CYP2D6 Phenotype Research Articles

Aberrant CYP2D6 metabolizer phenotypes do not show increased frequency in patients undergoing ECT after antidepressant therapy.

We investigated the accumulation of aberrant CYP2D6 genotypes and predicted metabolizer phenotypes (ultrarapid metabolizer, intermediate metabolizer and poor metabolizer) potentially affecting the antidepressant treatment response in depressive patients indicated for electroconvulsive therapy (ECT) compared with patients with a single episode of depression. Seventy-six Dutch White patients with unipolar or bipolar treatment-resistant depression who underwent ECT were genotyped using the Amplichip CYP450 Test for CYP2D6. Two hundred and eight patients with a single episode of unipolar or bipolar depression were used as controls. No difference was observed in the prevalence of CYP2D6 phenotypes (poor metabolizer, intermediate metabolizer, extensive metabolizer and ultrarapid metabolizer) between the ECT and the control patients (5.3, 38.7, 56.0 and 0.0% vs. 6.4, 51.0, 42.6 and 0.0%, respectively). The types of depression (odds ratio = 0.33, P = 0.018) and age (odds ratio = 1.55 for a 10-year increase, P < 0.001), but not CYP2D6 phenotype or activity score were associated with the response to antidepressant treatment. In conclusion, preemptive genotyping for CYP2D6 currently appears to have no clinical implications in treatment-resistant depressive patients indicated for ECT.

No influence of CYP2D6*10 genotype and phenotype on the pharmacokinetics of nebivolol in healthy Chinese subjects.

Nebivolol, a clinically important antihypertensive drug, mainly metabolized by cytochrome P450 (CYP) 2D6, shows wide interindividual variability in pharmacokinetics. The CYP2D6*10 allele (100C>T; rs1065852), present at a high frequency in the Chinese population, is associated with alteration in the pharmacokinetics of many drugs, but its effect on the pharmacokinetics of nebivolol is unknown. The aim of our study was to investigate whether the CYP2D6*10 genotype and phenotype are associated with changes in the pharmacokinetics of nebivolol in Chinese subjects. Twenty-four healthy subjects were divided into three groups according to CYP2D6*1/*1 (n=7), CYP2D6*1/*10 (n=5) and CYP2D6*10/*10 (n=12) genotypes. The *1/*1 homozygotes and *1/*10 heterozygotes were C allele carriers. All subjects received oral single dose of nebivolol and dextromethorphan. Blood and urine samples were gathered at various times. There were no statistically significant differences in the pharmacokinetics of nebivolol between the three CYP2D6*10 genotypes, and no gene-dose effect was seen. The pharmacokinetic parameters of CYP2D6*10/*10 subjects were also similar to those of CYP2D6*1 carriers. A weak relationship between CYP2D6 phenotype and nebivolol clearance was found. The CYP2D6*10 genotype and phenotype were not associated with significant alterations in the pharmacokinetics of nebivolol. CYP2D6*10 alone does not account for the large interindividual differences observed in the disposition of nebivolol among Chinese healthy subjects.

Characterization of the CYP2D6 drug metabolizing phenotypes of the Chilean mestizo population through polymorphism analyses

We tested the influence of four polymorphisms and gene duplication in CYP2D6 on in vivo enzyme activity in a Chilean mestizo population in order to identify the most relevant genetic profiles that account for observed phenotypes in this ethnic group.CYP2D6*2 (2850C>T), *3 (2549A>del), *4 (1846G>A), *17 (1023C>T) and gene duplication were determined by PCR-RFLP or PCRL in a group of 321 healthy volunteers. Individuals with different variant alleles were phenotyped by determining debrisoquine 4-hydroxylase activity as a metabolic ratio (MR) using a validated HPLC assay.Minor allele frequencies were 0.41, 0.01, 0.12 and 0.00 for CYP2D6*2, *3, *4 and *17 variants, respectively, and the duplication frequency was 0.003. Genotype analysis correlated with phenotypes in 18 of 23 subjects (78.3%). 11 subjects were extensive metabolizers (EM), 8 were intermediate metabolizers (IM), 2 were poor metabolizers (PM) and 2 were ultra-rapid metabolizers (UM) which is fairly coincident with expected phenotypes metabolic ratios ranged from 0.11 to 126.41. The influence of CYP2D6*3 was particularly notable, although only heterozygote carriers were present in our population. Individuals homozygous for *4 were always PM. As expected, the only subject with gene duplication was UM.In conclusion, there was a clear effect of genotype on observed CYP2D6 activity. Classification of EM, PM and UM through genotyping was useful to characterize CYP2D6 phenotype in the Chilean mestizo population.

Effects of Cytochrome P450 Inhibition and Induction on the Phenotyping Metrics of the Basel Cocktail: A Randomized Crossover Study.

Background and ObjectiveActivity of human cytochrome P450 enzymes (CYPs) shows high inter-and intra-individual variability, which is determined by genetic and non-genetic factors. Using a combination of CYP-specific probe drugs, phenotyping cocktails allow simultaneous assessment of the activity of different CYP isoforms. The objective of this study was to characterize the phenotyping metrics of the Basel cocktail in healthy male subjects with induced and inhibited CYP activity.MethodsIn a randomized crossover study, the probe drugs for simultaneous phenotyping of CYP1A2 (caffeine), CYP2B6 (efavirenz), CYP2C9 (losartan), 2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A4 (midazolam) were administered to 16 subjects without pretreatment (baseline), after pretreatment with a combination of CYP inhibitors (ciprofloxacin, ketoconazole, and paroxetine), and after CYP induction with rifampicin. All subjects were genotyped. Pharmacokinetic profiles of the probe drugs and their main metabolites and metabolic ratios 2, 4, 6, and 8 h after probe drug application were determined in plasma and compared with the corresponding area under the plasma concentration-time curve (AUC) ratios.ResultsThe Basel phenotyping cocktail was well tolerated by all subjects independent of pretreatment. Good correlations of metabolic ratios with AUC ratios of the corresponding probe drugs and their metabolites for all three conditions (baseline, CYP inhibition, and CYP induction) were found at 2 h after probe drug administration for CYP3A4, at 4 h for CYP1A2 and CYP2C19, and at 6 h for CYP2B6 and CYP2D6. While CYP inhibition significantly changed AUC ratios and metabolic ratios at these time points for all six CYP isoforms, CYP induction did not significantly change AUC ratios for CYP2C9. For CYP3A4, total 1′-hydroxymidazolam concentrations after pretreatment of samples with β-glucuronidase were needed to obtain adequate reflection of CYP induction by the metabolic ratio.ConclusionsInhibition of CYP activity can be detected with the Basel phenotyping cocktail for all six tested CYP isoforms at the proposed time points. The AUC ratio of losartan:losartan carboxylic acid in plasma does not seem suitable to detect induction of CYP2C9. The observed metabolic ratios for inhibited and induced CYP activity need to be confirmed for extensive metabolizers, and typical ratios for subjects with genetically altered CYP activity will need to be established in subsequent studies.ClinicalTrials.gov-ID: NCT01386593.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-015-0294-y) contains supplementary material, which is available to authorized users.

Screening for endogenous substrates reveals that CYP2D6 is a 5-methoxyindolethylamine O-demethylase.

The objective of this investigation was to screen for potential endogenous substrates for CYP2D6. Using recombinant CYP2D6, together with hepatic microsomes from CYP2D6-transgenic mice, human liver microsomes, and a specific anti-CYP2D6 monoclonal antibody, it was ascertained that CYP2D6 does not significantly metabolize the endogenous phenylethylamines 2-phenylethylamine, octopamine, synephrine, 3-methoxy-p-tyramine, 4-methoxy-m-tyramine, metanephrine, and normetanephrine, nor the indolethylamines tryptamine, serotonin, 6-methoxytryptamine, and melatonin, nor the beta-carbolines harman, norharman and tryptoline. However, the indolethylamines 5-methoxy-N,N-dimethyltryptamine (5-MDMT) and pinoline (6-methoxy-1,2,3,4-tetrahydro-beta-carboline) showed relatively high affinity for CYP2D6 in a spectral binding assay (K(s) 28 +/- 5, and 0.5 +/- 0.3 microm (mean +/- SEM), respectively) and were O-demethylated only by CYP2D6 in a panel of 15 recombinant common human P450s. Pinoline and 5-MDMT O-demethylase activities were 35- and 11-fold greater in liver microsomes from CYP2D6-humanized mice, respectively, than those in liver microsomes from control mice. Moreover, the increased activities were completely inhibited by an anti-CYP2D6 monoclonal antibody. Kinetic analysis with recombinant CYP2D6 gave K(m) and k(cat) values for 5-MDMT and pinoline O-demethylations of 12 +/- 1 microm and 65 +/- 1 min(-1) and 1.8 +/- 0.3 microm and 26 +/- 1 min(-1), respectively. These two substrates can be added to 5-methoxytryptamine, which we have recently reported to be an endogenous CYP2D6 substrate. CYP2D6 is therefore a relatively highly specific, high-affinity, high-capacity 5-methoxyindolethylamine O-demethylase. Polymorphic cytochrome CYP2D6 may therefore exert an influence on mood and behavior by the O-demethylation of these 5-methoxyindolethylamines found in the brain and pineal gland. These processes may also impact on mental and neurological health. The findings may open new vistas for the determination of CYP2D6 phenotype.

Further characterization of a 13C-dextromethorphan breath test for CYP2D6 phenotyping in breast cancer patients on tamoxifen therapy

In a previous study, we found that the CYP2D6 phenotype determined by 13C-dextromethorphan breath test (DM-BT) might be used to predict tamoxifen treatment outcome in breast cancer patients in the adjuvant setting. However, large variation in the delta-over-baseline (DOB) values was observed in the extensive metabolizer predicted phenotype group based on single point measures. In the present work we aimed to analyze the variability of phenotype results and determine reproducibility to further characterize the clinical utility of DM-BT by introducing multiple breath sampling instead of single breath sampling and by administration of a fixed dose of 13C-DM.

Influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers

Conversion of ibogaine to its active metabolite noribogaine appears to be mediated primarily by CYP2D6. We compared 168 hours pharmacokinetic profiles of both analytes after a single oral 20 mg dose of ibogaine in 21 healthy subjects who had been pretreated for 6 days with placebo or the CYP2D6 inhibitor paroxetine. In placebo-pretreated subjects, ibogaine was rapidly converted to noribogaine. Median peak noribogaine concentrations occurred at 4 hours. Compared with placebo-pretreated subjects, paroxetine-pretreated subjects had rapid (Tmax = 1.5 hours) and substantial absorption of ibogaine, with detectable levels out to 72 hours, and an elimination half-life of 10.2 hours. In this group, ibogaine was also rapidly converted to noribogaine with a median Tmax of 3 hours. Extent of noribogaine exposure was similar in both groups. CYP2D6 phenotype was robustly correlated with ibogaine AUC0-t (r = 0.82) and Cmax (r = 0.77). Active moiety (ibogaine plus noribogaine) exposure was ∼2-fold higher in paroxetine-pretreated subjects. Single 20 mg ibogaine doses were safe and well tolerated in all subjects. The doubling of exposure to active moiety in subjects with reduced CYP2D6 activity suggests it may be prudent to genotype patients awaiting ibogaine treatment, and to at least halve the intended dose of ibogaine in CYP2D6 poor metabolizers.

The influences of CYP2D6 genotypes and drug interactions on the pharmacokinetics of venlafaxine: exploring predictive biomarkers for treatment outcomes.

Two biomarkers: concentration ratio of O-desmethylvenlafaxine/venlafaxine and concentration sum of venlafaxine + O-desmethylvenlafaxine were adopted to indicate venlafaxine responses, but neither is validated. To evaluate the ability of two biomarkers in reflecting venlafaxine pharmacokinetic variations, and to further examine their relationship with venlafaxine treatment outcomes. Two well-defined influencing factors: CYP2D6 genotypes and drug interactions were enriched into a three-period crossover study to produce venlafaxine pharmacokinetic variations: In each period, healthy CYP2D6 extensive metabolizers (EM group; n = 12) and CYP2D6*10/*10 intermediate metabolizers (IM group; n = 12) were pretreated with clarithromycin (CYP3A4 inhibitor), or nothing (control), or clarithromycin + paroxetine (CYP3A4 + CYP2D6 inhibitors), before administration of a single-dose of 75mg venlafaxine. Both biomarkers were evaluated (1) for their relationship with the influencing factors in healthy volunteers and (2) for their relationships with the venlafaxine responses/adverse events reported in two patient studies. Significant venlafaxine pharmacokinetic variations were observed between the EM and IM groups (geometric mean ratio [95% CI] of area under the curve, 3.0 [1.8-5.1] in the control period), and between the control and clarithromycin + paroxetine periods (4.1 [3.5-4.7] and 2.0 [1.7-2.4] in the EM and IM group, respectively). O-Desmethylvenlafaxine/venlafaxine was superior to venlafaxine + O-desmethylvenlafaxine to reflect the influencing factors. In the patient studies, O-desmethylvenlafaxine/venlafaxine > 4 showed high precision in predicting venlafaxine responders/partial-responders (92%) and patients without venlafaxine-related adverse events (88%); the O-desmethylvenlafaxine/venlafaxine < 4 and venlafaxine + O-desmethylvenlafaxine > 400ng/ml combination showed higher precision (100%) than O-desmethylvenlafaxine/venlafaxine < 4 alone (65%) in predicting venlafaxine non-responders. We propose using O-desmethylvenlafaxine/venlafaxine for CYP2D6 phenotyping, and O-desmethylvenlafaxine/venlafaxine with venlafaxine + O-desmethylvenlafaxine for predicting venlafaxine treatment outcomes in future prospective studies.

Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans

CYP2D6 differences have already been demonstrated within Latin American populations by the CEIBA.FP Consortium of the Ibero-American Network of Pharmacogenetics (RIBEF, as per the acronym in Spanish). However, within the population of Costa Rica, no research has been conducted until now, even though this population has a trihybrid component ancestry that represents an interesting condition. Thus, the present study was aimed to determine the frequency of Ultra-rapid Metabolizers (UMs) and Poor Metabolizers (PMs) in a Costa Rican population, as well as to determine whether there are differences in the CYP2D6-predicted phenotype frequencies among three Costa Rican groups with different ethnic backgrounds. Additionally, these frequencies of PMs and UMs obtained were compared with Ibero-American populations published data. Finally, we also aimed to describe allele frequencies among different Costa Rican ethnic groups. This research has been undertaken within the framework of the RIBEF CEIBA Consortium studies on Latin American populations. A total of 385 individuals were included in the study: 139 mestizos, 197 Amerindians, and 49 Afro-Caribbeans. CYP2D6 genotypes were determined by XL-PCR and Real-Time PCR. The CYP2D6 variant alleles *2, *3, *4, *5, *6, *10, "17, *29, *35 and *41 were also determined. For the entire Costa Rican population, the frequency of PMs and UMs was 6% and 6.5%, respectively. The percentage of UMs in the mestizo population was higher than in the Amerindian population. CYP2D6 UMs vary from 3.6% to 10.1% and PMs from 1.4% to 10.2% among three Costa Rican groups. The highest frequencies of UMs (10.1%) and PMs (10.2%) were found in the mestizo and Amerindian populations, respectively. In conclusion, the frequencies of UMs and PMs for CYP2D6 varied widely across the mestizo, Amerindian and Afro-Caribbean Costa Rican populations. Future research in this population should be oriented to identify new CYP2D6 variants through sequencing methods, as well as to determine CYP2D6 phenotype, in order to establish the phenotype-genotype relation. Finally, further studies involving genetic markers of ancestry are needed in the Costa Rican population.

Detection of an endogenous urinary biomarker associated with CYP2D6 activity using global metabolomics.

We sought to discover endogenous urinary biomarkers of human CYP2D6 activity. Healthy pediatric subjects (n = 189) were phenotyped using dextromethorphan and randomized for candidate biomarker selection and validation. Global urinary metabolomics was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. Candidate biomarkers were tested in adults receiving fluoxetine, a CYP2D6 inhibitor. A biomarker, M1 (m/z 444.3102) was correlated with CYP2D6 activity in both the pediatric training and validation sets. Poor metabolizers had undetectable levels of M1, whereas it was present in subjects with other phenotypes. In adult subjects, a 9.56-fold decrease in M1 abundance was observed during CYP2D6 inhibition. Identification and validation of M1 may provide a noninvasive means of CYP2D6 phenotyping.

Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen

Tamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen. We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non-linear mixed effects modelling. Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (P < 0.0001) explained 54% of the observed variability in endoxifen formation (inter-individual variability reduced from 55% to 25%). We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to assess separately the impact of CYP2D6 and CYP3A mediated drug-drug interactions with tamoxifen without the necessity of administering this anti-oestrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice.

Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer.

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R2: 53%, P<10−77). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Complex Disease–, Gene–, and Drug–Drug Interactions: Impacts of Renal Function, CYP2D6 Phenotype, and OCT2 Activity on Veliparib Pharmacokinetics

Veliparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, undergoes renal excretion and liver metabolism. This study quantitatively assessed the interactions of veliparib with metabolizing enzyme (CYP2D6) and transporter (OCT2) in disease settings (renal impairment). Veliparib in vitro metabolism was examined in human liver microsomes and recombinant enzymes carrying wild-type CYP2D6 or functional defect variants (CYP2D6*10 and *4). Plasma pharmacokinetics were evaluated in 27 patients with cancer. A parent-metabolite joint population model was developed to characterize veliparib and metabolite (M8) pharmacokinetics and to identify patient factors influencing veliparib disposition. A physiologically based pharmacokinetic model integrated with a mechanistic kidney module was developed to quantitatively predict the individual and combined effects of renal function, CYP2D6 phenotype, and OCT2 activity on veliparib pharmacokinetics. In vitro intrinsic clearance of CYP2D6.1 and CYP2D6.10 for veliparib metabolism were 0.055 and 0.017 μL/min/pmol CYP, respectively. Population mean values for veliparib oral clearance and M8 clearance were 13.3 and 8.6 L/h, respectively. Creatinine clearance was identified as the significant covariate on veliparib oral clearance. Moderate renal impairment, CYP2D6 poor metabolizer, and co-administration of OCT2 inhibitor (cimetidine) increased veliparib steady-state exposure by 80%, 20%, and 30%, respectively. These factors collectively led to >2-fold increase in veliparib exposure. Renal function (creatinine clearance) is a significant predictor for veliparib exposure in patients with cancer. Although a single factor (i.e., renal impairment, CYP2D6 deficiency, and reduced OCT2 activity) shows a moderate impact, they collectively could result in a significant and potentially clinically relevant increase in veliparib exposure.

Polymorphisms in CYP2D6 have a greater effect on variability of risperidone pharmacokinetics than gender.

Within-subject coefficient of variation (CVw ) plays a decisive role in the determination of sample size in bioequivalence clinical trials. Highly variable drugs may require the participation of a large number of subjects. The aim of this study was to investigate whether gender and polymorphisms in CYP2D6 affect the CVw of risperidone. Two single-dose, two-period crossover studies of risperidone (n=70) were reanalysed to calculate CVw for AUCt and Cmax . Subjects were classified into four different CYP2D6 phenotype groups [poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM)]. The effect of gender was evaluated in EM and IM. CVw was lower in PM (13.3% for AUCt and 10.9% for Cmax ) and UM (17.4% and 8.7%) than in EM (28.7% and 34.7%) and IM (33.2% and 27.3%). Variability was slightly lower in women (27.9% for AUCt and 25.7% for Cmax ) than in men (33.3% and 37.2%, respectively). Genetic polymorphisms affect within-subject variability more than gender and could considerably affect sample size calculation. Therefore, subjects participating in bioequivalence trials should be genotyped.

Impact of age on serum concentrations of venlafaxine and escitalopram in different CYP2D6 and CYP2C19 genotype subgroups.

The aim of the present study was to investigate the effect of age on venlafaxine and escitalopram serum concentrations in various cytochrome P450 (CYP) 2D6 and CYP2C19 genotype subgroups. Serum concentration measurements from CYP-genotyped patients treated with venlafaxine (n = 255) or escitalopram (n = 541) were collected retrospectively from a therapeutic drug monitoring database. Patients were divided into three CYP2D6 (venlafaxine) or CYP2C19 (escitalopram) phenotype subgroups according to inherited genotype, i.e., poor metabolizers (PMs), heterozygous extensive metabolizers (HEMs), and extensive metabolizers (EMs), and subsequently distributed into three age groups, i.e., <40 (control), 40-65, and >65 years. The effect of age on dose-adjusted serum concentrations (i.e., nmol/L/mg/day) of venlafaxine and escitalopram in each of the phenotype subgroups was evaluated by separate multivariate mixed model analyses. In CYP2D6 PMs, the mean dose-adjusted serum concentration of venlafaxine was 8-fold higher in patients >65 years compared with those <40 years (p < 0.001). In comparison, the respective age-related differences in mean dose-adjusted serum concentrations of venlafaxine were much less pronounced in CYP2D6 HEMs and EMs (<2-fold differences between age groups). A similar genotype-related effect of age was not observed for escitalopram (<1.5-fold age differences in all CYP2C19 subgroups). This study suggests that the effect of age on serum concentration of venlafaxine is dependent on CYP genotype, in contrast to escitalopram. Thus, to prevent potential side effects, it might be particularly relevant to consider CYP2D6 genotyping prior to initiation of venlafaxine treatment in older patients.

Personalized Oxycodone Dosing: Using Pharmacogenetic Testing and Clinical Pharmacokinetics to Reduce Toxicity Risk and Increase Effectiveness

To develop a framework for integrating pharmacogenetics with clinical pharmacokinetics for personalized oxycodone dosing based on a patient's CYP2D6 phenotype. Randomized, crossover, double-blind, placebo-controlled. Subjects were genotyped as CYP2D6 ultra-rapid metabolizer, extensive metabolizer, or poor metabolizer phenotypes. Five subjects from each phenotype were randomly selected for inclusion in our study. Studies were performed in silico. The subjects were male, age 26 years, height 181.2 cm, and weight 76.3 kg. They were healthy without comorbidities, and their medical examinations were normal. The trajectories of phenotype-specific plasma oxycodone concentration-time profiles were analyzed using weighted nonlinear least-squares regression with WinSAAM software. A global two-stage population-based model data analysis procedure was used to analyze the studies. Clinical pharmacokinetics were calculated using the R package cpk, eliminating the need to perform hand-calculations. Our study shows how clinicians can reduce risk and increase effectiveness for oxycodone dosing by (1) determining the patient's likely metabolic response through testing a patient's CYP2D6 phenotype, and (2) calculating clinical pharmacokinetics specific to the patient's CYP2D6 phenotype to design a personalized oxycodone dosing regimen. Personalized oxycodone dosing is a new tool for a clinician treating chronic pain patients requiring oxycodone. By expressing a patient's CYP2D6 phenotype pharmacokinetically, a clinician (at least theoretically) can improve the safety and efficacy of oxycodone and decrease the risk for iatrogenically induced overdose or death. Pharmacokinomics provides a general framework for the integration of pharmacogenetics with clinical pharmacokinetics into clinical practice for gene-based prescribing.

Incorporation of Flurbiprofen in a 4‐Drug Cytochrome P450 Phenotyping Cocktail

Incorporation of Flurbiprofen in a 4‐Drug Cytochrome <scp>P</scp>450 Phenotyping Cocktail

Development, validation and clinical application of a HPLC-FL method for CYP2D6 phenotyping in South Brazilian breast cancer patients

ObjectiveTo develop and validate a method for determination of dextromethorphan (DMT) and dextrorphan (DTP) in plasma samples using HPLC-FL and to apply it to CYP2D6 phenotyping of a population from the South of Brazil. MethodsSamples were prepared by hydrolysis and liquid–liquid extraction. Analysis was conducted in a reversed phase column, with isocratic elution and fluorescence detection. One hundred and forty patients being treated with tamoxifen were given 30mg of dextromethorphan and their CYP2D6 phenotypes were determined on the basis of [DMT]/[DTP] metabolic ratios in plasma samples collected after 3h. ResultsTotal chromatography running time was 12min. Precision (CV%) was below 9.7% and accuracy was between 92.1 and 106.9%. The lower limits of quantification were 1ngmL−1 for DMT and 10ngmL−1 for DTP. Mean extraction yield of analytes was 86.6%. Mean age of patients was 55.7years. Phenotype frequencies were as follows: 7.1% poor metabolizers, 13.6% intermediate metabolizers, 77.1% extensive metabolizers and 2.1 ultra-rapid metabolizers. Metabolic ratios for patients on strong (n=11) and weak (n=16) CYP2D6 activity inhibitors were different from each other and also different from ratios for patients not taking enzyme inhibitors (n=113). ConclusionsA sensitive method for determination of dextromethorphan and its metabolite in plasma samples was developed and successfully applied, providing evidence of the impact that CYP2D6 inhibitors have on the enzyme's metabolic capacity.

Variation in the CYP2D6 genotype is not associated with carvedilol dose changes in patients with heart failure

Carvedilol is the standard of care for heart failure (HF) patients. Carvedilol is partially metabolized by the highly polymorphic enzyme, CYP2D6. To reach an effective dose while avoiding adverse drug reactions (ADRs), testing of CYP2D6 genotype prior to carvedilol initiation may be considered. The objectives of this study were to determine CYP2D6 metabolic genotypes in an Israeli cohort of HF patients and to investigate the relationship between genotype, carvedilol dose and number of ADRs to determine the importance of CYP2D6 genotyping prior to treatment initiation. Ninety-three patients with HF on carvedilol were CYP2D6 genotyped and classified as poor (PM), intermediate (IM), extensive (EM) or ultrarapid (UM) metabolizers. Carvedilol dose and ADRs were calculated and correlated with genotype using linear regression statistic analysis. The distribution of the CYP2D6 phenotype in the Israeli population with HF is similar to the European general population. There were no significant differences of carvedilol dose and number of ADRs among genotype groups. Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose changes. Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose during therapy for patients with HF. The Israeli CYP2D6 phenotype distribution in HF patients was consistent with the frequency in the general European population.

Impact of CYP2D6 polymorphisms on clinical efficacy and tolerability of metoprolol tartrate.

Metoprolol is a selective β-1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme, CYP2D6. Our objective was to investigate the influence of CYP2D6 polymorphisms on efficacy and tolerability of metoprolol tartrate. 281 study participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes by using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (p-value <0.0001) with poor metabolizers & intermediate metabolizers showing greater HR reduction. However, blood pressure response and adverse effect rates were not significantly different by CYP2D6 phenotype. Other than a significant difference in heart rate response, CYP2D6 polymorphisms were not a determinant of the variability in response or tolerability to metoprolol.