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1.
Clin Neurophysiol ; 128(9): 1774-1809, 2017 09.
Article in English | MEDLINE | ID: mdl-28709880

ABSTRACT

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.


Subject(s)
Brain/physiology , Practice Guidelines as Topic/standards , Transcranial Direct Current Stimulation/ethics , Transcranial Direct Current Stimulation/standards , Animals , Burns, Electric/etiology , Burns, Electric/prevention & control , Humans , Transcranial Direct Current Stimulation/adverse effects
2.
Eur Neuropsychopharmacol ; 27(6): 599-609, 2017 06.
Article in English | MEDLINE | ID: mdl-28342679

ABSTRACT

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.


Subject(s)
Bipolar Disorder/drug therapy , Bipolar Disorder/genetics , Pharmacogenetics/methods , Antipsychotic Agents/therapeutic use , Bipolar Disorder/diagnosis , Case-Control Studies , Humans , Lithium/therapeutic use
4.
Clin Pharmacol Ther ; 100(6): 606-616, 2016 12.
Article in English | MEDLINE | ID: mdl-27509179

ABSTRACT

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.


Subject(s)
Arylamine N-Acetyltransferase/genetics , Caffeine/metabolism , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1A2/genetics , Pharmacogenetics , Adolescent , Adult , Area Under Curve , Contraceptives, Oral, Hormonal/administration & dosage , Environment , Female , Humans , Male , Middle Aged , Polymorphism, Genetic , Smoking/metabolism , Twins, Dizygotic/genetics , Twins, Monozygotic/genetics , Young Adult
5.
Internist (Berl) ; 57(3): 289-97, 2016 Mar.
Article in German | MEDLINE | ID: mdl-26830424

ABSTRACT

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.


Subject(s)
Drug Monitoring/methods , Drug Therapy/methods , Genetic Testing/methods , Pharmacogenomic Testing/methods , Precision Medicine/methods , Europe , Evidence-Based Medicine , Genetic Markers/genetics , Humans
6.
Clin Pharmacol Ther ; 99(6): 633-41, 2016 06.
Article in English | MEDLINE | ID: mdl-26659468

ABSTRACT

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.


Subject(s)
Liver/drug effects , Liver/metabolism , Octamer Transcription Factor-1/genetics , Octamer Transcription Factor-1/metabolism , Polymorphism, Genetic , Serotonin Receptor Agonists/pharmacokinetics , Sumatriptan/pharmacokinetics , Alleles , Biological Availability , Cell Membrane Permeability/drug effects , Enzyme Inhibitors/pharmacology , Genotype , HEK293 Cells , Hepatocytes/metabolism , Humans , Migraine Disorders/drug therapy , Octamer Transcription Factor-1/antagonists & inhibitors , Serotonin Receptor Agonists/blood , Sumatriptan/blood , Tryptamines/pharmacokinetics
7.
Clin Pharmacol Ther ; 98(6): 611-21, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26344676

ABSTRACT

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.


Subject(s)
Heredity , Metoprolol/pharmacokinetics , Polymorphism, Genetic , Sulfonamides/pharmacokinetics , Adolescent , Adult , Area Under Curve , Biotransformation/genetics , Cytochrome P-450 CYP2C9/genetics , Cytochrome P-450 CYP2C9/metabolism , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Female , Genotype , Humans , Infusions, Intravenous , Liver-Specific Organic Anion Transporter 1 , Male , Metoprolol/administration & dosage , Middle Aged , Organic Anion Transporters/genetics , Organic Anion Transporters/metabolism , Pharmacogenetics , Phenotype , Sulfonamides/administration & dosage , Torsemide , Twins, Dizygotic/genetics , Twins, Monozygotic/genetics , Young Adult
8.
Transl Psychiatry ; 5: e553, 2015 04 21.
Article in English | MEDLINE | ID: mdl-25897834

ABSTRACT

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.


Subject(s)
Antidepressive Agents/therapeutic use , Depressive Disorder, Major/drug therapy , Selective Serotonin Reuptake Inhibitors/therapeutic use , Adult , Cell Cycle Proteins , Cytoskeletal Proteins , Depressive Disorder, Major/genetics , Female , Genome-Wide Association Study , Humans , Male , Middle Aged , Nerve Tissue Proteins/genetics , Neuregulin-1/genetics , Pharmacogenetics , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases/genetics , Remission Induction , Transcription Factors , Treatment Outcome , Voltage-Gated Sodium Channels/genetics
9.
Pharmacol Ther ; 141(1): 92-116, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24076267

ABSTRACT

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.


Subject(s)
Glucuronosyltransferase/genetics , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/metabolism , Pharmacokinetics , Polymorphism, Genetic , Uridine Diphosphate/metabolism , Analgesics/metabolism , Analgesics/pharmacokinetics , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacokinetics , Antihypertensive Agents/metabolism , Antihypertensive Agents/pharmacokinetics , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacokinetics , Glucuronosyltransferase/metabolism , Humans , Psychotropic Drugs/metabolism , Psychotropic Drugs/pharmacokinetics
10.
Article in German | MEDLINE | ID: mdl-24170080

ABSTRACT

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.


Subject(s)
Drug Monitoring/standards , Evidence-Based Medicine , Genetic Markers/genetics , Pathology, Molecular/standards , Pharmacogenetics/standards , Practice Guidelines as Topic , Precision Medicine/standards
11.
Mol Psychiatry ; 18(3): 273-87, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22565785

ABSTRACT

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.


Subject(s)
Brain/enzymology , Brain/physiology , Inactivation, Metabolic/genetics , Mental Disorders/drug therapy , Polymorphism, Genetic/genetics , Psychotropic Drugs/pharmacokinetics , Animals , Humans , Mental Disorders/genetics , Personality/genetics , Polymorphism, Genetic/physiology
12.
Pharmacogenomics J ; 12(1): 45-53, 2012 Feb.
Article in English | MEDLINE | ID: mdl-20877298

ABSTRACT

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.


Subject(s)
Diuretics/pharmacology , Polymorphism, Genetic , Sodium Potassium Chloride Symporter Inhibitors/pharmacology , Adult , Cross-Over Studies , Humans , Male , Water-Electrolyte Balance/genetics
13.
Pharmacogenomics J ; 12(1): 22-9, 2012 Feb.
Article in English | MEDLINE | ID: mdl-20921968

ABSTRACT

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.


Subject(s)
Cell Membrane/metabolism , Indoles/therapeutic use , Ondansetron/therapeutic use , Organic Cation Transporter 1/genetics , Polymorphism, Genetic/genetics , Serotonin 5-HT3 Receptor Antagonists/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Antiemetics/blood , Antiemetics/pharmacology , Antiemetics/therapeutic use , Cell Membrane/drug effects , Female , HEK293 Cells , Humans , Indoles/blood , Indoles/pharmacology , Male , Middle Aged , Ondansetron/blood , Ondansetron/pharmacology , Serotonin 5-HT3 Receptor Antagonists/blood , Serotonin 5-HT3 Receptor Antagonists/pharmacology , Treatment Outcome , Tropisetron , Young Adult
14.
Clin Pharmacol Ther ; 90(1): 143-50, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21562485

ABSTRACT

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.


Subject(s)
Analgesics, Opioid/pharmacokinetics , Organic Cation Transporter 1/genetics , Organic Cation Transporter 1/metabolism , Tramadol/pharmacokinetics , Adolescent , Adult , Algorithms , Alleles , Area Under Curve , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP2D6/genetics , Genotype , HEK293 Cells , Humans , Kinetics , Membranes, Artificial , Miosis/chemically induced , Polymorphism, Genetic , Pupil/drug effects , Tramadol/analogs & derivatives , Tramadol/metabolism , Young Adult
15.
Clin Pharmacol Ther ; 89(2): 198-209, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21209614

ABSTRACT

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.


Subject(s)
Clinical Trials as Topic , Pharmacogenetics , Research Design , Case-Control Studies , Cross-Sectional Studies , Drug Discovery , Humans , Product Surveillance, Postmarketing
16.
Clin Pharmacol Ther ; 86(3): 299-306, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19536068

ABSTRACT

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.


Subject(s)
Hypoglycemic Agents/pharmacokinetics , Kidney/metabolism , Metformin/pharmacokinetics , Octamer Transcription Factor-1/genetics , Organic Cation Transport Proteins/genetics , Adult , Aging/physiology , Body Mass Index , Creatinine/metabolism , Genotype , Humans , Immunohistochemistry , Male , Organic Cation Transporter 2 , Phenotype , Polymorphism, Genetic/genetics , Polymorphism, Single Nucleotide , Symporters , Testosterone/blood
17.
Clin Pharmacol Ther ; 86(1): 54-61, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19369937

ABSTRACT

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.


Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Aryl Hydrocarbon Hydroxylases/metabolism , Adult , Aged , Aryl Hydrocarbon Hydroxylases/biosynthesis , Biomarkers/metabolism , Cytochrome P-450 CYP2C9 , Enzyme Induction/drug effects , Enzyme Induction/genetics , Female , Genetic Variation/physiology , Genotype , Humans , Male , Metabolic Clearance Rate/drug effects , Metabolic Clearance Rate/genetics , Middle Aged , Tolbutamide/pharmacology , Young Adult
18.
Clin Pharmacol Ther ; 85(3): 273-6, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19005461

ABSTRACT

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.


Subject(s)
Alleles , Aryl Hydrocarbon Hydroxylases/genetics , Dronabinol/pharmacokinetics , Genetic Variation/genetics , Polymorphism, Genetic/genetics , Adolescent , Adult , Aged , Aryl Hydrocarbon Hydroxylases/metabolism , Cytochrome P-450 CYP2C9 , Dronabinol/blood , Female , Gene Frequency/genetics , Humans , Male , Middle Aged , Sex Factors , Young Adult
19.
J Anal Toxicol ; 32(2): 178-82, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18334103

ABSTRACT

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.


Subject(s)
Analgesics, Opioid/analysis , Codeine/analysis , Cytochrome P-450 CYP2D6/metabolism , Morphine Derivatives/analysis , Substance Abuse Detection , Analgesics, Opioid/pharmacokinetics , Biotransformation , Codeine/pharmacokinetics , Cytochrome P-450 CYP2D6/genetics , Gene Duplication , Genotype , Humans , Phenotype
20.
Clin Pharmacol Ther ; 83(5): 749-57, 2008 May.
Article in English | MEDLINE | ID: mdl-17914442

ABSTRACT

Melphalan is associated with severe side effects such as mucositis, diarrhea, and myelosuppression. We investigated how much the individual severity of these side effects is predicted by pharmacokinetics. In addition, we studied glutathione S-transferase GSTM1, GSTT1, and GSTP1 polymorphisms in relation to adverse events. A high interindividual pharmacokinetic variability was observed in 84 patients. There was a linear correlation between creatinine and melphalan clearance (P=0.0004). Patients treated with a dose > or = 70 mg/m(2) had a 23-fold increased risk to develop mucositis (P<0.001) and a 12-fold increased risk to develop diarrhea (P<0.001) compared with lower doses. The GSTP1 codon 105 polymorphism may be relevant for development of mucositis and the GSTT1 deletion may predict diarrhea, but these findings require confirmation. Melphalan-induced side effects were significantly dependent only on dose. Therapeutic drug monitoring or genotyping for GST does not appear to be very helpful in optimizing therapy with melphalan.


Subject(s)
Glutathione Transferase/genetics , Glutathione Transferase/metabolism , Melphalan/adverse effects , Melphalan/pharmacokinetics , Adult , Aged , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/adverse effects , Antineoplastic Agents, Alkylating/pharmacokinetics , Dose-Response Relationship, Drug , Female , Genotype , Glutathione S-Transferase pi/genetics , Glutathione S-Transferase pi/metabolism , Humans , Male , Melphalan/administration & dosage , Middle Aged , Polymorphism, Genetic
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