RESUMEN
AIMS: To investigate the effect of aging, sex and cytochrome P450 (CYP) genotypes on the exposure of quetiapine (QUE) and the pharmacologically active metabolite N-desalkylquetiapine (NDQ). METHODS: Patients with serum concentrations of QUE and NDQ were included retrospectively from a therapeutic drug monitoring service. The outcome measures were concentration:dose (C:D) ratios of QUE and NDQ, and NDQ:QUE metabolic ratio. Linear mixed model analyses were used to evaluate the effects of age, sex and, subsequently, CYP2D6/3A genotypes. RESULTS: The average age of the included population (n = 8118 patients) was 44 years (13.5% ≥65 years). The C:D ratio of QUE and NDQ gradually increased in patients aged >50 years compared to those aged 18-30 years, with 28 and 29% increase, respectively, for patients aged >70 years (P < .001). Compared to males, females had 15% lower QUE C:D ratio and 10% higher C:D ratio of NDQ (both P < .001). The NDQ:QUE metabolic ratio was 30% higher in females than in males (P < .001). For females ≥65 years, the NDQ C:D ratio was 36% higher compared to males <65 years (P < .001). A significantly higher NDQ C:D ratio was observed for CYP2D6 intermediate (+7%, P = .012) and poor (+17%, P = .001) compared to normal metabolizers. No effects of CYP3A4*22 and CYP3A5*1 allele variants were observed. CONCLUSION: This study shows an increase of the QUE and NDQ exposures during aging. Old age, female sex and CYP2D6 allele variants encoding reduced activity are factors associated with high NDQ exposure. Therefore, females ≥65 years carrying CYP2D6 allele variants encoding reduced activity have the highest risk of dose-dependent side effects of NDQ during QUE treatment.
Asunto(s)
Citocromo P-450 CYP2D6 , Sistema Enzimático del Citocromo P-450 , Masculino , Humanos , Femenino , Adulto , Fumarato de Quetiapina/efectos adversos , Citocromo P-450 CYP2D6/genética , Estudios Retrospectivos , Sistema Enzimático del Citocromo P-450/genética , Citocromo P-450 CYP3A/metabolismo , GenotipoRESUMEN
BACKGROUND: Valproic acid (VPA) is frequently used with clozapine (CLZ) as mood stabilizer and/or seizure prophylaxis. Valproic acid is known to reduce N-desmethylclozapine (N-DMC) but not CLZ levels. This leads to the hypothesis that VPA induces the CLZ metabolism via non-N-desmethylation pathways. Therefore, we aimed to investigate the effect of concurrent VPA use on the serum concentrations of a spectrum of CLZ metabolites in patients, adjusting for smoking. METHODS: In total, 288 patients with an overall number of 737 serum concentration measurements of CLZ and metabolites concurrently using VPA (cases, n = 22) or no interacting drugs (controls, n = 266) were included from a routine therapeutic drug monitoring service. Linear mixed model analyses were performed to compare the dose-adjusted concentrations (C/D) of CLZ, N-DMC, CLZ 5N/N+-glucuronides, and metabolite-to-parent ratios in cases versus controls. RESULTS: After adjusting for covariates, the N-DMC (-40%, P < 0.001) and N+-glucuronide C/Ds (-78%, P < 0.001) were reduced in cases versus controls, while the CLZ C/D was unchanged (P > 0.7). In contrast, the 5N-glucuronide C/D (+250%, P < 0.001) and 5N-glucuronide-to-CLZ ratios (+120%, P = 0.01) were increased in cases versus controls. CONCLUSIONS: Our findings show that complex changes in CLZ metabolism underly the pharmacokinetic interaction with VPA. The lower levels of N-DMC seem to be caused by VPA-mediated induction of CLZ 5N-glucuronide formation, subsequently leading to reduced substrate availability for N-desmethylation. Whether the changes in CLZ metabolism caused by VPA affects the clinical outcome warrants further investigation.
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Clozapina/sangre , Esquizofrenia/sangre , Esquizofrenia/tratamiento farmacológico , Tranquilizantes/sangre , Ácido Valproico/sangre , Adulto , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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/efectos adversos , Antipsicóticos/farmacocinética , Palmitato de Paliperidona/administración & dosificación , Palmitato de Paliperidona/farmacocinética , Esquizofrenia/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antipsicóticos/administración & dosificación , Antipsicóticos/sangre , Preparaciones de Acción Retardada , Monitoreo de Drogas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Palmitato de Paliperidona/sangre , Estudios Retrospectivos , Factores Sexuales , Adulto JovenRESUMEN
PURPOSE: Zuclopenthixol is an antipsychotic available as oral and long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age on zuclopenthixol exposure during oral and LAI administrations without and with adjustment for CYP2D6 genotype. METHODS: Data on serum concentrations of zuclopenthixol and CYP2D6 genotype (available for 28.2% of the population) from patients using oral or LAI zuclopenthixol were included retrospectively from a therapeutic drug monitoring service during the period 2005-2019. As a measure of exposure, dose-adjusted serum concentration (C/D ratio) was used. Based on age, patients were grouped to older (≥ 65 years) or younger (18-64 years). Linear mixed model analyses without and with adjustment for CYP2D6 genotype were used. RESULTS: Serum concentrations of zuclopenthixol from 1145 (14.1% older) and 899 patients (24.6% older) in the LAI and oral groups were included, respectively. Compared with younger patients, older patients had a higher C/D ratio of zuclopenthixol for LAI (+ 25-33%, p < 0.001) and oral formulation (+ 25-29%, p ≤ 0.003) without and with adjustment for CYP2D6 genotype. The doses were lower in older versus younger patients (oral: - 30%; LAI: - 20%; p < 0.001). Compared with the younger LAI users without reduced CYP2D6 function, a higher C/D ratio was observed in the older LAI users with reduced CYP2D6 function (+ 104%, p < 0.001). CONCLUSION: The present study showed that zuclopenthixol exposure increases in older patients and that the older LAI users with reduced CYP2D6 function are exposed to high serum concentrations. Also, the present study showed that similar dose reductions are required for oral and LAI users.
Asunto(s)
Antipsicóticos/farmacocinética , Clopentixol/farmacocinética , Citocromo P-450 CYP2D6/genética , Esquizofrenia/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antipsicóticos/administración & dosificación , Clopentixol/administración & dosificación , Citocromo P-450 CYP2D6/metabolismo , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Femenino , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , Noruega , Variantes Farmacogenómicas , Estudios Retrospectivos , Esquizofrenia/sangre , Adulto JovenRESUMEN
BACKGROUND: Older patients with mental disorders are particularly likely to be affected by negative consequences of the infection control measures that have been implemented as a result of the COVID-19 pandemic. MATERIAL AND METHOD: A questionnaire survey was sent to 18 departments of geriatric psychiatry from all four health regions in Norway. RESULTS: Altogether 83 therapists from various occupational groups responded, with representatives from all the health regions. Almost one-half (45.8 %) reported an exacerbation of patients' mental condition to a large or very large degree due to social isolation, and an equal proportion (48.2 %) reported that normal follow-up was limited. The contact between the specialist and primary health services was reduced, and 15.6 % reported that patients had failed to receive the necessary somatic medical assistance to a large or very large degree. INTERPRETATION: The service for older patients with mental disorders in the specialist health service was reduced as a result of the COVID-19 pandemic, while coordination with the primary health service was also curtailed, and many patients deteriorated mentally as a result of the infection control measures. Collaboration between the specialist and primary health services may be an important focus area for this patient group.
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COVID-19 , Servicios de Salud Mental , Anciano , Humanos , Noruega/epidemiología , Pandemias , SARS-CoV-2RESUMEN
PURPOSE: Tailoring medication dosing for the individual patient is complex, and many factors can influence drug exposure. We investigated the effect of age and CYP2D6 genotype on aripiprazole and dehydroaripiprazole exposure in patients using long-acting injectable (LAI) or oral aripiprazole. METHODS: Matched data on serum concentration of aripiprazole and CYP2D6 genotype of patients using oral or LAI aripiprazole were included retrospectively from a therapeutic drug monitoring service. The patients were divided into the following CYP2D6 genotype-defined categories: poor metabolizers (PMs), intermediate metabolizers (IMs), normal metabolizers (NMs), and ultrarapid metabolizers (UMs). Linear mixed model analyses were used to evaluate the impact of CYP2D6 genotype on dose-adjusted serum concentrations of the active moiety of aripiprazole+dehydroaripiprazole in relation to age and formulation. RESULTS: We identified 635 patients (mean age = 40.1 years, 9.4% ≥ 65 years, 53.7% females) using LAI (n = 166) or oral formulation (n = 469). The genotype-predicted CYP2D6 phenotype subgroups were 2.4% UMs, 82.0% NMs, 8.0% IMs, and 7.2% PMs. Age did not significantly affect exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (p = 0.071) or oral (p = 0.14) subgroups. Compared with CYP2D6 NMs, PMs and IMs had significantly increased exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (1.7-fold higher, p < 0.001, and 1.5-fold higher, p < 0.001) and oral (1.7-fold higher, p < 0.001, and 1.6-fold higher, p < 0.001) subgroups. CONCLUSIONS: In conclusion, doses should be adjusted according to CYP2D6 genotype when initiating treatment with aripiprazole LAI or tablets, while advanced age do not affect the exposure of the active moiety of aripiprazole treatment regardless of formulation.
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Factores de Edad , Aripiprazol/administración & dosificación , Aripiprazol/sangre , Citocromo P-450 CYP2D6/genética , Piperazinas/administración & dosificación , Piperazinas/sangre , Quinolonas/administración & dosificación , Quinolonas/sangre , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores SexualesRESUMEN
BACKGROUND: The combination of olanzapine and valproic acid (VPA) is regularly prescribed in the treatment of bipolar or schizoaffective disorders. The VPA has been shown to reduce olanzapine concentration, but the mechanism behind this interaction remains unknown. We aimed to investigate the effect of VPA on olanzapine concentration during oral versus long-acting injectable (LAI) formulation in a real-life setting. METHODS: From a therapeutic drug monitoring service, prescribed doses and serum concentrations from 2791 olanzapine-treated patients (9433 measurements) were included. RESULTS: The number of patients on olanzapine-LAI treatment was 328, whereas 2463 were using oral olanzapine. The frequency of patients comedicated with VPA was 9.4% for olanzapine tablets and 5.8% for olanzapine-LAI. The VPA had no effect on olanzapine dose-adjusted concentrations in LAI users (1.6 vs 1.7 [ng/mL]/[mg/d]; P = 0.38), whereas in the oral group the dose-adjusted olanzapine concentration was lower in VPA users (2.2 vs 2.7 [ng/mL]/[mg/d]; P < 0.001). For smokers in the oral olanzapine group using VPA, 8.7% of the measurements were in the subtherapeutic range (<10 ng/mL) compared with 6.0% in nonusers (P = 0.003). IMPLICATIONS: These findings show that the VPA-olanzapine interaction involves a presystemic mechanism and is therefore restricted to oral olanzapine treatment. For oral treatment of olanzapine, comedication with VPA implies a risk of insufficient effect, which may be of clinical relevance in smokers in particular. Thus, it is important to be aware of the interaction potential with VPA during oral olanzapine use, whereas for LAI-treated patients fewer precautions are required from a pharmacokinetic point of view.
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Antimaníacos/farmacología , Antipsicóticos/administración & dosificación , Antipsicóticos/sangre , Trastorno Bipolar/tratamiento farmacológico , Interacciones Farmacológicas , Olanzapina/administración & dosificación , Olanzapina/sangre , Trastornos Psicóticos/tratamiento farmacológico , Fumar/sangre , Ácido Valproico/farmacología , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Preparaciones de Acción Retardada , Monitoreo de Drogas , Quimioterapia Combinada , Femenino , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: It is generally agreed that prescribing of antipsychotic drugs to older patients should be reduced, but figures for the prescribing of these drugs to older patients living at home in Norway are not available. The study aimed to investigate developments in prescribing of antipsychotic drugs among older patients living at home from 2006 to 2018, and whether there were differences in prescribing rates between the age groups 65-74 years, 75-84 years and 85 years or older. MATERIAL AND METHOD: Data were retrieved from the Norwegian Prescription Database. All persons aged 65 years or older who were dispensed at least one antipsychotic drug in 2006, 2010, 2014 and 2018 were included, and gender-specific prevalence for the ten most widely used antipsychotic drugs was calculated. RESULTS: The proportion of patients aged 65 or older who were prescribed antipsychotic drugs in the period decreased for both sexes. For the age group 65-74 years, an increase was found from 2014 to 2018. There was a clear decrease in the prescribing rate for prochlorperazine and levomepromazine, whereas prescriptions for quetiapine increased. INTERPRETATION: Attention should be paid to the increase in prescribing of antipsychotic drugs for the youngest age group of older patients (65-74 years) in the last four years, along with the increase in prescribing of quetiapine for older patients.
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Antipsicóticos/administración & dosificación , Prescripciones de Medicamentos/estadística & datos numéricos , Utilización de Medicamentos , Vida Independiente , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Noruega , Prevalencia , Sistema de RegistrosRESUMEN
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.
Asunto(s)
Antipsicóticos/administración & dosificación , Trastornos Mentales/tratamiento farmacológico , Olanzapina/administración & dosificación , Administración Oral , Adolescente , Adulto , Anciano , Antipsicóticos/sangre , Preparaciones de Acción Retardada , Femenino , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , Olanzapina/sangre , Adulto JovenRESUMEN
BACKGROUND: Polypharmacy is common among older persons who are also vulnerable to side effects. We aimed to characterize patients who on admission to a geriatric psychiatric hospital had major medication side effects interfering with daily performance. METHODS: Cross-sectional cohort study of patients consecutively admitted to a geriatric psychiatric hospital from 2006, 06 December to 2008, 24 October. The UKU side effect rating scale was performed, and patients were divided into those with no/minor side effects versus those with major side effects. Blood levels of 56 psychotropic drugs and 27 safety laboratory tests were measured upon admission. RESULTS: Of 206 patients included in the analysis, 70 (34%) had major side effects related to drug treatment. The most frequent side effects were asthenia (31%), reduced salivation (31%), concentration difficulties (28%), memory impairment (24%), and orthostatic dizziness (18%). The significant characteristics predicting major side effects were female gender (OR = 2.4, 95% confidence interval (CI) = 1.1-5.5), main diagnosis of affective disorder (OR = 4.3, 95% CI = 1.5-12.3), unreported use of psychotropic medications (OR = 2.0, 95% CI = 1.0-4.1), a higher number of reported psychotropic medications (OR = 1.7, 95% CI = 1.2-2.3), a higher number of reported medications for somatic disorders (OR = 1.2, 95% CI = 1.1-1.5), and a higher score on the Charlson comorbidity index (OR = 1.2, 95% CI = 1.0-1.4) (r 2 = 0.238, p < 0.001). CONCLUSIONS: Clinicians should be especially aware of side effects related to drug treatment in geriatric psychiatric female patients with a high use of psychotropic and other medications and somatic comorbidity. Unreported use of psychotropic medications was also related to the risk for side effects, and clinicians should make an effort to ascertain all medications taken by geriatric psychiatric patients.
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Actividades Cotidianas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Hospitalización , Trastornos del Humor/tratamiento farmacológico , Polifarmacia , Psicotrópicos/efectos adversos , Factores de Edad , Anciano , Anciano de 80 o más Años , Estudios Transversales , Delirio/complicaciones , Delirio/psicología , Demencia/complicaciones , Demencia/psicología , Trastorno Depresivo Mayor/diagnóstico , Femenino , Anciano Frágil/estadística & datos numéricos , Humanos , Modelos Logísticos , Masculino , Noruega/epidemiología , Psicotrópicos/uso terapéutico , Factores SocioeconómicosRESUMEN
PURPOSE: The aim of this observational study was to describe the type, number, and serum concentration levels of psychotropic drugs in elderly patients, on admission to a geriatric psychiatric inpatient unit. We further wanted to investigate the use and unreported use of psychotropic drugs by analyzing for a broad spectrum of drugs in the serum samples. METHODS: A total of 236 patients were included. Drug use, patient characteristics, and diagnoses were recorded, and serum analysis was performed for a total of 56 psychotropic drugs in 233 of the patients. RESULTS: Nine out of ten patients (88%) used one or more psychotropic drugs on admission to hospital; the mean use was 2.8 (95% confidence interval (CI) 2.6-2.9) drugs. In 25 patients (11%), drugs reported used were not detected in serum. Unreported use of drugs (serum analysis revealing one or more drugs not reported) was found in 100 patients (43%). This was more common in younger patients. Psychotropic polypharmacy (use of three or more psychotropic drugs) was found in 109 patients (47%). Patients with a main diagnosis of affective disorder used the most psychotropic drugs. CONCLUSIONS: Psychotropic drugs are commonly used among geriatric psychiatric patients on admission to hospital. Psychotropic polypharmacy is a major concern among these patients. There was considerable unreported use of drugs within this population, and a low threshold for a broader serum analysis for psychotropic drugs appears indicated.
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Utilización de Medicamentos/estadística & datos numéricos , Trastornos Mentales/sangre , Psicotrópicos/sangre , Anciano , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Benzodiazepinas/sangre , Benzodiazepinas/uso terapéutico , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Trastornos Mentales/tratamiento farmacológico , Polifarmacia , Psicotrópicos/uso terapéuticoRESUMEN
OBJECTIVES: This survey assessed psychiatry residents'/early-career psychiatrists' attitudes towards the utility of therapeutic drug monitoring (TDM) of antipsychotics. METHODS: A previously developed questionnaire on attitudes on TDM utility during antipsychotic treatment was cross-sectionally disseminated by national coordinators between 01/01/2022-31/12/2023. The frequency of using TDM for antipsychotics other than clozapine was the main outcome in a linear regression analysis, including sex, clinical setting, caseload, and factors generated by an exploratory factor analysis. Comparisons between residents and early-career psychiatrists, respondents working in in- and outpatient settings, and low-/middle- and high-income countries were performed. RESULTS: Altogether, 1,237 respondents completed the survey, with 37.9% having never used TDM for antipsychotics. Seven factors explained 41% of response variance; six of them were associated with frequency of TDM use (p < 0.05). Items with highest loadings for factors included clinical benefits of TDM (factors A and E: 0.7), negative expectations for beliefs of patients towards TDM (factor B: 0.6-0.7), weak TDM scientific evidence (factor C: 0.8), and TDM availability (factor D: -0.8). Respondents from low-/middle-income countries were less likely to frequently/almost always use TDM compared to high-income countries (9.4% vs. 21.5%, p < 0.001). DISCUSSION: TDM use for antipsychotics was poor and associated with limited knowledge and insufficient availability.
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Antipsicóticos , Actitud del Personal de Salud , Monitoreo de Drogas , Psiquiatría , Humanos , Antipsicóticos/uso terapéutico , Femenino , Masculino , Estudios Transversales , Encuestas y Cuestionarios , Adulto , Internado y Residencia , Europa (Continente) , Pautas de la Práctica en Medicina/estadística & datos numéricos , Sociedades Médicas , PsiquiatrasRESUMEN
BACKGROUND: Glucuronidation is an important metabolic pathway of clozapine (CLZ), but the impact of various uridine 5'diphospho-glucuronosyltransferases (UGT) polymorphisms on the exposure and metabolism of CLZ in vivo is unclear. OBJECTIVE: The objective of this study was to investigate the impact of UGT2B haplotype and UGT1A4*3 allele variants on the formation of CLZ glucuronide metabolites (5N- and N+-glucuronide) and CLZ exposure in patients' serum after adjusting for sex, age, and smoking habits. METHODS: The study was based on serum samples from CLZ-treated patients (n=79) subjected to routine therapeutic drug monitoring (TDM) at Diakonhjemmet Hospital, Oslo, Norway. From the same patients, the following UGT variants were genotyped using Real-Time PCR: UGT2B:GA haplotype (defined as UGT2B:GA; rs1513559A>G and rs416593T>A) and UGT1A4*3 (rs2011425T>G). Serum concentrations of CLZ 5N- and N+-glucuronide were measured by UPLC high-resolution mass spectrometry. RESULTS: None of the genotypes had significant impact on CLZ exposure (p>0.05). However, compared to UGT2B:AT/AT and UGT1A4*1/*1, the 5N-glucuronide exposure was reduced in UGT2B:GA/GA carriers (-75 %, p=0.03) while the exposure was non-significantly increased in UGT1A4*3 carriers (+100 %, p=0.14), respectively. The N+-glucuronide exposure was unchanged in UGT1A4*3 vs. noncarriers (p=0.28), but significantly reduced in heterozygous (-50 %, p=0.016) and homozygous carriers (-70 %, p=0.021) of UGT2B:GA compared to UGT2B:AT/AT carriers, respectively. CONCLUSION: The UGT2B:GA and UGT1A4*3 variants had no impact on CLZ exposure but were associated with differences and preferences in CLZ glucuronidation. The latter might be of potential relevance for CLZ tolerability since levels of the N+-glucuronide metabolite may reflect the generation and trapping of reactive metabolites involved in CLZ-induced toxicity.