The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease.

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aß42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aß42 suggesting that TREM2's role in AD may involve tau dysfunction.

The role of clusterin, complement receptor 1, and phosphatidylinositol binding clathrin assembly protein in Alzheimer disease risk and cerebrospinal fluid biomarker levels.

CONTEXT: Two recent and simultaneously published genome-wide association studies independently implicated clusterin (CLU), complement receptor 1 (CR1), and phosphatidylinositol binding clathrin assembly protein (PICALM) as putative novel Alzheimer disease (AD) risk loci. Despite their strong statistical support, all 3 signals emerged from heterogeneous case-control populations and lack replication in different settings. OBJECTIVE: To determine whether genetic variants in CLU, CR1, and PICALM confer risk for AD in independent data sets (n = 4254) and to test the impact of these markers on cerebrospinal fluid (CSF)-Aß42 and total-tau protein levels (n = 425). DESIGN: Genetic association study using family-based and case-control designs. SETTING: Ambulatory or hospitalized care. PARTICIPANTS: Family samples originate from mostly multiplex pedigrees recruited at different centers in the United States (1245 families, 2654 individuals with AD, and 1175 unaffected relatives). Unrelated case-control subjects originate from 1 clinical center in Germany (214 individuals with AD and 211 controls). All subjects were of European descent. MAIN OUTCOME MEASURES: The association between 5 genetic variants in CLU, CR1, and PICALM and risk for AD, and the correlation between these 5 genetic variants and CSF-Aß42 and tau levels. RESULTS: All 3 investigated loci showed significant associations between risk for AD (1-tailed P values ranging from <.001 to .02) and consistent effect sizes and direction. For each locus, the overall evidence of association was substantially strengthened on meta-analysis of all available data (2-tailed P values ranging from 1.1 × 10(-16) to 4.1 × 10⁻7). Of all markers tested, only rs541458 in PICALM was shown to have an effect on CSF protein levels, suggesting that the AD risk allele is associated with decreased CSF Aß42 levels (2-tailed P = .002). CONCLUSIONS: This study provides compelling independent evidence that genetic variants in CLU, CR1, and PICALM are genetically associated with risk for AD. Furthermore, the CSF biomarker analyses provide a first insight into the potentially predominant pathogenetic mechanism(s) underlying the association between AD risk and PICALM.

Do activities of cytochrome P450 (CYP)3A, CYP2D6 and P-glycoprotein differ between healthy volunteers and HIV-infected patients?

BACKGROUND: In inflammation and infection, cytochrome P450 (CYP) enzyme activities are down-regulated. Information on possible discrepancies in activities of CYP enzymes and drug transporters between HIV-infected patients and healthy people is limited. METHODS: We used midazolam, dextromethorphan and digoxin as in vivo phenotyping probes for CYP3A (CYP3A4/5), CYP2D6 and P-glycoprotein activities, respectively, and compared these activities between 12 healthy Caucasian volunteers and 30 treatment-naive HIV-infected patients. RESULTS: Among the HIV-infected patients, the overall CYP3A activity (apparent oral midazolam clearance) was approximately 50% of the activity observed in healthy volunteers (point estimate 0.490, 90% confidence interval [CI] 0.377-0.638). The CYP2D6 activity (plasma ratio area under the curve [AUC]; AUC(dextromethorphan)/AUC(dextrorphan)) was essentially unchanged (point estimate 1.289, 90% CI 0.778-2.136). P-glycoprotein activity was slightly lower in patients (digoxin maximum concentration point estimate 1.304, 90% CI 1.034-1.644). CONCLUSIONS: The overall CYP3A activity was approximately 50% lower in HIV-infected patients than in healthy volunteers. The CYP2D6 activity was highly variable, but, on average was not different between groups, whereas a marginally lower P-glycoprotein activity was observed in treatment-naive HIV-infected patients.

Impact of CYP2C8 and 2C9 polymorphisms on coronary artery disease and myocardial infarction in the LURIC cohort.

AIMS: As data on the cardiovascular risk associated with CYP2C8 and CYP2C9 polymorphisms is controversial, we performed a cross-sectional analysis of subjects enrolled in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. MATERIALS & METHODS: CYP2C8 and CYP2C9 genetic polymorphisms were determined with real-time PCR in 2827 patients. Based on angiography, 1052 of these patients had coronary artery disease (CAD) and 615 did not; 1160 patients had signs or a history of myocardial infarction (MI) in addition to CAD. The association of genotypes with CAD and MI was determined by logistic regression analysis, adjusted for age, sex, dyslipidemia, hypertension, diabetes mellitus and smoking status. RESULTS: Frequencies of CYP2C8 and 2C9 variants were neither significantly different between CAD and control patients, nor between MI and control patients. Men carrying the CYP2C9*3 allele had an increased risk of MI (odds ratio [OR]: 1.67; 95% CI: 1.06-2.63; p = 0.03) and women carrying the CYP2C9*3 allele had a decreased risk of CAD (OR: 0.65; 95%CI: 0.42-0.9; p = 0.05). CONCLUSION: Overall, LURIC data confirmed that there is no major cardiovascular risk associated with CYP2C8 and CYP2C9 variants in a cardiovascular risk population of patients having undergone coronary angiography.

Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency.

OBJECTIVE: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug-metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. DESIGN: We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. METHODS: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. We also performed genotyping for variant CYP alleles known to affect drug metabolism. RESULTS: Though CYP enzyme genotyping predicted normal or high enzymatic activities in both subjects, in vivo assessment showed subnormal activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in the patient and of CYP1A2 and CYP2C9 in her mother. CONCLUSIONS: Our results provide in vivo evidence for an important role of POR in regulating drug metabolism and detoxification. In patients with ORD, in vivo assessment of drug-metabolizing activities with subsequent tailoring of drug therapy and steroid replacement should be considered.

A systematic review of cost-effectiveness analyses of pharmacogenetic-guided dosing in treatment with coumarin derivatives.

Anticoagulant therapy with coumarin derivatives is often sub- or supra-therapeutic, resulting in an increased risk of thromboembolic events or hemorrhage, respectively. Pharmacogenetic-guided dosing has been proposed as an effective way of reducing bleeding rates. Clinical trials to confirm the safety, efficacy and effectiveness of this strategy are ongoing, but in addition, it is also necessary to consider the cost-effectiveness of this strategy. This article describes the findings of a systematic review of published cost-effectiveness analyses of pharmacogenetic-guided dosing of coumarin derivatives. Similarities and differences in the approaches used were examined and the quality of the analyses was assessed. The results of the analyses are not sufficient to determine whether or not pharmacogenetic-guided dosing of coumarins is cost effective. More reliable cost-effectiveness estimates need to become available before it is possible to recommend whether or not this strategy should be applied in clinical practice.

Pharmacogenetics in psychiatry--a useful clinical tool or wishful thinking for the future?

More than fifty years of pharmacogenetic research have produced many examples of the impact of inherited variability in the response to psychotropic drugs. These successes, however, have as yet failed to translate into broadly applicable strategies for the improvement of individual drug treatment in psychiatry. One important argument against the widespread adoption of pharmacogenetics as a clinical tool is the lack of evidence showing its impact on medical decision making and on risk benefit ratio for the patients. The individual drug metabolizing capacity is assessed by genotyping drug metabolizing enzymes. The potential implications of information gained from genotyping are dose adjustments according to genotype. However, even when the consequences of genotype on pharmacokinetics are significant and well known, as in the case of many tricyclic antidepressants and several SSRIs, there is still considerable controversy on whether adjustment of dosage driven by genetic information may improve therapeutic efficacy, and/or adverse events is prevented, to an extent of any practical importance in clinical practice. Different types of pharmacogenetic studies may improve our understanding of the functional consequence of a genetic variant in the clinical setting. The use of intermediate phenotypes instead of broad outcome parameters such as drug response or remission might improve our knowledge on what exactly happens if an individual with a specific genotype takes a certain drug. Here, we review the potential impact of an integrated approach, including the assessment of intermediate phenotypes for the effect of genetic polymorphism, the monitoring of therapy progress, and response prediction in depression.

Human lymphoblastoid cell line panels: novel tools for assessing shared drug pathways.

AIMS: While powerful in silico tools are emerging for predicting drug targets and pathways, general in vitro tools for assessing such predictions are lacking. We present a novel in vitro method for distinguishing shared versus distinct drug pathways based on comparative cell growth inhibition profiles across a small panel of human lymphoblastoid cell lines (LCLs) from individual donors. MATERIALS & METHODS: LCLs from unrelated healthy donors were examined in parallel for growth inhibition profiles of various drugs, including antidepressants (paroxetine, fluoxetine, fluvoxamine, citalopram, amitriptyline and imipramine); anticancer drugs (5-fluorouracil, 6-mercaptopurine, azathioprine, methotrexate and resveratrol); steroid drugs (dexamethasone, beclomethasone and prednisolone); and antipsychotic drugs (haloperidol and clozapine). Cell growth was assessed by the colorimetric 2,3-bis(2-methoxy-4-nitro-5-sulfophenly)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide method following 72 h of drug exposure. RESULTS: LCLs from unrelated individuals exhibited a wide range of sensitivities to growth inhibition by a given drug, which were independent of basal cell replication rates. Yet, each individual cell line demonstrated a consistent sensitivity to multiple drugs from the same family. High goodness-of-fit values (R(2) > 0.6) were consistently observed for plots comparing the growth-inhibition profiles for paired drugs sharing a similar pathway, for example antidepressants, steroid drugs, antipsychotics, or 6-mercaptopurine compared with azathioprine, but not for drugs with different pathways. The method's utility is demonstrated by the observation that chlorpheniramine, an antihistamine drug long suspected to also possess antidepressant-like properties, exhibits a growth-inhibition profile very similar to antidepressants. CONCLUSION: Comparing the growth-inhibition profiles of drugs (or compounds) of interest with the profiles of drugs with known pathways may assist in drug pathway classification. The method is useful for in vitro assessment of in silico-generated drug pathway predictions and for distinguishing shared versus distinct pathways for compounds of interest. Comparative transcriptomics analysis of human lymphoblastoid cell lines exhibiting 'edge' sensitivities can subsequently be utilized in the search for drug response biomarkers for personalized pharmacotherapy. The limitations and advantages of the method are discussed.

Baseline brain perfusion and the serotonin transporter promoter polymorphism.

BACKGROUND: The serotonin transporter length repeat polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) has been associated in healthy subjects with changes in basal perfusion levels in the limbic system and ventral prefrontal areas, regions involved in the pathophysiology of depression and anxiety, suggesting the existence of a neurobiological trait predisposing to these disorders. We reassess the findings of an increased baseline perfusion in the amygdala and ventral prefrontal areas in healthy carriers of the risk genotype in a much larger sample than in previous studies. METHODS: A cohort of 183 healthy European individuals underwent perfusion imaging with continuous arterial spin-labeling (CASL) while resting quietly in the scanner for 8 minutes. Participants were genotyped to assess the occurrence of the short allele and the Lg and La variants of the long repeat. RESULTS: No association between the 5-HTTLPR polymorphism and baseline brain perfusion was detected in the regions of interest or elsewhere in the brain. In the amygdala, variability in baseline perfusion was explained in large part by global cerebral flow levels (between 50% and 55%), in minor part by sex (between 4% and 5%), but not by genotype (less than .5%). Power analyses showed that the study was of sufficient size to be informative. CONCLUSIONS: The findings did not confirm the existence of a biological marker of the effect of 5-HTTLPR polymorphism in the amygdala or in the orbitofrontal cortex.

Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design.

The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogenetic-guided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.

Sex-specific differences in side effects of psychotropic drugs: genes or gender?

Sex differences observed in the adverse effects associated with psychotropic drugs have not been reported consistently in the literature. In this review, we discuss the current published data on sex differences observed in the occurrence, symptomatology and reporting of the adverse effects associated with psychotropic drug effects, and discuss their clinical relevance. We reviewed the published data up to April 2009 on sex differences in the side effects of antipsychotics, antidepressant and mood stabilizers, by systematically searching PubMed using combinations of search terms and retrieving relevant references specifically reporting on these issues. The majority of the data was retrieved from clinical studies where the main outcome parameters did not relate specifically to sex differences. In most instances, sex was associated with other factors influencing side effects such as age, disease and body weight. Sex-related differences were reported in the side effects associated with antipsychotic drug-induced weight gain and metabolic syndrome, symptoms of sexual dysfunction caused by antidepressants and antipsychotic drugs and cardiac arrhythmic side effects associated with antipsychotic drugs. Women might differ from men not only in incidence but also in the presentation of clinical symptoms associated with adverse psychotropic drug effects. Clinicians should be made aware of the differences reported in the literature regarding the symptomatology, severity and recognition of the adverse psychotropic drug effects found in men and women.

The role of human CYP2C8 and CYP2C9 variants in pioglitazone metabolism in vitro.

The cytochrome P450 enzyme CYP2C8 appears to have a major role in pioglitazone metabolism. The present study was conducted to further clarify the role of individual CYPs and of the CYP2C8/9 polymorphisms in the primary metabolism of pioglitazone in vitro. Pioglitazone (2-400 microM) was incubated with isolated cytochrome P450 enzymes or human liver microsomes, some of them carrying either the CYP2C8*3/*3 genotype (and also the CYP2C9*2/*2 genotype) or the CYP2C8*1/*1 genotype (five samples each). The formation of the primary pioglitazone metabolite M-IV was monitored by HPLC. Enzyme kinetics were estimated assuming a single binding site. Mean intrinsic clearance of pioglitazone to the metabolite M-IV was highest for CYP2C8 and CYP1A2 with 58 pmol M-IV/min/nmol CYP P450/microM pioglitazone each, 53 for CYP2D6*1, 40 for CYP2C19*1, and 34 for CYP2C9*2, respectively. CYP2A6, CYP2B6, CYP2C9*1, CYP2C9*3, CYP2E1, CYP3A4 and CYP3A5 did not form quantifiable amounts of M-IV. CYP2C8*1/*1 microsomes (25 +/- 4 pmol M-IV/min/mg protein/muM pioglitazone) showed lower intrinsic clearance of pioglitazone than CYP2C8*3/*3 microsomes (35 +/- 9, p = 0.04). In all samples, metabolite formation showed substrate inhibition, while pioglitazone did not inhibit CYP2C8-mediated paclitaxel metabolism. CYP2C8, CYP1A2 and CYP2D6 are major CYPs forming M-IV in vitro. The higher activity of CYP2C8*3/CYP2C9*2 microsomes may result from a contribution of CYP2C9*2, or from differences in CYP2C8 expression. The evidence for substrate-specific inhibitory effects of pioglitazone on CYP2C-mediated metabolism needs to be tested in further studies.

Drug monitoring in child and adolescent psychiatry for improved efficacy and safety of psychopharmacotherapy.

Most psychotropic drugs used in the treatment of children and adolescents are applied "off label" with a direct risk of under- or overdosing and a delayed risk of long-term side effects. The selection of doses in paediatric psychiatric patients requires a consideration of pharmacokinetic parameters and the development of central nervous system, and warrants specific studies in children and adolescents. Because these are lacking for most of the psychotropic drugs applied in the Child and Adolescent and Psychiatry, therapeutic drug monitoring (TDM) is a valid tool to optimise pharmacotherapy and to enable to adjust the dosage of drugs according to the characteristics of the individual patient. Multi-centre TDM studies enable the identification of age- and development-dependent therapeutic ranges of blood concentrations and facilitate a highly qualified standardized documentation in the child and adolescent health care system. In addition, they will provide data for future research on psychopharmacological treatment in children and adolescents, as a baseline for example for clinically relevant interactions with various co-medications. Therefore, a German-Austrian-Swiss "Competence Network on Therapeutic Drug Monitoring in Child and Adolescent Psychiatry" was founded 1 introducing a comprehensive internet data base for the collection of demographic, safety and efficacy data as well as blood concentrations of psychotropic drugs in children and adolescents.

CYP2D6 genotyping for psychiatric patients treated with risperidone: considerations for cost-effectiveness studies.

In order to ascertain data availability and feasibility for conducting cost-effectiveness studies in pharmacogenetics, and as part of a European Commission Joint Research Center, Institute for Prospective Technological Studies (JRC-IPTS) study, data concerning risperidone use and cytochrome P450 (CYP2D6) genotyping in medical care was collected in Germany, Spain and the USA, and are summarized in this perspective. The gene coding for CYP2D6 is highly polymorphic, resulting in a significant part of the population being poor metabolizers and ultrarapid metabolizers. Individuals who are CYP2D6 poor metabolizers, have an increased risk of adverse drug reactions (ADRs) when treated with CYP2D6-metabolized drugs, suggesting that CYP2D6 genotyping might be beneficial for patient care. This might be especially important in psychiatry, where approximately 50% of the patients use at least one drug primarily metabolized by CYP2D6. In particular, ADRs and poor response to treatment are major problems for some antipsychotics, including risperidone. However, there are no published cost-effectiveness studies on CYP2D6 genotyping, and the benefit that pharmacogenetic testing might represent by identifying problematic patients is still unclear. The present European Commission study found that current clinical and economical data concerning the frequency and direct healthcare costs of risperidone-related ADRs, the relation of such ADRs with the patients CYP2D6 genotypes, and costs for CYP2D6 genotyping, are not sufficient for determining if routine CYP2D6 genotyping might be cost beneficial for patients treated with risperidone. Therefore, efforts should be put on performing prospective cost-benefit studies with randomized treatment according to the CYP2D6 genotype to establish the utility of CYP2D6 genotyping for personalizing antipsychotic treatment.

Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism.

BACKGROUND: Both atorvastatin and rifampicin are substrates of OATP1B1 (organic anion transporting polypeptide 1B1) encoded by SLCO1B1 gene. Rifampicin is a potent inhibitor of SLCO1B1 (IC50 1.5 umol/l) and SLCO1B1 521T>C functional genetic polymorphism alters the kinetics of atorvastatin in vivo. We hypothesize that rifampicin might influence atorvastatin kinetics in a SLCO1B1 polymorphism dependent manner. METHODS: Sixteen subjects with known SLCO1B1 genotypes (6 c.521TT, 6 c.521TC and 4 c.521CC) were divided into 2 groups (atorvastatin-placebo group, n=8; atorvastatin-rifampicin group, n=8) randomly. In this 2-phase crossover study, atorvastatin (40 mg single-oral dose) pharmacokinetics after co-administration of placebo and rifampicin (600 mg single-oral dose) were measured for up to 48 h by liquid chromatography-mass spectrometry (LC-MS). In the third phase, rifampicin (450 mg single-oral dose) pharmacokinetics was measured additionally. RESULTS: Rifampicin increased atorvastatin plasma concentration in accordance with SLCO1B1 521T>C genotype while the increasing percentage of AUC((0-48)) among c.521TT, c.521TC and c.521CC individuals were 833+/-245% vs 468+/-233% vs 330+/-223% (P=0.007). However, SLCO1B1 521T>C exerted no impact on rifampicin pharmacokinetics (P>0.05). CONCLUSIONS: These results suggested that rifampicin elevated the plasma concentration of atorvastatin depending on SLCO1B1 genotype and rifampicin pharmacokinetics were not altered by SLCO1B1 genotype.

Determination of CYP2D6 gene copy number by multiplex polymerase chain reaction analysis.

Cytochrome P450 2D6 (CYP2D6) copy number variation (CNV) influences the metabolism of 15-25% of clinical drugs. Here we describe a novel multiplex polymerase chain reaction (PCR) analysis method that accurately detects CYP2D6 CNV and CYP2D6*9 allele. It includes the amplification of 2 CYP2D6 and 7 control (AQP1, CYP3A4, MDR1, and SDHB) fluorescent PCR products that are separated on a capillary sequencer and normalized using reference samples. The technique was validated using 27 PCR-restriction fragment length polymorphism (RFLP) pregenotyped samples and further tested in 75 Caucasian samples. The method assigns the correct CYP2D6 copy number, independent of already characterized CYP2D6 single nucleotide polymorphisms (SNPs), and could easily be applied to clinical samples.

Cytochrome P450 2D6 genotyping: potential role in improving treatment outcomes in psychiatric disorders.

The specific reaction toward a given drug varies a lot between individuals and, for many drugs, pharmacogenetic polymorphisms are known to affect biotransformation and clinical outcome. Estimation of the individual's drug-metabolizing capacity can be undertaken by genotyping drug-metabolizing enzymes involved in the respective drug metabolism. Consequences that arise from genotyping may be the adjustment of dose according to genotype, choice of therapeutic strategy, or even choice of drug. One of the first fields where the clinical application of pharmacogenetics may be used is in that of antipsychotic and antidepressant drug treatment because there is a special need for individualized therapy in psychiatry. The pharmacokinetics of many TCAs, some SSRIs and other antidepressant drugs is significantly altered by polymorphisms; however, some controversy still exists as to whether therapeutic efficacy may be improved and/or adverse events can be prevented by genetically driven adjustment of drug dosage. Pharmacogenetic diagnostics may be an important factor in individualizing drug treatment according to the genetic make-up of the patients. However, routine application of pharmacogenetic dose adjustment in clinical practice requires prospective validation.

In vivo role of cytochrome P450 2E1 and glutathione-S-transferase activity for acrylamide toxicokinetics in humans.

Acrylamide, a potential food carcinogen in humans, is biotransformed to the epoxide glycidamide in vivo. Both acrylamide and glycidamide are conjugated with glutathione, possibly via glutathione-S-transferases (GST), and bind covalently to proteins and nucleic acids. We investigated acrylamide toxicokinetics in 16 healthy volunteers in a four-period change-over trial and evaluated the respective role of cytochrome P450 2E1 (CYP2E1) and GSTs. Participants ingested self-prepared potato chips containing acrylamide (1 mg) without comedication, after CYP2E1 inhibition (500 mg disulfiram, single dose) or induction (48 g/d ethanol for 1 week), and were phenotyped for CYP2E1 with chlorzoxazone (250 mg, single dose). Unchanged acrylamide and the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA) and N-acetyl-S-(2-hydroxy-2-carbamoylethyl)-cysteine (GAMA) accounted for urinary excretion [geometric mean (percent coefficient of variation)] of 2.9% (42), 65% (23), and 1.7% (65) of the acrylamide dose in the reference period. Hemoglobin adducts increased clearly following the acrylamide test-meal. The cumulative amounts of acrylamide, AAMA, and GAMA excreted and increases in AA adducts changed significantly during CYP2E1 blockade [point estimate (90% confidence interval)] to the 1.34-fold (1.14-1.58), 1.18-fold (1.02-1.36), 0.44-fold (0.31-0.61), and 1.08-fold (1.02-1.15) of the reference period, respectively, but were not changed significantly during moderate CYP2E1 induction. Individual baseline CYP2E1 activity, CYP2E1*6, GSTP1 313A>G and 341T>C single nucleotide polymorphisms, and GSTM1-and GSTT1-null genotypes had no major effect on acrylamide disposition. The changes in acrylamide toxicokinetics upon CYP2E1 blockade provide evidence that CYP2E1 is a major but not the only enzyme mediating acrylamide epoxidation in vivo to glycidamide in humans. No obvious genetic risks or protective factors in xenobiotic-metabolizing enzymes could be determined for exposed subjects.

Relative potency of proton-pump inhibitors-comparison of effects on intragastric pH.

AIM: Comparative potency of proton-pump inhibitors (PPIs) is an important clinical issue. Most available trials have compared the different PPIs at one or a few selected specific dosages, making it difficult to derive quantitative equivalence dosages. Here we derived PPI dose equivalents based on a comprehensive assessment of dose-dependent effects on intragastric pH. METHODS: All available clinical studies reporting the effects of PPIs on mean 24-h intragastric pH were sought from electronic databases including Medline. Studies included were restricted to those targeting the Caucasian population, and healthy volunteers or gastroesophageal reflux disease (GERD) patients. The dose-effect relationships for mean 24-h intragastric pH and for percentage of time with pH > 4 in 24 h were analyzed for each PPI using pharmacodynamic modeling with NONMEM and a model integrating all available data. RESULTS: Fifty-seven studies fulfilled the inclusion criteria. Based on the mean 24-h gastric pH, the relative potencies of the five PPIs compared to omeprazole were 0.23, 0.90, 1.00, 1.60, and 1.82 for pantoprazole, lansoprazole, omeprazole, esomeprazole, and rabeprazole, respectively. Compared with healthy volunteers, patients with GERD needed a 1.9-fold higher dose and Helicobacter pylori-positive individuals needed only about 20% of the dose to achieve a given increase in mean 24-h intragastric pH. CONCLUSION: The present meta-analysis provides quantitative estimates on clinical potency of individual PPIs that may be helpful when switching between PPIs and for assessing the cost-effectiveness of specific PPIs. However, our estimates must be viewed with caution because only a limited dose range has been tested and not exactly the same study conditions were applied for the different substances.

Pharmacogenetics-guided dose modifications of antidepressants.

The efficacy of a drug therapy is influenced by many different factors, such as age, weight, comorbidity, and comedication, which vary among patients, as do the fixed parameters of sex and genotype. Enzymes involved in drug metabolism are genetically polymorphic, meaning that their activities differ depending on certain genotypes. Drugs are metabolized slowly in individuals carrying a genetic polymorphism that causes absent or decreased enzyme activity, and these individuals are at an increased risk for adverse drug reactions or therapeutic failure. However, drug therapy could be ineffective if the drug is metabolized too quickly because of a genetic polymorphism. Knowledge of these polymorphisms before beginning a drug therapy could help in choosing the right agent at a safe dosage, especially those with a narrow therapeutic index and a high risk for the development of adverse drug effects. Particularly, two polymorphic drug metabolizing enzymes, belonging to the cytochrome P450 (CYP) family, are responsible for the metabolism of many antidepressant drugs: CYP2D6 and CYP2C19. In addition to antidepressive drugs, several drugs used in cancer therapy, beta-blockers, proton pump inhibitors, and opioid analgesics are metabolized by these enzymes.