| 1. |
- Carlsson, Björn, et al.
(författare)
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Enantioselective Analysis of Citalopram and Metabolites in Adolescents
- 2001
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Ingår i: Therapeutic drug monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356. ; 23, s. 658-
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Tidskriftsartikel (refereegranskat)abstract
- Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent despite its increasing use in these age groups. The aim of this study was to investigate a group of adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites desmethylcitalopram and didesmethylcitalopram. Moreover, the authors studied the genotypes for the polymorphic cytochrome P450 enzymes CYP2D6 and CYP2C19 in relation to the different enantiomers. The S/R ratios of citalopram and desmethylcitalopram found in this study of 19 adolescents were similar to studies involving older patients. The concentrations of the R-(-)- and S-(+)-enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies, the R-(-)-enantiomer (distomer) being the major enantiomer. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the CYP2C19 enzyme.
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| 2. |
- Chang, Ming, et al.
(författare)
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CYP2C19*17 affects R-warfarin plasma clearance and warfarin INR/dose ratio in patients on stable warfarin maintenance therapy
- 2015
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 71:4, s. 433-439
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to assess the influence of CYP2C19*17 on R-warfarin clearance as well as the effect of CYP2C19, CYP2C8, CYP2C9, and VKORC1 polymorphisms together with non-genetic factors on warfarin international normalized ratio (INR)/daily dose. One hundred fifty Caucasian Italian outpatients with data on steady-state plasma concentrations of S- and R-warfarin were genotyped for CYP2C19 (*2, *3, *4, *17), CYP2C9 (*2, *3), CYP2C8*3, and VKORC1*2. The statistical analysis was performed on the effect of genotypes/haplotypes, age, sex, and body weight on the clearance of warfarin enantiomers and dose-normalized INR. R-warfarin clearance was 32 % higher in carriers of CYP2C19*17 than in carriers of CYP2C19*2 (mean 2.5 mL/min, 95 % confidence interval (CI) 2.3-2.8 vs. 1.9 mL/min, 95 % CI 1.7-2.2; P (post hoc) = 0.01). Patients with CYP2C19*1/*1 genotype had an intermediate clearance (mean 2.1 mL/min, 95 % CI 1.8-2.4). The genotypes of VKORC1, CYP2C9, and CYP2C19, together with non-genetic factors (age, sex, and body weight) explained 52 % of the variability in warfarin INR/daily dose, of which CYP2C19 genotypes accounted for 7 %. This is the first study to include the gain-of-function CYP2C19*17 allele when assessing the impact of CYP2C19 polymorphisms on the clearance of warfarin enantiomers. CYP2C19 genotypes influenced the clearance of R-warfarin and contributed significantly to the variability in INR/daily dose, indirectly indicating a clinical relevance of R-warfarin.
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| 3. |
- Dahl, Marja-Liisa, et al.
(författare)
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Cytochromes P450
- 2006
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Ingår i: Psychopharmacogenetics. - : M Springer science + Businesss Media Inc.
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Bokkapitel (refereegranskat)
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| 4. |
- De Fazio, Salvatore, et al.
(författare)
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Role of CYP3AS in abnormal clearance of methadone
- 2008
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Ingår i: The Annals of Pharmacotherapy. - 1060-0280 .- 1542-6270. ; 42:6, s. 893-897
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To report a case of unusually low concentrations of methadone in a polydrug abuser during maintenance treatment with methadone. CASE SUMMARY: A 25-year-old man (weight 55 kg, height 165 cm) with a 12-year history of polydrug abuse was admitted to an opiates withdrawal methadone program. At the time of our observation, he was using both cannabinoids and heroin; no other medical conditions were discovered. Within the opiates withdrawal methadone program, under medical supervision, the patient started methadone therapy (20 mg/day). Two weeks later, an Abuscreen assay for methadone screening in the urine was negative and, to prevent the development of withdrawal symptoms, the dose of methadone was increased to 60 mg/day. One day later, the patient was asked to collect another urine sample in the presence of a nurse. The Abuscreen for methadone in urine remained negative. Evaluation of urinary samples collected over 24 hours documented low concentrations of methadone and high levels of 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (the primary metabolite of methadone). Evaluation for the presence of the most common polymorphisms in the cytochrome P450 and P-glycoprotein genes showed that the patient was heterozygous for the CYP3A5*1 allele and for 2 single nucleotide polymorphisms in the P-glyooprotein gene (1236C/T and 3435C/T). DISCUSSION: In this patient, poor methadone adherence was ruled out because of the presence of physicians and nurses during both methadone maintenance treatment and Abuscreen screening. Moreover, because the patient reported only heroin and cannabis at the time of evaluation, drug interactions were ruled out as possible causes for the rapid clearance of methadone. CONCLUSIONS: In this case, CYP3A5 polymorphism may have played a role in the rapid methadone metabolism.
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| 5. |
- De Luca, C., et al.
(författare)
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Idiopathic environmental intolerances (IEI) : from molecular epidemiology to molecular medicine
- 2010
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Ingår i: Indian Journal of Experimental Biology. - 0019-5189. ; 48:7, s. 625-635
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Forskningsöversikt (refereegranskat)abstract
- Inherited or acquired impairment of xenobiotics metabolism is a postulated mechanism underlying environment-associated pathologies such as multiple chemical sensitivity, fibromyalgia, chronic fatigue syndrome, dental amalgam disease, and others, also collectively named idiopathic environmental intolerances (IEI). In view of the poor current knowledge of their etiology and pathogenesis, and the absence of recognised genetic and metabolic markers of the diseases. They are often considered "medically unexplained syndromes",. These disabling conditions share the features of polysymptomatic multi-organ syndromes, considered by part of the medical community to be aberrant responses triggered by exposure to low-dose organic and inorganic chemicals and metals, in concentrations far below average reference levels admitted for environmental toxicants. A genetic predisposition to altered biotransformation of environmental chemicals, drugs, and metals, and of endogenous low-molecular weight metabolites, caused by polymorphisms of genes coding for xenobiotic metabolizing enzymes, their receptors and transcription factors appears to be involved in the susceptibility to these environment-associated pathologies, along with epigenetic factors. Free radical/antioxidant homeostasis may also be heavily implicated, indirectly by affecting the regulation of xenobiotic metabolizing enzymes, and directly by causing increased levels of oxidative products, implicated in the chronic damage of cells and tissues, which is in part correlated with clinical symptoms. More systematic studies of molecular epidemiology, toxico- and pharmaco-genomics, elucidating the mechanisms of regulation, expression, induction, and activity of antioxidant/detoxifying enzymes, and the possible role of inflammatory mediators, promise a better understanding of this pathologically increased sensitivity to low-level chemical stimuli, and a solid basis for effective individualized antioxidant- and/or chelator-based treatments.
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| 6. |
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| 7. |
- Gokalp, Osman, et al.
(författare)
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Mild hypoglycaemic attacks induced by sulphonylureas related to CYP2C9, CYP2C19 and CYP2C8 polymorphisms in routine clinical setting
- 2011
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 67:12, s. 1223-1229
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate the impact of polymorphisms in the cytochrome P450 (CYP) 2C9, 2C19 and 2C8 genes on the risk of mild hypoglycaemic attacks in patients treated with sulphonylureas. One hundred and eight type 2 diabetic patients (50 men, 58 women), treated with oral antidiabetics, including at least one from the sulphonylurea group (glimepiride n = 50, gliclazide n = 46, or glipizide n = 12) for 3 months or longer, were included in the study. Symptoms of hypoglycaemia (sweating, tremor, anxiety and palpitations) during a 3 month period were recorded and confirmed by home glucose measurements. Gender, age, body mass index, creatinine clearance, HbA1c, oral antidiabetic dose and concomitant medication were assessed together with functional CYP2C9, CYP2C19 and CYP2C8 polymorphisms, analysed by real-time PCR methods. Fifteen patients (eight men, seven women) reported hypoglycaemia symptoms which were validated by their home glucose measurements (< 70 mg/dl). Heterozygosity and homozygosity for CYP2C9 variant alleles (*2 or *3) tended to be more frequent among patients who reported hypoglycaemic attacks (60 and 7%) than those who did not (39 and 3%). Similarly, the CYP2C8*1/*3 genotype tended to be more frequent in patients with (47%) than without (27%) hypoglycaemia, while no such trend was observed for CYP2C19 variants. However, only in the gliclazide group a significant association between CYP2C9 genotype and hypoglycaemic attacks was observed (P = 0.035). None of the other covariates showed any significant association with the risk of hypoglycaemic attacks. CYP2C9 polymorphisms leading to decreased enzyme activity show a modest impact on the risk of mild hypoglycaemia attacks during oral antidiabetic treatment, with a significant association in patients treated with gliclazide.
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| 8. |
- Gunes, Arzu, et al.
(författare)
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ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety
- 2008
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 30:5, s. 628-633
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Tidskriftsartikel (refereegranskat)abstract
- Risperidone is metabolized to its active metabolite, 9-hydroxy risperidone, mainly by the cytochrome P450 enzymes CYP2D6 and 3A4. Its antipsychotic effect is assumed to be related to the active moiety, that is, the sum of risperidone and 9-hydroxyrisperidone. Both risperidone and 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp), a transport protein involved in drug absorption, distribution, and elimination. The aim of the present study was to evaluate the influence of polymorphisrns in genes encoding CYP3A5 and P-gp (ABCB1) on the steady-state plasma levels of risperidone, 9-hydroxyrisperidone, and the active moiety, taking CYP2D6 genotype status into account. Forty-six white patients with schizophrenia treated with risperidone (1-10 mg/d) in monotherapy for 4-6 weeks were genotyped, and their plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. Dose-corrected plasma concentrations (C/D) of risperidone, 9-hydroxyrisperidone, and active moiety showed up to 68-, 9-, and 10-fold interindividual variation, respectively. Six patients carried 1 CYP3A5*1 allele and therefore were likely to express the CYP3A5 enzyme. The CYP3A5 genotype did not influence risperidone, 9-hydroxyrisperidone, or active moiety C/Ds. The CYP2D6 genotype in these 46 patients was again associated with risperidone C/D (P = 0.001) but not with 9-hydroxyrisperidone C/D or active moiety C/D, as previously shown by our group in 37 of these patients. Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower C/Ds of 9-hydroxyrisperidone (P = 0.026) and active moiety (P = 0.028) than patients carrying other ABCB1 genotypes. In conclusion, our results confirmed the significant effect of CYP2D6 genotype oil the steady-state plasma levels of risperidone and showed that ABCB1 polymorphisins have a moderate effect oil those of 9-hydroxyrisperidone and the active moiety.
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| 9. |
- Gunes, Arzu, et al.
(författare)
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Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine and clozapine
- 2009
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Ingår i: Journal of Clinical Psychopharmacology. - 0271-0749 .- 1533-712X. ; 29:1, s. 65-68
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Tidskriftsartikel (refereegranskat)abstract
- Serotonin 2C and 2A receptor (5-HT2C and 5-HT2A) antagonisms are hypothesized to play a role in the metabolic adverse effects induced by olanzapine and clozapine. Associations between polymorphisms in 5-HT2C and 5-HT2A receptor coding genes, HTR2C and HTR2A, with antipsychotic-induced weight gain have been reported. The impact of HTR2C and HTR2A polymorphisms on body mass index (BMI), glucose-insulin homeostasis, and blood lipid levels was evaluated in 46 patients with schizophrenia or schizoaffective disorder and treated with olanzapine (n = 28) or clozapine (n = 18) for at least 6 months. Olanzapine-treated patients with HTR2C haplotype C (-759C, -697C, and 23Ser) had higher BMI (P = 0.029) and C peptide levels (P = 0.029) compared with patients with haplotype B (-759T, -697C, and 23Cys). The frequency of patients homozygous for the HTR2C haplotype A (-759C, -697G, and 23Cys) was significantly higher among clozapine-treated patients with obesity (BMI >/= 30 kg/m) compared with nonobese patients (P = 0.015; odds ratio, 28; 95% confidence interval, 2-380). Patients carrying the HTR2A haplotype 2 (-1438A, 102T, and 452His) had significantly higher C peptide levels compared with haplotype 3 (-1438A, 102T, and 452Tyr) carriers in the olanzapine group (P = 0.034) and in the overall study population (P = 0.019). None of the haplotypes were associated with serum levels of insulin, triglycerides, and cholesterol or with homeostasis model assessment index for insulin resistance. In conclusion, both HTR2C and HTR2A gene polymorphisms seem to be associated with the occurrence of metabolic abnormalities in patients treated with olanzapine or clozapine.
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| 10. |
- Gunes, Arzu, et al.
(författare)
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Further evidence for association between 5-HT2C receptor gene polymorphisms and extrapyramidal side effects in male schizophrenic patients
- 2008
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 64:5, s. 477-482
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Antipsychotic-induced extrapyramidal side effects (EPS) are still a major problem in the treatment of schizophrenia. Serotonin 2C receptors (5-HT(2C)) have regulatory effects on dopaminergic pathways in brain regions involved with EPS. Polymorphisms in the 5-HT(2C) gene (HTR2C) have been suggested to be associated with the risk of developing EPS. OBJECTIVE: Our purpose was to evaluate the impact of polymorphisms in the HTR2C gene on the occurrence of EPS in male schizophrenic patients. METHODS: Ninety-nine male Caucasian chronic schizophrenic patients on long-term treatment with classical antipsychotics were genotyped for the -997 G/A, -759 C/T, -697 G/C and Cys23Ser polymorphisms of HTR2C. EPS (dystonia, parkinsonism, tardive dyskinesia) were assessed by the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale. Fifty-one patients had current or previous history of EPS, whereas 48 patients had no symptoms or history of EPS. To rule out a possible association between HTR2C polymorphisms and schizophrenia, 112 healthy male volunteers were also genotyped. RESULTS: Allele frequencies of -997A, -759T and -697C did not differ between the groups, whereas patients with EPS had a significantly (p = 0.025) higher frequency of the 23Ser allele (0.29) than did patients without EPS (0.15) or healthy volunteers (0.13). A similar trend was observed for a haplotype including the -997G, -759C, -697C and 23Ser alleles (p = 0.04). CONCLUSIONS: Results confirm previously reported associations between the HTR2C 23Ser allele and EPS occurrence and suggest the novel finding of an HTR2C haplotype association with EPS in male chronic schizophrenic patients.
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