    ABSTRACT: The association of non-functional variants in CETP with efficacy of statins has been subject of debate. We evaluated whether three functional CETP variants influence statin efficacy. The effect of CETP genotypes on achieved HDL-cholesterol (HDLc), LDL-cholesterol (LDLc) and total cholesterol levels during statin treatment was estimated by meta-analyzing linear regression outcomes of three studies (11,021 individuals). The effect of these SNPs on statin response in protecting against myocardial infarction (MI) was estimated by meta-analysis of statin*SNP interaction terms from logistic regression in five studies (16,570 individuals). The enhancer SNP rs3764261 significantly increased HDLc by 0.02 mmol/L per T allele (p=6E-05), and reduced protection against MI by statins (interaction-OR=1.19 per T allele; p=0.04). Focusing on functional CETP variants, we showed that in carriers of the rs3764261 T variant HDLc increased more during statin treatment, and protection against MI by statins appeared to be reduced, when compared to non-carriers.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 30 September 2013 doi:10.1038/clpt.2013.194.
    Clinical Pharmacology &#38 Therapeutics 09/2013; · 6.85 Impact Factor
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    ABSTRACT: Aim: Little information is available regarding the influence of CYP3A5 genetic polymorphisms on tacrolimus dose requirement in pediatric liver transplantation. Patients & methods: We performed a retrospective study among 179 pediatric liver recipients grafted between 2002 and 2009 in order to determine the influence of donor CYP3A5 genotype along with clinical variables on tacrolimus daily dose requirement during the first weeks following transplantation. Results: Mean stable tacrolimus daily dose requirement was higher among children who received a liver expressing CYP3A5 (carrying the CYPA3A5*1 allele) compared with those with a liver that did not express CYP3A5 (CYP3A5*3/*3 genotype): 0.29 ± 0.20 vs 0.18 ± 0.13 mg.kg(-1).d(-1), p = 0.005, respectively. A younger recipient age and fluconazole prescription were also significantly associated with tacrolimus daily dose requirement. Time to reach stable tacrolimus therapeutic trough concentrations was prolonged among patients with a CYP3A5-expressing graft (26 vs 21 days, p = 0.04). Conclusion: Donor CYP3A5 genotype partially explains tacrolimus dose requirement. Original submitted 30 January 2013; Revision submitted 2 May 2013.
    Pharmacogenomics 07/2013; 14(9):1017-25. · 3.43 Impact Factor
  • European Neuropsychopharmacology 03/2013; 23:S18–S19. · 5.40 Impact Factor
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    ABSTRACT: OBJECTIVE: In a previous analysis involving protocol ANRS 12154, interindividual variability in steady-state nevirapine clearance among HIV-infected Cambodians was partially explained by CYP2B6 516G→T (CYP2B6*6). Here, we examine whether additional genetic variants predict nevirapine clearance in this cohort. METHODS: Analyses included Phnom Penh ESTHER (Ensemble pour une Solidarité Thérapeutique Hospitalière en Réseau) cohort participants who had consented for genetic testing. All participants were receiving nevirapine plus two nucleoside analogs. The mean individual nevirapine clearance estimates were derived from a population model developed on nevirapine concentrations at 18 and 36 months of therapy. Polymorphisms were assayed in ABCB1, CYP2A6, CYP2B6, CYP2C19, CYP3A4, CYP3A5, and NR1I2. RESULTS: Of 198 assayed loci, 130 were polymorphic. Among 129 individuals with evaluable genetic data, nevirapine clearance ranged from 1.06 to 5.00 l/h in 128 individuals and was 7.81 l/h in one individual. In bivariate linear regression, CYP2B6 516G→T (CYP2B6*6) was associated with lower nevirapine clearances (P=3.5×10). In a multivariate linear regression model conditioned on CYP2B6 516G→T, independent associations were identified with CYP2B6 rs7251950, CYP2B6 rs2279343, and CYP3A4 rs2687116. The CYP3A4 association disappeared after censoring the outlier clearance value. A model that included CYP2B6 516G→T (P=1.0×10), rs7251950 (P=4.8×10), and rs2279343 (P=7.1×10) explained 11% of interindividual variability in nevirapine clearance. CONCLUSION: Among HIV-infected Cambodians, several CYP2B6 polymorphisms were associated independently with steady-state nevirapine clearance. The prediction of nevirapine clearance was improved by considering several polymorphisms in combination.
    Pharmacogenetics and Genomics 10/2012; · 3.45 Impact Factor
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    ABSTRACT: We investigated population pharmacokinetics and pharmacogenetics of ritonavir-boosted atazanavir (ATV), using drug intake times exactly recorded by the Medication Event Monitoring System. The ANRS 134-COPHAR 3 trial was conducted in 35 HIV-infected treatment-naive patients. ATV (300 mg), ritonavir (100 mg), and tenofovir (300 mg) + emtricitabine (200 mg), in bottles with MEMS caps, were taken once daily for 6 months. Six blood samples were collected at week 4 to measure drug concentrations, and trough levels were measured bimonthly. A model integrating ATV and ritonavir pharmacokinetics and pharmacogenetics used nonlinear mixed effects. Use of exact dosing data halved unexplained variability in ATV clearance. The ritonavir-ATV interaction model suggested that optimal boosting effect is achievable at lower ritonavir exposures. Patients with at least one copy of the CYP3A5*1 allele exhibited 28% higher oral clearance. We provide evidence that variability in ATV pharmacokinetics is defined by adherence, CYP3A5 genotype, and ritonavir exposure.
    Clinical Pharmacology &#38 Therapeutics 10/2012; 92(5):575-83. · 6.85 Impact Factor
  • L Encéphale 09/2012; 38(4):S4. · 0.60 Impact Factor
  • L Encéphale 09/2012; 38(4):S3–S4. · 0.60 Impact Factor
  • Journal of clinical psychopharmacology 06/2012; 32(3):429-31. · 5.09 Impact Factor
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    ABSTRACT: In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the responses to fluindione, an oral anticoagulant drug, in a general population of octogenarian inpatients.Measurements of fluindione concentrations and international normalized ratio (INR ) were obtained for 131 inpatients in whom fluindione treatment was initiated. Treatment was adjusted according to routine clinical practice. The data were analyzed using nonlinear mixed-effects modeling, and the parameters were estimated using MONOLI X 3.2. The pharmacokinetics (PK) of fluindione was monocompartmental, whereas the evolution of INR was modeled in accordance with a turnover model (inhibition of vitamin K recycling). Interindividual variability (II V) was very large. Clearance decreased with age and with prior administration of cordarone. Patients who had undergone surgery before the study had lower IC50 values, leading to an increased sensitivity to fluindione. Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione.
    Clinical Pharmacology &#38 Therapeutics 04/2012; 91(5):777-86. · 6.85 Impact Factor

Publication Stats

2k Citations
412.28 Total Impact Points

Institutions

  • 2003–2013
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Université de Bretagne Occidentale
      Brest, Brittany, France
  • 2007–2011
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
    • Centre Hospitalier Régional Universitaire de Lille
      Lille, Nord-Pas-de-Calais, France
    • Centre Hospitalier Universitaire de Brest
      Brest, Brittany, France
  • 2010
    • Al-Quds University
      • Department of Physiology and Pharmacology
      Abū Dīs, WE, Palestinian Territory
  • 2001–2010
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
  • 2009
    • The University of Western Ontario
      • Department of Medicine
      London, Ontario, Canada
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      Lutetia Parisorum, Île-de-France, France