RESUMEN
PURPOSE: Individual variability in the endogenous CYP3A metabolite 4ß-hydroxycholesterol (4ßOHC) is substantial, but to which extent this is determined by genetic and nongenetic factors remains unclear. The aim of the study was to evaluate the explanatory power of candidate genetic variants and key nongenetic factors on individual variability in 4ßOHC levels in a large naturalistic patient population. METHODS: We measured 4ßOHC concentration in serum samples from 655 patients and used multiple linear regression analysis to estimate the quantitative effects of CYP3A4*22, CYP3A5*3, and POR*28 variant alleles, comedication with CYP3A inducers, inhibitors and substrates, sex, and age on individual 4ßOHC levels. RESULTS: 4ßOHC concentration ranged >100-fold in the population, and the multiple linear regression model explained about one fourth of the variability (R 2 = 0.23). Only comedication with inducers or inhibitors, sex, and POR genotype were significantly associated with individual variability in 4ßOHC level. The estimated quantitative effects on 4ßOHC levels were greatest for inducer comedication (+>313%, P < 0.001), inhibitor comedication (-34%, P = 0.021), and female sex (+30%, P < 0.001), while only a modestly elevated 4ßOHC level was observed in carriers vs. noncarriers of POR*28 (+11%, P = 0.023). CONCLUSIONS: These findings suggest that the CYP3A4*22, CYP3A5*3, and POR*28 variant alleles are of limited importance for overall individual variability in 4ßOHC levels compared to nongenetic factors.
Asunto(s)
Citocromo P-450 CYP3A/genética , Hidroxicolesteroles/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
PURPOSE: Valproic acid (VPA) has an extensive interindividual pharmacokinetic variability. Published data regarding the impact of gender, age, and CYP2C9/2C19 genetics on VPA variability are conflicting, and the purpose of present study is to clarify the effect of these factors on dose-adjusted steady-state serum VPA concentration (C:D ratio) in a large, naturalistic patient material. METHODS: In patients who had been subjected to cytochrome P450 (CYP) genotyping and therapeutic drug monitoring of VPA, information about serum concentrations, dose, gender, age, and CYP2C9/2C19 genotypes was retrospectively collected from a routine TDM database during the period 2008-2012. The effects of age, gender, and CYP2C9/CYP2C19 genotypes on C:D ratios of VPA were investigated by multivariate analyses (mixed model) including sampling time as covariate. RESULTS: In total, 857 serum concentrations from 252 patients were included. A significant gender effect was observed with a 1.3-fold higher estimated C:D ratio in females than in males, i.e., geometric means 0.34 vs. 0.27 µM/mg/day, respectively (p < 0.001). A similar and significant difference in estimated geometric means was found between patients >65 vs. ≤65 years, i.e., 0.36 vs. 0.26 µM/mg/day (p < 0.001), respectively. Finally, no association between the various CYP2C9/2C19 variant genotypes and C:D ratio of VPA was observed (p > 0.1). CONCLUSION: The present study shows that age and gender significantly influence VPA serum concentration. In order to obtain similar drug exposure, our findings suggest that older female patients would generally require 30-50 % lower dosing of VPA compared to younger males. Moreover, we conclude that CYP2C9/2C19 genotype is not relevant for variability in VPA exposure.
Asunto(s)
Anticonvulsivantes/sangre , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Ácido Valproico/sangre , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticonvulsivantes/farmacocinética , Monitoreo de Drogas , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Ácido Valproico/farmacocinética , Adulto JovenRESUMEN
The widely used antipsychotic drug, olanzapine (OLA) shows large interindividual variability in metabolic clearance. Although the role of the enzymes CYP1A2, CYP2D6 and UGT1A4 has been extensively explored, little is known about the in vivo role of flavin-containing monooxygenases (FMOs) catalyzing the N-oxidation of OLA in vitro. We investigated the influence of FMO1 and 3 polymorphisms on the steady state serum concentrations of OLA and its N-oxide metabolite in 379 patients. The upstream FMO1*6 was associated with increased dose-adjusted serum OLA concentrations (C/Ds; P=0.008), an effect further enhanced by FMO1rs7877C>T in smokers. The influence of FMO3 polymorphisms was limited to variability in OLA N-oxide. Homozygous carriers of FMO3rs2266780A>G (p.E308G) displayed 50% lower C/D of OLA N-oxide compared with subjects homo- or heterozygous for the A-variant (P<0.003). Our data support the role of FMO3 in the N-oxidation of OLA and implicate for the first time the contribution of FMO1 and its functional *6 variant in OLA disposition.
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Benzodiazepinas/sangre , Trastornos Mentales/tratamiento farmacológico , Óxidos/sangre , Oxigenasas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Benzodiazepinas/uso terapéutico , Femenino , Humanos , Masculino , Trastornos Mentales/sangre , Trastornos Mentales/genética , Persona de Mediana Edad , Olanzapina , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
Olanzapine, a world leader in antipsychotic drugs, is used in the treatment of schizophrenia and bipolar disorder. There is considerable interpatient variability in its hepatic clearance. Polymorphic glucuronidation of olanzapine by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) was investigated retrospectively in patient samples taken for routine therapeutic drug monitoring (TDM) and in recombinant metabolic systems in vitro. Multivariate analyses revealed that patients who were heterozygous as well as those who were homozygous for the UGT1A4*3 allelic variant had significantly higher concentrations of the major metabolite olanzapine 10-N-glucuronide in serum (+38% (P = 0.011) and +246% (P < 0.001), respectively). This finding was in line with the significant increases in glucuronidation activity of olanzapine observed with recombinant UGT1A4.3 (Val-48) as compared with UGT1A4.1 (Leu-48) (1.3-fold difference, P < 0.001). By contrast, serum concentrations of the parent drug were not significantly influenced by UGT1A4 genotype. Our findings therefore indicate that UGT1A4-mediated metabolism is not a major contributor to interpatient variability in olanzapine levels. However, with respect to other drugs for which UGT1A4 has a dominant role in clearance, increased glucuronidation encoded by UGT1A4*3 might impact the risk for subtherapeutic drug exposure.
Asunto(s)
Antipsicóticos/farmacocinética , Benzodiazepinas/farmacocinética , Trastorno Bipolar/metabolismo , Glucurónidos/metabolismo , Glucuronosiltransferasa/metabolismo , Esquizofrenia/metabolismo , Antipsicóticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Femenino , Genotipo , Glucuronosiltransferasa/genética , Humanos , Hígado/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica , Análisis Multivariante , Noruega , Olanzapina , Estudios Retrospectivos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genéticaRESUMEN
In therapeutic drug monitoring (TDM) practice of psychotropic agents, it is common to summarize plasma concentrations of parent drugs and metabolites when these are considered equipotent. However, there is no clear definition of the term equipotent and one should be aware that metabolites referred to as equipotent in the literature could display several-fold differences in affinities toward target proteins. The fact that the parent drug and metabolite may have different abilities to penetrate the blood-brain-barrier further complicates the picture. Potential differences in brain distribution imply that various metabolite/drug ratios representing the same total concentration in plasma reflect different active concentrations in the brain. Plasma metabolite/drug ratios could differ extensively according to metabolic phenotype and administration route. An example is risperidone where the plasma metabolite/drug ratio is 30-fold lower in cytochrome P450 2D6 poor metabolizers compared to ultrarapid metabolizers, and four-fold lower after intramuscular compared to oral administration. As risperidone is more lipophilic and less effluxed by P-glycoprotein in the blood-brain-barrier than the active metabolite 9-hydroxyrisperidone, one might speculate that patients with high plasma metabolite/drug ratios obtain lower active concentrations in the brain. However, the relative drug-metabolite brain distribution needs to be quantified in humans to clarify to what degree drug and metabolite plasma levels reflect active brain concentrations. The present review illustrates the complexity of active metabolites in TDM with focus on amitriptyline, clomipramine, doxepin, imipramine, fluoxetine, venlafaxine and risperidone, all psychotropic drugs where target plasma concentration ranges are based on the sum of parent drug and metabolite. In addition, perspectives on the possibility of using distribution- and activity-weighted plasma concentrations are provided.