RESUMEN
Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence.
Asunto(s)
Encéfalo/fisiología , Guías de Práctica Clínica como Asunto/normas , Estimulación Transcraneal de Corriente Directa/ética , Estimulación Transcraneal de Corriente Directa/normas , Animales , Quemaduras por Electricidad/etiología , Quemaduras por Electricidad/prevención & control , Humanos , Estimulación Transcraneal de Corriente Directa/efectos adversosRESUMEN
The hopes for readily implementable precision medicine are high. For many complex disorders, such as bipolar disorder, these hopes critically hinge on tangible successes in pharmacogenetics of treatment response or susceptibility to adverse events. In this article, we review the current state of pharmacogenomics of bipolar disorder including latest results from candidate genes and genome-wide association studies. The majority of studies focus on response to lithium treatment. Although a host of genes has been studied, hardly any replicated findings have emerged so far. Very small samples sizes and heterogeneous phenotype definition may be considered the major impediments to success in this field. Drawing from current experiences and successes in studies on diagnostic psychiatric phenotypes, we suggest several approaches for our way forward.
Asunto(s)
Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/genética , Farmacogenética/métodos , Antipsicóticos/uso terapéutico , Trastorno Bipolar/diagnóstico , Estudios de Casos y Controles , Humanos , Litio/uso terapéuticoRESUMEN
Heritability of caffeine pharmacokinetics and cytochrome P450 1A2 (CYP1A2) activity is controversial. Here, we analyzed the pharmacokinetics of caffeine, an in vivo probe drug for CYP1A2 and arylamine N-acetyltransferase 2 (NAT2) activity, in monozygotic (MZ) and dizygotic (DZ) twins. In the entire group, common and unique environmental effects explained most variation in caffeine area under the curve (AUC). Apparently, smoking and hormonal contraceptives masked the genetic effects on CYP1A2 activity. However, when excluding smokers and users of hormonal contraceptives, 89% of caffeine AUC variation was due to genetic effects and, even in the entire group, 8% of caffeine AUC variation could be explained by a CYP1A1/1A2 promotor polymorphism (rs2470893). In contrast, nearly all of the variations (99%) of NAT2 activity were explained by genetic effects. This study illustrates two very different situations in pharmacogenetics from an almost exclusively genetic determination of NAT2 activity with no environmental modulation to only moderate genetic effects on CYP1A2 activity with strong environmental modulation.
Asunto(s)
Arilamina N-Acetiltransferasa/genética , Cafeína/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Farmacogenética , Adolescente , Adulto , Área Bajo la Curva , Anticonceptivos Hormonales Orales/administración & dosificación , Ambiente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Fumar/metabolismo , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genética , Adulto JovenRESUMEN
BACKGROUND: Pharmacogenetics are an important component in the individualization of treatment; however, pharmacogenetic diagnostics have so far not been used to any great extent in clinical practice. A consistent consideration of individual patient factors, such as pharmacogenetics may help to improve drug therapy and increase individual safety and efficacy aspects. OBJECTIVE: A brief summary of structures and effects of genetic variations on drug efficacy is presented. Some frequently prescribed pharmaceuticals are specified. Furthermore, the feasibility of pharmacogenetic diagnostics and dose recommendations in the clinical practice are described. CURRENT DATA: The European Medicines Agency (EMA) as the European approval authority has already extended the drug labels of more than 70 pharmaceuticals by information on pharmacogenetic biomarkers and the U.S. Food and Drug Administration (FDA) more than 150. This is a crucial step towards targeted medicine. Guidelines on dose and therapy adjustments are provided by the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. CONCLUSION: It is fundamental to consider individual patient factors for successful drug therapy. Dose and therapy recommendations based on pharmacogenetic diagnostics are highly important for individualization as well as improvement of safety and efficiency of drug therapy.
Asunto(s)
Monitoreo de Drogas/métodos , Quimioterapia/métodos , Pruebas Genéticas/métodos , Pruebas de Farmacogenómica/métodos , Medicina de Precisión/métodos , Europa (Continente) , Medicina Basada en la Evidencia , Marcadores Genéticos/genética , HumanosRESUMEN
The low bioavailability of the anti-migraine drug sumatriptan is partially caused by first-pass hepatic metabolism. In this study, we analyzed the impact of the hepatic organic cation transporter OCT1 on sumatriptan cellular uptake, and of OCT1 polymorphisms on sumatriptan pharmacokinetics. OCT1 transported sumatriptan with high capacity and sumatriptan uptake into human hepatocytes was strongly inhibited by the OCT1 inhibitor MPP(+) . Sumatriptan uptake was not affected by the Met420del polymorphism, but was strongly reduced by Arg61Cys and Gly401Ser, and completely abolished by Gly465Arg and Cys88Arg. Plasma concentrations in humans with two deficient OCT1 alleles were 215% of those with fully active OCT1 (P = 0.0003). OCT1 also transported naratriptan, rizatriptan, and zolmitriptan, suggesting a possible impact of OCT1 polymorphisms on the pharmacokinetics of other triptans as well. In conclusion, OCT1 is a high-capacity transporter of sumatriptan and polymorphisms causing OCT1 deficiency have similar effects on sumatriptan pharmacokinetics as those observed in subjects with liver impairment.
Asunto(s)
Hígado/efectos de los fármacos , Hígado/metabolismo , Factor 1 de Transcripción de Unión a Octámeros/genética , Factor 1 de Transcripción de Unión a Octámeros/metabolismo , Polimorfismo Genético , Agonistas de Receptores de Serotonina/farmacocinética , Sumatriptán/farmacocinética , Alelos , Disponibilidad Biológica , Permeabilidad de la Membrana Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Genotipo , Células HEK293 , Hepatocitos/metabolismo , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Factor 1 de Transcripción de Unión a Octámeros/antagonistas & inhibidores , Agonistas de Receptores de Serotonina/sangre , Sumatriptán/sangre , Triptaminas/farmacocinéticaRESUMEN
Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9, and OATP1B1 has been extensively studied. However, it is still unknown how much of the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated.
Asunto(s)
Herencia , Metoprolol/farmacocinética , Polimorfismo Genético , Sulfonamidas/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Biotransformación/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Femenino , Genotipo , Humanos , Infusiones Intravenosas , Transportador 1 de Anión Orgánico Específico del Hígado , Masculino , Metoprolol/administración & dosificación , Persona de Mediana Edad , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Farmacogenética , Fenotipo , Sulfonamidas/administración & dosificación , Torasemida , Gemelos Dicigóticos/genética , Gemelos Monocigóticos/genética , Adulto JovenRESUMEN
Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. The top association result in the meta-analysis of response represents SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.
Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Adulto , Proteínas de Ciclo Celular , Proteínas del Citoesqueleto , Trastorno Depresivo Mayor/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Neurregulina-1/genética , Farmacogenética , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Inducción de Remisión , Factores de Transcripción , Resultado del Tratamiento , Canales de Sodio Activados por Voltaje/genéticaRESUMEN
UDP-glucuronosyltransferases (UGT) catalyze the biotransformation of many endobiotics and xenobiotics, and are coded by polymorphic genes. However, knowledge about the effects of these polymorphisms is rarely used for the individualization of drug therapy. Here, we present a quantitative systematic review of clinical studies on the impact of UGT variants on drug metabolism to clarify the potential for genotype-adjusted therapy recommendations. Data on UGT polymorphisms and dose-related pharmacokinetic parameters in man were retrieved by a systematic search in public databases. Mean estimates of pharmacokinetic parameters were extracted for each group of carriers of UGT variants to assess their effect size. Pooled estimates and relative confidence bounds were computed with a random-effects meta-analytic approach whenever multiple studies on the same variant, ethnic group, and substrate were available. Information was retrieved on 30 polymorphic metabolic pathways involving 10 UGT enzymes. For irinotecan and mycophenolic acid a wealth of data was available for assessing the impact of genetic polymorphisms on pharmacokinetics under different dosages, between ethnicities, under comedication, and under toxicity. Evidence for effects of potential clinical relevance exists for 19 drugs, but the data are not sufficient to assess effect size with the precision required to issue dose recommendations. In conclusion, compared to other drug metabolizing enzymes much less systematic research has been conducted on the polymorphisms of UGT enzymes. However, there is evidence of the existence of large monogenetic functional polymorphisms affecting pharmacokinetics and suggesting a potential use of UGT polymorphisms for the individualization of drug therapy.
Asunto(s)
Glucuronosiltransferasa/genética , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Polimorfismo Genético , Uridina Difosfato/metabolismo , Analgésicos/metabolismo , Analgésicos/farmacocinética , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacocinética , Antihipertensivos/metabolismo , Antihipertensivos/farmacocinética , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Glucuronosiltransferasa/metabolismo , Humanos , Psicotrópicos/metabolismo , Psicotrópicos/farmacocinéticaRESUMEN
The broad clinical application of pharmacogenetic diagnostics for individualised drug treatment is still limited. With the exception of oncological therapies where molecular tumor makers are frequently used to decide upon individual drug therapies, pharmacogenetic testing is not generally offered in clinical laboratory diagnostics, because the costs are not covered by general health insurance and it is not evident what consequences the results of a genotyping test may have for the individual drug treatment. Especially in the context of pharmacokinetics, bioequivalence-based concepts have been developed that allow the individual drug dosage or therapy to be adjusted to genetic polymorphisms in drug metabolism, drug transport that affect drug absorption, metabolism and elimination. Pharmacogenetic aspects are increasingly included in the product information (e.g., on its website the FDA lists more than 60 drug labels that include pharmacogenetic information). However, most pharmacogenetic information on drug labels does not give recommendations for clinical decisions to be made based on individual genotypes. This gap is currently being closed by the development of international consortia aiming to base clinical recommendations on the best available evidence by systematic review of the existing data. The Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network (CPIC) is an international community-driven organisation that is developing peer-reviewed, freely available gene/drug guidelines that are published in full at PharmGKB (http://www.pharmgkb.org). The aim of these guidelines is to give therapeutic recommendations such as dose adjustments or suggestions for the choice of an alternative drug in the case of specific genotypes (phenotypes) that predict slow metabolism or transport of drugs or safety risks or risks of therapeutic failure. These guidelines are not mandatory but serve to facilitate the translation of pharmacogenetic knowledge from bench to bedside.
Asunto(s)
Monitoreo de Drogas/normas , Medicina Basada en la Evidencia , Marcadores Genéticos/genética , Patología Molecular/normas , Farmacogenética/normas , Guías de Práctica Clínica como Asunto , Medicina de Precisión/normasRESUMEN
Polymorphic drug-metabolizing enzymes (DMEs) are responsible for the metabolism of the majority of psychotropic drugs. By explaining a large portion of variability in individual drug metabolism, pharmacogenetics offers a diagnostic tool in the burgeoning era of personalized medicine. This review updates existing evidence on the influence of pharmacogenetic variants on drug exposure and discusses the rationale for genetic testing in the clinical context. Dose adjustments based on pharmacogenetic knowledge are the first step to translate pharmacogenetics into clinical practice. However, also clinical factors, such as the consequences on toxicity and therapeutic failure, must be considered to provide clinical recommendations and assess the cost-effectiveness of pharmacogenetic treatment strategies. DME polymorphisms are relevant not only for clinical pharmacology and practice but also for research in psychiatry and neuroscience. Several DMEs, above all the cytochrome P (CYP) enzymes, are expressed in the brain, where they may contribute to the local biochemical homeostasis. Of particular interest is the possibility of DMEs playing a physiological role through their action on endogenous substrates, which may underlie the reported associations between genetic polymorphisms and cognitive function, personality and vulnerability to mental disorders. Neuroimaging studies have recently presented evidence of an effect of the CYP2D6 polymorphism on basic brain function. This review summarizes evidence on the effect of DME polymorphisms on brain function that adds to the well-known effects of DME polymorphisms on pharmacokinetics in explaining the range of phenotypes that are relevant to psychiatric practice.
Asunto(s)
Encéfalo/enzimología , Encéfalo/fisiología , Inactivación Metabólica/genética , Trastornos Mentales/tratamiento farmacológico , Polimorfismo Genético/genética , Psicotrópicos/farmacocinética , Animales , Humanos , Trastornos Mentales/genética , Personalidad/genética , Polimorfismo Genético/fisiologíaRESUMEN
After uptake into liver cells, the antiemetic drugs tropisetron and ondansetron undergo metabolic inactivation by cytochrome P450 2D6 (CYP2D6). We investigated whether the hepatic organic cation transporter 1 (OCT1; SLC22A1) mediates cellular uptake and whether common OCT1 loss-of-function polymorphisms affect pharmacokinetics and efficacy of both drugs. Both tropisetron and ondansetron inhibited ASP(+) uptake in OCT1-overexpressing HEK293 cells. Overexpression of wild-type, but not OCT1 loss-of-function variants, significantly increased tropisetron uptake. Correspondingly, patients with two loss-of-function OCT1 alleles had higher tropisetron plasma concentrations (n=59, P<0.04) and higher clinical efficacy (n=91, P=0.009) compared with carriers of fully active OCT1. Overexpression of OCT1 did not increase ondansetron uptake. Nevertheless, OCT1 genotypes correlated with pharmacokinetics (n=45, P<0.05) and clinical efficacy (n=222, P<0.02) of ondansetron, the effect size of OCT1 genotypes on pharmacokinetics and efficacy was greater for tropisetron than for ondansetron. In conclusion, in addition to the known effects of CYP2D6, OCT1 deficiency may increase efficacy of tropisetron and potentially of ondansetron by limiting their hepatic uptake.
Asunto(s)
Membrana Celular/metabolismo , Indoles/uso terapéutico , Ondansetrón/uso terapéutico , Transportador 1 de Catión Orgánico/genética , Polimorfismo Genético/genética , Antagonistas del Receptor de Serotonina 5-HT3/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antieméticos/sangre , Antieméticos/farmacología , Antieméticos/uso terapéutico , Membrana Celular/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Indoles/sangre , Indoles/farmacología , Masculino , Persona de Mediana Edad , Ondansetrón/sangre , Ondansetrón/farmacología , Antagonistas del Receptor de Serotonina 5-HT3/sangre , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , Resultado del Tratamiento , Tropisetrón , Adulto JovenRESUMEN
Little is known about the genetic impact on loop diuretic effects. We newly investigated five genetic polymorphisms in 95 healthy volunteers, who had ingested bumetanide, frusemide and torsemide. The subjects excreted means of 20.2 g sodium chloride, 2.87 g potassium and 261 mg calcium over 24 h. Concerning sodium chloride, the subjects excreted 2.2 g less per two T-alleles of C825T in the G nucleotide ß-subunit 3 (GNB3), 3.2 g less per two Met32-alleles of Val32Met in the atrial natriuretic peptide precursor (ANP) and 2.8 g more per two Arg152-alleles of Ter152Arg in ANP (P=0.007, 0.05 and 0.007). Concerning potassium, the subjects excreted 0.42 g more per two ANP Arg152-alleles (P=0.023). Concerning calcium, the subjects excreted 32 mg more per two deletion-alleles of the insertion/deletion polymorphism in the angiotensin-converting enzyme, 44 mg more per two Trp460-alleles of Gly460Trp in α-adducin (ADD1) and 42 mg less per two GNB3 T-alleles (P=0.006, 0.023 and 0.008). The common genetic impact together with three polymorphisms in the sodium chloride cotransporter and the epithelial sodium channel was 20, 15, 10 and 23% of the variation in the urinary excretion of sodium chloride, volume, potassium and calcium. This exceeded the fraction of variation explained by differences in the pharmacokinetics: 13, 10, 11 and 6%. Thus, genetic variation seems to be a stronger predictor of the loop diuretic drug response than pharmacokinetic variation.
Asunto(s)
Diuréticos/farmacología , Polimorfismo Genético , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacología , Adulto , Estudios Cruzados , Humanos , Masculino , Equilibrio Hidroelectrolítico/genéticaRESUMEN
We investigated whether tramadol or its active metabolite, O-desmethyltramadol, are substrates of the organic cation transporter OCT1 and whether polymorphisms in OCT1 affect tramadol and O-desmethyltramadol pharmacokinetics. Tramadol showed high permeability through parallel artificial membrane permeability assays (PAMPAs). Tramadol uptake in HEK293 cells did not change after OCT1 overexpression, and the concentrations of tramadol in the plasma of healthy volunteers were independent of their OCT1 genotypes. In contrast, O-desmethyltramadol showed low membrane permeability, and OCT1 overexpression increased O-desmethyltramadol uptake 2.4-fold. This increase in uptake was reversed by OCT1 inhibitors and absent when loss-of-function OCT1 variants were overexpressed. Volunteers carrying loss-of-function OCT1 polymorphisms had significantly higher plasma concentrations of O-desmethyltramadol (P = 0.002, n = 41) and significantly prolonged miosis, a surrogate marker of opioidergic effects (P = 0.005, n = 24). In conclusion, polymorphisms in OCT1 influence the pharmacokinetics of O-desmethyltramadol, presumably by affecting its uptake into liver cells, and thus may modulate the efficacy of tramadol treatment.
Asunto(s)
Analgésicos Opioides/farmacocinética , Transportador 1 de Catión Orgánico/genética , Transportador 1 de Catión Orgánico/metabolismo , Tramadol/farmacocinética , Adolescente , Adulto , Algoritmos , Alelos , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP2D6/genética , Genotipo , Células HEK293 , Humanos , Cinética , Membranas Artificiales , Miosis/inducido químicamente , Polimorfismo Genético , Pupila/efectos de los fármacos , Tramadol/análogos & derivados , Tramadol/metabolismo , Adulto JovenRESUMEN
The growing interest in incorporating pharmacogenetics (PGx) into drug development and clinical practice raises several questions: which study designs best reveal relevant pharmacogenetic biomarkers, best clarify specific hypotheses in PGx, and result in the largest gain of clinical evidence in this field? In this review, we present and compare a variety of PGx-related study designs. The type and quality of evidence gained by each category of study design is evaluated, and an appropriate timeline for the integration of pharmacogenetic studies into drug development is proposed. A summary of the pros and cons of the different study designs might help investigators decide how best to incorporate PGx into drug research. Using different scenarios to explain how genetic polymorphisms influence drug action, we illustrate how this knowledge can be translated into individualized drug choices, individualized dosage determination based on pharmacogenetic diagnostics, and other types of monitoring in order to make drug therapies safer and more effective.
Asunto(s)
Ensayos Clínicos como Asunto , Farmacogenética , Proyectos de Investigación , Estudios de Casos y Controles , Estudios Transversales , Descubrimiento de Drogas , Humanos , Vigilancia de Productos ComercializadosRESUMEN
Organic cation transporters (OCTs) can mediate metformin transmembrane transport. We explored metformin pharmacokinetics in relation to genetic variations in OCT1, OCT2, OCT3, OCTN1, and MATE1 in 103 healthy male Caucasians. Renal clearance varied 3.8-fold and was significantly dependent on creatinine clearance (r(2) = 0.42, P < 0.0001), age (r(2) = 0.09, P = 0.002), and OCT1 polymorphisms. Carriers of zero, one, and two low-activity OCT1 alleles (Arg61Cys, Gly401Ser, 420del, or Gly465Arg) had mean renal clearances of 30.6, 33.1, and 37.1 l/h, respectively (P = 0.04, after adjustment for creatinine clearance and age). Immunohistochemical staining of human kidneys demonstrated OCT1 expression on the apical side of proximal and distal tubules. Increased renal clearance, in parallel with the known decreased hepatic uptake, may contribute to reduced metformin efficacy in low-activity genotypes. Renal OCT1 expression may be important not only in relation to metformin but with respect to other drugs as well.
Asunto(s)
Hipoglucemiantes/farmacocinética , Riñón/metabolismo , Metformina/farmacocinética , Factor 1 de Transcripción de Unión a Octámeros/genética , Proteínas de Transporte de Catión Orgánico/genética , Adulto , Envejecimiento/fisiología , Índice de Masa Corporal , Creatinina/metabolismo , Genotipo , Humanos , Inmunohistoquímica , Masculino , Transportador 2 de Cátion Orgánico , Fenotipo , Polimorfismo Genético/genética , Polimorfismo de Nucleótido Simple , Simportadores , Testosterona/sangreRESUMEN
Pharmacokinetics in individual subjects is determined by genes and environment. The relative contributions of enzyme induction and inherited genomic variation to cytochrome P450 enzyme 2C9 (CYP2C9) activity are unknown. In 130 volunteers, CYP2C9 activity was measured in vivo using tolbutamide as a probe drug. Tolbutamide was administered orally, and the pharmacokinetics of the drug was analyzed twice--before and after four doses of 450 mg rifampin. Mean total apparent clearances (Cl/F) in the genotype groups CYP2C9*1/*1, *1/*2, *1/*3, *2/*3, and *3/*3 before rifampin were 0.78, 0.74, 0.52, 0.40, and 0.13 l/h, respectively. After rifampin administration, these clearances increased in all genotype groups by a median factor of 1.9 (range 1.1-4.8). The combined effects of genes and environment could be predicted by a simple additive model. Thus, enzyme induction resulted in an approximately twofold difference in CYP2C9 activity, irrespective of the CYP2C9 genotypes. But the difference in activity levels between the CYP2C9*1/*1 and *3/*3 genotypes before the administration of rifampin was sixfold.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Adulto , Anciano , Hidrocarburo de Aril Hidroxilasas/biosíntesis , Biomarcadores/metabolismo , Citocromo P-450 CYP2C9 , Inducción Enzimática/efectos de los fármacos , Inducción Enzimática/genética , Femenino , Variación Genética/fisiología , Genotipo , Humanos , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Tasa de Depuración Metabólica/genética , Persona de Mediana Edad , Tolbutamida/farmacología , Adulto JovenRESUMEN
The impact of the CYP2C9 polymorphism on the pharmacokinetics of orally administered 9-tetrahydrocannabinol (THC) was studied in 43 healthy volunteers. THC pharmacokinetics did not differ by CYP2C9*2 allele status. However, the median area under the curve of THC was threefold higher and that of 11-nor-9-carboxy-9-tetrahydrocannabinol was 70% lower in CYP2C9*3/*3 homozygotes than in CYP2C9*1/*1 homozygotes. CYP2C9*3 carriers also showed a trend toward increased sedation following administration of THC. Therefore, the CYP2C9*3 variant may influence both the therapeutic and adverse effects of THC.
Asunto(s)
Alelos , Hidrocarburo de Aril Hidroxilasas/genética , Dronabinol/farmacocinética , Variación Genética/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Anciano , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP2C9 , Dronabinol/sangre , Femenino , Frecuencia de los Genes/genética , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Adulto JovenRESUMEN
The concentration ratio of morphine (Mor) over codeine (Cod) in opiate positive blood samples is used to discriminate between the use of illegal heroin (high ratios) and therapeutic codeine (low ratios). However, genetically caused CYP2D6 ultra-rapid metabolism might lead to Mor/Cod comparable to heroin intake. A single oral dose of 30 mg codeine was administered to 11 CYP2D6 ultrarapid metabolizers (UMs) and 12 extensive metabolizers (EMs). Codeine and its morphine metabolites and Mor/Cod were quantified in plasma and urine by liquid chromatography with tandem mass spectrometry within 24 h after codeine intake. The Mor/Cod in plasma were below 1 for both UMs and EMs during the first 12 h. After 12 h, 9% of the 11 UM and none of the 12 EM had ratios > 1. In urine, Mor/Cod ratios were below one for all EMs and UMs during the first 12 h. Thus, CYP2D6 genotyping in general will not explain Mor/Cod ratios > 1 in plasma or urine, unless the time of drug intake is more than 24 h previous.
Asunto(s)
Analgésicos Opioides/análisis , Codeína/análisis , Citocromo P-450 CYP2D6/metabolismo , Derivados de la Morfina/análisis , Detección de Abuso de Sustancias , Analgésicos Opioides/farmacocinética , Biotransformación , Codeína/farmacocinética , Citocromo P-450 CYP2D6/genética , Duplicación de Gen , Genotipo , Humanos , FenotipoRESUMEN
Genetic polymorphisms in superoxide-producing NAD(P)H oxidase have been linked to cardiovascular diseases including anthracycline-induced cardiotoxicity. We quantified NAD(P)H oxidase activity in granulocytes of 81 healthy Caucasian volunteers (in addition, 51 in an independent confirmatory study) by chemiluminescence using the luminol analogue L-012. Expression of CYBA, NCF4 and RAC2 coding for NAD(P)H oxidase subunits was measured in whole blood cells in 59 study participants by real-time PCR. Of the five variants investigated (-930A>G, 242C>T, 640A>G in CYBA and the recently reported -368G>A in NCF4 and 7508T>A in RAC2), only CYBA 640A>G was consistently associated with superoxide production (640GG carriers 28% less than AA individuals, P=0.05 in each cohort, P=0.005 in combined analysis). RAC2 7508T>A was related to higher expression of RAC2 (P=0.02) and NCF4 (P=0.04). In summary, CYBA 640A>G rather than 242C>T was associated with reduced activity. The quantitatively moderate effect and the high intra-individual variability should be considered for further study design.