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AIMS: The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real-world population. METHODS: Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N-desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype-predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration-to-dose (CD) ratio and metabolite-to-parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal-Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. RESULTS: A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P < .001), 28% in CYP2C19 IMs (P < .001) and 31% in CYP2C19 PMs (P = .04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. CONCLUSIONS: CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone.
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PURPOSE: Lamotrigine was previously reported to reduce serum concentration of quetiapine. The aim of this study was to investigate whether lamotrigine dose or quetiapine formulation was of importance for the drug interaction. METHODS: Patients combining lamotrigine with quetiapine (cases) were included retrospectively from a routine therapeutic drug monitoring (TDM) service, as were a control group of patients using quetiapine without any interacting drugs. The case and control groups were divided into groups using immediate release (IR) and extended release (XR) quetiapine. The case group was further split into high-dose (> 200 mg/day) and low-dose (≤ 200 mg/day) lamotrigine users. Quetiapine concentration-to-dose (C/D) ratio and metabolite-to-parent ratio (MPR) were compared between the control group and dose-separated case groups using ANOVA test and t-tests. RESULTS: In total, 406 patients were included. The mean C/D ratio of IR quetiapine was 46% lower in the high-dose lamotrigine group compared with the control group (P < 0.001), while no interaction effect was present in the low dose lamotrigine group (P = 0.7). Regardless of lamotrigine dose, there was no difference in quetiapine C/D ratio for patients using the XR formulation (P = 0.4). The quetiapine MPR was unaffected regardless of formulation and lamotrigine dose (P ≥ 0.06). CONCLUSION: The effect of lamotrigine in reducing quetiapine concentration is only significant for patients using quetiapine IR tablets who are treated with lamotrigine doses > 200 mg/day. Because of high variability in the interaction effect, TDM of quetiapine should be recommended during co-prescription of high-dose lamotrigine.
Assuntos
Antipsicóticos , Preparações de Ação Retardada , Relação Dose-Resposta a Droga , Interações Medicamentosas , Lamotrigina , Fumarato de Quetiapina , Comprimidos , Humanos , Lamotrigina/farmacocinética , Lamotrigina/administração & dosagem , Lamotrigina/sangue , Lamotrigina/uso terapêutico , Fumarato de Quetiapina/farmacocinética , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/sangue , Masculino , Feminino , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Antipsicóticos/sangue , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Monitoramento de Medicamentos/métodos , Triazinas/farmacocinética , Triazinas/sangue , Triazinas/administração & dosagem , IdosoRESUMO
BACKGROUND: Paroxetine is a selective serotonin reuptake inhibitor metabolized by cytochrome P450 (CYP)2D6. Only small-scale studies have reported the impact of CYP2D6 genotype on paroxetine exposure, and international guidelines differ in their recommendations on whether paroxetine should be administered according to CYP2D6 genotype. To clarify this issue, the aim of the present study was to investigate the impact of CYP2D6 genotype on paroxetine serum concentration in a large population of patients after adjusting for CYP2C19 genotype, age, and sex. METHODS: Patients from a therapeutic drug monitoring database with records on their paroxetine serum concentrations and CYP2D6 and CYP2C19 genotyping between 2010 and 2021 were included in the study. The impact of CYP2D6 and CYP2C19 genotypes, age, and sex on the paroxetine concentration-to-dose (C/D) ratio was investigated by multiple linear regression analysis. Patients treated with relevant CYP inhibitors or inducers were excluded. RESULTS: In total, 304 patients were included in the study: 17 CYP2D6 poor metabolizers (PMs), 114 intermediate metabolizers (IMs), 168 extensive metabolizers (EMs), and 5 ultrarapid metabolizers. Multiple linear regression analysis showed that CYP2D6 IMs and PMs had 2.2-fold and 3.8-fold higher paroxetine C/D-ratios than extensive metabolizers, respectively ( P < 0.001). Patients who were CYP2C19 IMs (n = 70) or PMs (n = 13) had 1.6-fold higher paroxetine C/D ratio than extensive metabolizers ( P = 0.04). An age ≥65 years was associated with a 2.9-fold increased C/D ratio ( P < 0.001), whereas sex was not significantly associated with paroxetine exposure. CONCLUSIONS: The present study showed that CYP2D6 genotype is of significant importance for paroxetine dose adjustments. For CYP2D6 PMs, 25% of the regular paroxetine starting dose may be sufficient, whereas CYP2D6 IMs could receive 50% of the regular dosage. This well-powered study shows that the guidelines should consider the importance of CYP2D6 genotype for personalized dosing of paroxetine.
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Citocromo P-450 CYP2D6 , Paroxetina , Humanos , Idoso , Paroxetina/uso terapêutico , Paroxetina/farmacologia , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2C19/genética , Genótipo , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are used by over 180,000 people in Norway. The enzymes CYP2D6 and CYP2C19 are key in the metabolism of SSRI antidepressants. The serotonin transporter coded by SLC6A4 may be significant for the efficacy of the drugs. MATERIAL AND METHOD: All patients who had undergone genotyping for CYP2D6, CYP2C19 and SLC6A4 at the Centre for Psychopharmacology in 2020 were included, irrespective of indication. For those patients where data were available, CYP2C19 genotype was linked to serum concentration measurement of escitalopram, which is the most commonly used SSRI drug. RESULTS: Out of 3,492 patients, 432 (12.4 %) had a combination of genotypes of CYP2D6, CYP2C19 and SLC6A4 considered to lead to the most favourable metabolism and efficacy of SSRI antidepressants. The dose requirement in patients with poor CYP2C19 metabolism was more than halved to achieve the same concentration of escitalopram compared to patients with normal metabolism. INTERPRETATION: Our findings demonstrate the low prevalence of the most favourable genotype combination for response to SSRIs. Genotype combinations probably contribute to the wide variation between individuals in the efficacy of these drugs and the fact that treatment does not produce the desired outcome in many patients.
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Antidepressivos , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Escitalopram , Inibidores Seletivos de Recaptação de Serotonina , Proteínas da Membrana Plasmática de Transporte de Serotonina , Antidepressivos/sangue , Antidepressivos/uso terapêutico , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Escitalopram/sangue , Escitalopram/uso terapêutico , Genótipo , Humanos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores Seletivos de Recaptação de Serotonina/sangue , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
PURPOSE: The aim of this study was to investigate the potential dose-dependent CYP2D6 inhibition by bupropion (BUP) in patients with depression. METHODS: Patients combining BUP with venlafaxine were included from a therapeutic drug monitoring (TDM) database at the Diakonhjemmet Hospital (Oslo, Norway). The O/N-desmethylvenlafaxine metabolic ratio measured in TDM samples was used as a biomarker for CYP2D6 phenotype and was compared between patients treated with BUP 150 mg/d and 300 mg/d or greater. In addition, reference groups of venlafaxine-treated patients genotyped as CYP2D6 poor metabolizers (PMs, no CYP2D6 activity) and normal metabolizers (NMs, fully functional CYP2D6 activity) were included. FINDINGS: A total of 221 patients were included in the study. The median O/N-desmethylvenlafaxine metabolic ratio was significantly higher in patients treated with BUP 150 mg/d (n = 59) versus 300 mg/d or greater (n = 34, 1.77 vs 0.96, P < 0.001). In CYP2D6 NMs (n = 62) and PMs (n = 66), the median metabolic ratios were 40.55 and 0.48, respectively. For patients treated with BUP 150 mg/d, 11 (19%) of the 59 patients were phenoconverted to PMs, whereas this was the case for 17 (50%) of the 34 patients treated with BUP 300 mg/d or greater. CONCLUSIONS: Bupropion exhibits a clear dose-dependent CYP2D6 inhibitory effect during treatment of patients with depression. This finding is of clinical relevance when adjusting dosing of CYP2D6 substrates during comedication with BUP. Half of the patients treated with high-dose BUP are converted to CYP2D6 PM phenotype. Because of the variability in CYP2D6 inhibition, TDM of CYP2D6 substrates should be considered to provide individualized dose adjustments during comedication with BUP.
Assuntos
Antidepressivos de Segunda Geração/administração & dosagem , Bupropiona/administração & dosagem , Inibidores do Citocromo P-450 CYP2D6/administração & dosagem , Depressão/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antidepressivos de Segunda Geração/farmacologia , Bupropiona/farmacologia , Citocromo P-450 CYP2D6/efeitos dos fármacos , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Succinato de Desvenlafaxina/farmacocinética , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Cloridrato de Venlafaxina/administração & dosagem , Adulto JovemRESUMO
PURPOSE: Paliperidone palmitate is an antipsychotic medication available as long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age and gender on paliperidone exposure after administration of LAI formulations. METHODS: Data on serum concentrations of paliperidone from patients using LAI during were included retrospectively from a therapeutic drug monitoring (TDM) service. Information about dose was obtained from the requisition forms. As a measure of exposure, daily dose-adjusted serum concentration (C/D ratio) was used. Based on initial analysis of C/D ratios versus age, a breaking point close to 50 years was observed, thus deciding the grouping of patients as older (≥50 years) or younger (15-49 years). Linear mixed model analyses, allowing multiple measurements per patients, were used. RESULTS: In total, 1223 patients were included, whereof 1158 patients used paliperidone LAI in once-monthly intervals. In these patients (27.9% older), older patients had significantly higher paliperidone C/D ratio than younger patients (+20%, p<0.001). Compared to males, females had higher C/D ratio (+14%; p<0.001). Subsequently, older female users of once-monthly LAI intervals had 41% higher paliperidone C/D ratios compared to younger males (15.0 vs. 21.2 nM/mg; p<0.001). Compared to females aged 21-30 years, females with high age (≥70 years) had at least 105% higher paliperidone C/D ratio (p<0.001). CONCLUSION: The present study shows that older age and female gender are associated with higher paliperidone exposure than younger age and males, respectively. Particularly, older female patients (>50 years) are likely exposed to high concentration and cautious dosing in this subgroup is required.
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Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Palmitato de Paliperidona/administração & dosagem , Palmitato de Paliperidona/farmacocinética , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/administração & dosagem , Antipsicóticos/sangue , Preparações de Ação Retardada , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona/sangue , Estudos Retrospectivos , Fatores Sexuais , Adulto JovemRESUMO
PURPOSE: The antidepressant venlafaxine is largely O-desmethylated by CYP2D6, whereas CYP2C19 mediates an alternative metabolic route of venlafaxine through N-desmethylation. The aim of this study was to investigate the combined effect of genotype-predicted CYP2D6 and CYP2C19 phenotypes on serum concentrations of venlafaxine and metabolites in a large patient population. METHODS: Patients were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital in Oslo (Norway) between January 01, 2007, and December 31, 2017. The study population was divided into different phenotype subgroups according to the combinations of CYP2D6/CYP2C19 phenotypes; intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers, and compared using combined normal metabolizers (NMs) as reference. FINDINGS: The dose-adjusted serum concentration of venlafaxine was 4- and 13-fold increased in combined CYP2D6 IM/CYP2C19 PMs and combined PMs, respectively, compared with combined NMs (P < 0.001). The sum concentration of venlafaxine + ODV (pharmacological active moiety) was increased 1.9 and 3.6-fold, respectively, in the same phenotype groups. Furthermore, the dose-adjusted active moiety exposure was similar in combined IMs as combined CYP2D6 PM/CYP2C19 NMs. CYP2D6 and CYP2C19 phenotypes explained 46% of the interindividual variability in dose-adjusted venlafaxine serum concentrations, whereas CYP2D6 alone explained 24%. CONCLUSIONS: The combined CYP2D6/CYP2C19 phenotype has a significant impact on serum concentrations of venlafaxine and also on the active moiety of venlafaxine + ODV, than CYP2D6 alone. In clinical practice, it is therefore important to take into account phenotype variabilities of both enzymes when assessing the risk of dose-dependent adverse effects during venlafaxine treatment.
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Antidepressivos/sangue , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Succinato de Desvenlafaxina/sangue , Cloridrato de Venlafaxina/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antidepressivos/uso terapêutico , Succinato de Desvenlafaxina/uso terapêutico , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Cloridrato de Venlafaxina/uso terapêutico , Adulto JovemRESUMO
AIMS: CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. METHODS: A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. RESULTS: MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P < 0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9-10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. CONCLUSIONS: CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.
Assuntos
Antidepressivos de Segunda Geração/farmacocinética , Citocromo P-450 CYP2D6/metabolismo , Monitoramento de Medicamentos/estatística & dados numéricos , Cloridrato de Venlafaxina/farmacocinética , Idoso , Alelos , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/sangue , Cicloexanóis/administração & dosagem , Cicloexanóis/sangue , Cicloexanóis/farmacocinética , Citocromo P-450 CYP2D6/genética , Succinato de Desvenlafaxina/administração & dosagem , Succinato de Desvenlafaxina/sangue , Succinato de Desvenlafaxina/farmacocinética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Noruega , Estudos Retrospectivos , Cloridrato de Venlafaxina/administração & dosagem , Cloridrato de Venlafaxina/sangueRESUMO
BACKGROUND: Valproic acid (VPA) is frequently used together with clozapine (CLZ) as mood-stabilizer or for the prevention of seizures in patients with psychotic disorders. VPA is known to reduce levels of the pharmacologically active CLZ-metabolite N-desmethylclozapine (N-DMC), but factors determining the degree of this interaction are unknown. Here, we investigated the relationship between VPA dose and serum concentration on N-DMC levels in a large patient population adjusting for sex, age, and smoking habits as covariates. METHODS: A total of 763 patients with steady-state serum concentrations of CLZ and N-DMC concurrently using VPA (cases, n = 76) or no interacting drugs (controls, n = 687) were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital, Oslo, between March 2005 and December 2016. In addition to information about prescribed doses, age, sex, smoking habits, and use of other interacting drugs were obtained. The effects of VPA dose and serum concentration on dose-adjusted N-DMC levels were evaluated by univariate correlation and multivariate linear mixed-model analyses adjusting for covariates. RESULTS: The dose-adjusted N-DMC levels were approximately 38% lower in VPA users (cases) versus nonusers (controls) (P < 0.001). Within the VPA cases, a negatively correlation between VPA dose and dose-adjusted N-DMC levels was observed with an estimated reduction of 1.42% per 100-mg VPA dose (P = 0.033) after adjusting for sex, age, and smoking. By contrast, there was no correlation between VPA serum concentration and dose-adjusted N-DMC levels (P = 0.873). CONCLUSIONS: The study shows that VPA dose, not concentration, is of relevance for the degree of reduction in N-DMC level in clozapine-treated patients. Presystemic induction of UGT enzymes or efflux transporters might underlie the reduction in N-DMC level during concurrent use of VPA. Our findings indicate that a VPA daily dose of 1500 mg or higher provides a further 21% reduction in N-DMC concentration. This is likely a relevant change in the exposure of this active metabolite where low levels are associated with implications of CLZ therapy.
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Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Clozapina/análogos & derivados , Ácido Valproico/administração & dosagem , Ácido Valproico/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Clozapina/sangue , Interações Medicamentosas , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: Olanzapine is a commonly prescribed antipsychotic available as oral and long-acting injectable (LAI) formulations. Data are lacking on the use and safety of olanzapine-LAI in older patients. The aim of this study was to investigate the effect of increasing age on olanzapine exposure during oral versus LAI administration in a real-life setting. METHODS: This observational study was based on routine therapeutic drug monitoring data collected during 2005-2017. As a measure of exposure, absolute concentrations and concentration/dose ratios of olanzapine were defined as outcome variables. Linear mixed-model analyzes were used to allow for inclusion of multiple samples per patient and adjustment for covariate effects. RESULTS: Olanzapine concentrations and doses from 8,288 patients (21,378 measurements) were included. The number of patients on oral treatment was 7,893 (42%, 50 years or older), while 395 were using olanzapine-LAI (27%, 50 years or older). In contrast to oral use, where the dose-adjusted concentration of olanzapine increased significantly for patients 50 years or older (P < 0.001), increasing age had no effect on olanzapine concentration following LAI administration (P = 0.550). The effects of smoking habits and gender were equal in oral and olanzapine-LAI users. CONCLUSION: While the dose-adjusted systemic exposure of olanzapine increases by age after oral administration, these novel findings from a large patient population show that systemic exposure of olanzapine-LAI is unaffected by age, probably due to the lacking influence of age-related changes in gastrointestinal absorption and/or presystemic metabolism. From a pharmacokinetic point of view, it is therefore no reason to restrict the use of olanzapine-LAI in older patients requiring long-term treatment.
Assuntos
Antipsicóticos/administração & dosagem , Transtornos Mentais/tratamento farmacológico , Olanzapina/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Antipsicóticos/sangue , Preparações de Ação Retardada , Feminino , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Olanzapina/sangue , Adulto JovemRESUMO
BACKGROUND: Enzyme-inducing antiepileptic drugs (EIAEDs) are among the clinically most important inducers of cytochrome P450 (CYP) 3A4, but there is limited evidence regarding the comparative potency of each EIAED in raising CYP3A4 activity. The aim of this study was to estimate CYP3A4-inductive potency of EIAEDs by comparing CYP3A4 activity in patients treated with carbamazepine, phenobarbital, or phenytoin. METHODS: Residual serum samples from patients treated with EIAEDs or levetiracetam were collected from a therapeutic drug monitoring service for analysis of 4ß-hydroxycholesterol (4ßOHC), which is an indicator of CYP3A4 activity. The samples were collected between January and September 2016 at Diakonhjemmet Hospital, Oslo, Norway. Concentration of 4ßOHC, EIAEDs, and levetiracetam was measured by ultra-performance liquid chromatography tandem mass spectrometry. Kruskal-Wallis and Mann-Whitney tests were used for comparison of 4ßOHC levels between the subgroups. RESULTS: In total, 4ßOHC measurements for 343 and 339 patients treated with EIAEDs and levetiracetam, respectively, were included in the study. Compared with levetiracetam-treated patients, the median 4ßOHC concentration was 3.3-fold, 5.8-fold, and 6.9-fold higher in patients using phenobarbital, phenytoin, or carbamazepine, respectively (P < 0.0001). Phenytoin users (n = 65) and carbamazepine users (n = 225) had 1.8- and 2.1-fold higher median 4ßOHC concentration than phenobarbital users (n = 28), respectively (P ≤ 0.0001). CONCLUSIONS: This study shows that phenytoin and carbamazepine have approximately twice the CYP3A4-inducing potency of phenobarbital. The results indicate that 2-fold higher doses of CYP3A4-metabolized drugs may generally be required during concurrent treatment with phenytoin or carbamazepine compared with phenobarbital.
Assuntos
Carbamazepina/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Indução Enzimática/efeitos dos fármacos , Hidroxicolesteróis/sangue , Fenobarbital/farmacologia , Fenitoína/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacologia , Biomarcadores/sangue , Carbamazepina/sangue , Indutores do Citocromo P-450 CYP3A/sangue , Monitoramento de Medicamentos , Feminino , Humanos , Levetiracetam/sangue , Levetiracetam/farmacologia , Masculino , Pessoa de Meia-Idade , Fenobarbital/sangue , Fenitoína/sangue , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Previous studies have reported inconsistent findings regarding the impact of the UGT1A4*3 variant allele on lamotrigine (LTG) exposure. As no studies have controlled for nongenetic factors, the aim of this study was to compare serum concentrations of LTG in carriers versus noncarriers of UGT1A4*3 adjusting for differences in age, sex, and valproic acid (VPA) comedication. METHODS: Matched data on serum concentration of LTG and UGT1A4 genotype patients with known information about VPA comedication were included retrospectively from a therapeutic drug monitoring service. Linear mixed-model analysis was used to evaluate the impact of the UGT1A4*3 variant on dose-adjusted serum concentrations (C/D ratio) of LTG. Subanalyses were performed to assess the impact of UGT1A4*3 in relation to age, sex, and VPA comedication. RESULTS: In total, 534 patients (1735 LTG serum concentrations) were included. In the study population, UGT1A4*3 carriers (n = 87; 16.3%) were estimated to have a 13% lower LTG C/D ratio compared with noncarriers (P = 0.01). Subanalyses showed that the quantitative impact of UGT1A4*3 was greatest in postmenopausal women (>50 years) without VPA comedication. In these patients (n = 99), UGT1A4*3 carriers displayed a 40% lower LTG C/D ratio than noncarriers (P = 0.001). The UGT1A4*3 variant had no significant effect on LTG C/D ratio in the other subpopulations (P > 0.1). Regardless of patient subgroup, the concomitant use of VPA was the strongest determinant of LTG exposure by increasing the C/D ratio 2.5-fold (P < 0.001). CONCLUSIONS: This study shows that UGT1A4*3 generally has a modest impact on LTG exposure, but it could lead to clinically relevant lowering in LTG serum concentration among postmenopausal women. The clinical impact of UGT1A4*3 in these patients needs to be assessed in relation to comedication with VPA, which is associated with a substantial increase in serum concentration of LTG.
Assuntos
Monitoramento de Medicamentos , Genótipo , Glucuronosiltransferase/genética , Lamotrigina/sangue , Pós-Menopausa/sangue , Pós-Menopausa/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alelos , Bases de Dados Factuais , Monitoramento de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Estudos Retrospectivos , Fatores Sexuais , Ácido Valproico/farmacocinética , Adulto JovemRESUMO
End-stage renal disease impairs drug metabolism via cytochrome P450 CYP3A; however, it is unclear whether CYP3A activity recovers after kidney transplantation. Therefore, the aim of this study was to evaluate the change in CYP3A activity measured as 4ß-hydroxycholesterol (4ßOHC) concentration after kidney transplantation. In total, data from 58 renal transplant recipients with 550 prospective 4ßOHC measurements were included in the study. One sample per patient was collected before transplantation, and 2-12 samples per patient were collected 1-82 days after transplantation. The measured pretransplant 4ßOHC concentrations ranged by >7-fold, with a median value of 22.8 ng/ml. Linear mixed-model analysis identified a 0.16-ng/ml increase in 4ßOHC concentration per day after transplantation (P < 0.001), indicating a regain in CYP3A activity. Increasing estimated glomerular filtration rate after transplantation was associated with increasing 4ßOHC concentration (P < 0.001), supporting that CYP3A activity increases with recovering uremia. In conclusion, this study indicates that CYP3A activity is regained subsequent to kidney transplantation.
Assuntos
Citocromo P-450 CYP3A/metabolismo , Transplante de Rim , Fígado/enzimologia , Adulto , Idoso , Creatinina/sangue , Citocromo P-450 CYP3A/genética , Feminino , Genótipo , Taxa de Filtração Glomerular , Humanos , Hidroxicolesteróis/metabolismo , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Uremia/metabolismo , Uremia/cirurgia , Adulto JovemRESUMO
AIM: 4ß-Hydroxycholesterol (4ßOHC) is sensitive towards induction or inhibition of CYP3A4, but its potential usefulness as a dosing biomarker remains to be demonstrated. The aim of this study was to investigate the correlation between 4ßOHC levels and steady-state concentrations (Css) of quetiapine, a CYP3A4 substrate with high presystemic metabolism, in psychiatric patients. METHODS: Serum samples from 151 patients treated with quetiapine as immediate release (IR; n = 98) or slow release (XR; n = 53) tablets were included for analysis of 4ßOHC. In all patients, Css of quetiapine had been measured at trough level, i.e. 10-14 and 17-25 h post-dosing for IR and XR tablets, respectively. Correlations between 4ßOHC levels and dose-adjusted Css (C/D ratios) of quetiapine were tested by univariate (Spearman's) and multivariate (multiple linear regression) analyses. Gender, age (≥60 vs. <60 years) and tablet formulation were included as potential covariates in the multivariate analysis. RESULTS: Correlations between 4ßOHC levels and quetiapine C/D ratios were highly significant both for IR- and XR-treated patients (P < 0.0001). Estimated Spearman r values were -0.47 (95% confidence interval -0.62, -0.30) and -0.56 (-0.72, -0.33), respectively. The relationship between 4ßOHC level and quetiapine C/D ratio was also significant in the multiple linear regression analysis (P < 0.001), including gender (P = 0.023) and age (P = 0.003) as significant covariates. CONCLUSIONS: The present study shows that 4ßOHC level is significantly correlated with steady-state concentration of quetiapine. This supports the potential usefulness of 4ßOHC as a phenotype biomarker for individualized dosing of quetiapine and other drugs where systemic exposure is mainly determined by CYP3A4 metabolism.
Assuntos
Antipsicóticos/farmacocinética , Biomarcadores Farmacológicos/sangue , Citocromo P-450 CYP3A/metabolismo , Hidroxicolesteróis/sangue , Transtornos Mentais/tratamento farmacológico , Fumarato de Quetiapina/farmacocinética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/uso terapêutico , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Feminino , Humanos , Masculino , Transtornos Mentais/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Fumarato de Quetiapina/uso terapêutico , Fatores Sexuais , Comprimidos , Adulto JovemRESUMO
AIM: 4ß-hydroxycholesterol (4ßOHC) is an endogenous CYP3A(4) biomarker, which is elevated by use of the CYP3A4 inducer carbamazepine. Our aim was to compare to what extent serum concentration of 4ßOHC correlates with dose (presystemic exposure) and steady-state concentration (systemic exposure) of carbamazepine. METHODS: The study was based on a therapeutic drug monitoring material, including information about daily doses and steady-state concentrations (Css ) of carbamazepine. 4ßOHC concentrations were determined in residual serum samples of 55 randomly selected carbamazepine-treated patients and 54 levetiracetam-treated patients (negative controls) by UPLC-APCI-MS/MS after liquid-liquid extraction. Correlation analyses between 4ßOHC concentration and daily dose and Css of carbamazepine, respectively, were performed by Spearman's tests. In addition, 4ßOHC concentrations in females vs. males were compared in induced and non-induced patients. RESULTS: Median 4ßOHC concentration was ~10-fold higher in carbamazepine- vs. levetiracetam-treated patients (650 vs. 54 nmol l(-1) , P < 0.0001). There was a significant, positive correlation between carbamazepine dose and 4ßOHC concentration (Spearman r = 0.53, 95% confidence interval [CI] 0.27, 0.72, P < 0.001). No significant correlation between carbamazepine Css and 4ßOHC concentration was found (Spearman r = 0.14; 95% CI -0.14, 0.40, P = 0.3). Enzyme-induced females had significantly higher 4ßOHC concentrations than males (P < 0.001), while no significant gender difference was found in non-induced patients (P = 0.52). CONCLUSION: Serum concentrations of 4ßOHC correlate with presystemic, but not systemic exposure of the CYP3A4 inducer carbamazepine. This suggests a stronger inductive effect of carbamazepine on presystemic than systemic CYP3A4 phenotype and might indicate a role of the intestine in 4ßOHC formation. Moreover, CYP3A4 inducibility seems to be higher in females than males.
Assuntos
Anticonvulsivantes , Carbamazepina , Indutores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A/biossíntese , Hidroxicolesteróis/sangue , Intestinos/enzimologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Biomarcadores/sangue , Carbamazepina/administração & dosagem , Carbamazepina/sangue , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Indutores do Citocromo P-450 CYP3A/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Estudos Retrospectivos , Fatores Sexuais , Adulto JovemRESUMO
PURPOSE: To investigate the predictive value of the risperidone and venlafaxine metabolic ratios and CYP2D6 genotype. METHODS: The determination of risperidone, 9-hydroxyrisperidone, and venlafaxine, O-desmethylvenlafaxine, N-desmethylvenlafaxine and CYP2D6 genotype was performed in 425 and 491 patients, respectively. The receiver operator characteristic method and the area under the receiver operator characteristic curve were used to illustrate the predictive value of risperidone metabolic ratio for the individual CYP2D6 genotype. To evaluate the proposed cutoff levels of >1 to identify individuals with a poor CYP2D6 genotype, the sensitivity, specificity, positive predictive values, and negative predictive values were calculated. RESULTS: Area under the receiver operator characteristic curve to predict poor metabolizers for risperidone/9-hydroxyrisperidone and N-desmethylvenlafaxine/O-desmethylvenlafaxine ratios was 93% and 99%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value (confidence interval) of a risperidone/9-hydroxyrisperidone ratio >1 to predict a CYP2D6 poor metabolizer genotype were 91% (76%-97%), 86% (83%-89%), 35% (26%-46%), and 99% (97%-100%), respectively. The corresponding measures for N-desmethylvenlafaxine/O-desmethylvenlafaxine were 93% (76%-97%), 87% (83%-89%), 40% (32%-51%), and 99% (98%-100%). CONCLUSIONS: Risperidone/9-hydroxyrisperidone and N-desmethylvenlafaxine/O-desmethylvenlafaxine metabolic ratios >1 strongly predict individuals with poor metabolizer genotype, which could guide psychotropic drug treatment to avoid adverse drug reactions and to increase their therapeutic efficacy in patients prescribed these drugs.
Assuntos
Citocromo P-450 CYP2D6/genética , Genótipo , Risperidona/farmacocinética , Cloridrato de Venlafaxina/farmacocinética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antidepressivos de Segunda Geração/farmacocinética , Antipsicóticos/farmacocinética , Criança , Cicloexanóis/farmacocinética , Succinato de Desvenlafaxina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona/farmacocinética , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
BACKGROUND: The clinical effect of bupropion is mediated by its active metabolite hydroxybupropion. Previous studies have reported conflicting impact of the CYP2B6*6 variant allele on the formation of hydroxybupropion from bupropion. The aim of this study was to clarify the effect of CYP2B6*6 and secondarily CYP2D6 genotype on steady-state serum concentrations of bupropion and hydroxybupropion in a large population of psychiatric patients. METHODS: Retrospective information about dose-adjusted serum concentrations (C/D ratios) of bupropion and hydroxybupropion, CYP2B6 genotype (ie, data on the 2B6*6 polymorphisms 516G>T and 785A>G) and CYP2D6 genotype, was obtained from a therapeutic drug monitoring database (n = 132 patients). C/D ratios of bupropion and hydroxybupropion, and metabolic ratios, were compared between CYP2B6 genotype subgroups by multivariate mixed-model analyses (2B6*1/*1 was defined as control group). In the analyses, CYP2D6 genotype was also included as a covariate. RESULTS: Homozygous 2B6*6 carriers (n = 7) had significantly lower C/D ratios of hydroxybupropion compared with controls (n = 79), that is, estimated mean 5.8 versus 13.0 nmol·L·mg (P < 0.001). C/D ratio of hydroxybupropion in heterozygous *6 carriers (12.1 nmol·L·mg; n = 46) did not significantly differ compared with controls (P = 0.32). The hydroxybupropion/bupropion metabolic ratios in heterozygous and homozygous 2B6*6 carriers were significantly lower than in controls (P = 0.001 and P < 0.001, respectively). CYP2D6 genotype did not significantly alter the hydroxybupropion C/D ratio, but higher bupropion values were observed in poor versus extensive CYP2D6 metabolizers (P = 0.020). CONCLUSIONS: This study shows that the CYP2B6*6 variant allele is associated with significantly reduced formation of the active bupropion metabolite in psychiatric patients. Our findings suggest that dose-adjusted serum concentrations of hydroxybupropion at steady state is approximately halved in homozygous CYP2B6*6 carriers, which might imply risk of reduced clinical response in this patient subgroup. The CYP2D6 genotype does not affect hydroxybupropion concentrations and is therefore unlikely to impact bupropion treatment.
Assuntos
Bupropiona/análogos & derivados , Bupropiona/sangue , Citocromo P-450 CYP2B6/genética , Monitoramento de Medicamentos , Adulto , Citocromo P-450 CYP2D6/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Duloxetine is metabolized by cytochrome P450 (CYP)1A2 and CYP2D6. The aim of this study was to investigate the effect of the CYP2D6 genotype on duloxetine serum concentration adjusting for age and sex. Patients were included retrospectively from a therapeutic drug monitoring service. Multiple linear regression analysis was used to investigate the effect of CYP2D6 genotype, age and sex on the duloxetine concentration-to-dose (C/D) ratio. In total, 269 patients were included and assigned to the following genotype-predicted phenotype subgroups: CYP2D6 poor metabolizers (PMs, n = 23), intermediate metabolizers (IMs, n = 121), normal metabolizers (NMs, n = 120) and ultrarapid metabolizers (UMs, n = 5). Multiple linear regression analysis revealed a 95% higher duloxetine C/D ratio in PMs compared with NMs (p = 0.009). Patients ≥65 years had a 56% higher C/D ratio than younger patients (p = 0.01), while women had a 46% higher C/D ratio than men (p = 0.04). In conclusion, the CYP2D6 PM phenotype is associated with a twofold higher concentration at recommended dosing compared with the NM phenotype. CYP2D6 PM females above 65 years are at particular risk of high duloxetine levels as they may obtain a threefold higher C/D ratio compared with younger, male NMs.