CYP2D6 Phenotype Research Articles

The Use of In Vitro Data and Physiologically-Based Pharmacokinetic Modeling to Predict Drug Metabolite Exposure: Desipramine Exposure in Cytochrome P4502D6 Extensive and Poor Metabolizers Following Administration of Imipramine.

Major circulating drug metabolites can be as important as the drugs themselves in efficacy and safety, so establishing methods whereby exposure to major metabolites following administration of parent drug can be predicted is important. In this study, imipramine, a tricyclic antidepressant, and its major metabolite desipramine were selected as a model system to develop metabolite prediction methods. Imipramine undergoes N-demethylation to form the active metabolite desipramine, and both imipramine and desipramine are converted to hydroxylated metabolites by the polymorphic enzyme CYP2D6. The objective of the present study is to determine whether the human pharmacokinetics of desipramine following dosing of imipramine can be predicted using static and dynamic physiologically-based pharmacokinetic (PBPK) models from in vitro input data for CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) populations. The intrinsic metabolic clearances of parent drug and metabolite were estimated using human liver microsomes (CYP2D6 PM and EM) and hepatocytes. Passive diffusion clearance of desipramine, used in the estimation of availability of the metabolite, was predicted from passive permeability and hepatocyte surface area. The predicted area under the curve (AUCm/AUCp) of desipramine/imipramine was 12- to 20-fold higher in PM compared with EM subjects following i.v. or oral doses of imipramine using the static model. Moreover, the PBPK model was able to recover simultaneously plasma profiles of imipramine and desipramine in populations with different phenotypes of CYP2D6. This example suggested that mechanistic PBPK modeling combined with information obtained from in vitro studies can provide quantitative solutions to predict in vivo pharmacokinetics of drugs and major metabolites in a target human population.

A service improvement project to review prescribing information provided by general practitioners for new referrals to a UK National Health Service hospital pain clinic: potential implications of CYP2D6 enzyme inhibition.

Chronic pain is often managed using co-prescription of analgesics and adjuvants, with concomitant medication prescribed for comorbidities. Patients may have suboptimal response to some analgesics or be at risk of drug interactions or adverse drug reactions (ADRs) due to polypharmacy affecting CYP2D6 enzyme activity. The aim of the service improvement project was to determine the proportion of patients referred to a specialist pain service in the UK National Health Service (NHS) by general practitioners (GPs) who may be at risk of suboptimal analgesic response or ADRs due to CYP2D6 inhibition through polypharmacy. This was achieved by reviewing clinical prescribing information provided by GPs at time of referral. It was hoped that the findings could be used to aid clinical and prescribing decisions without conducting CYP2D6 genotyping or phenotyping. A review of letters from 250 patients referred to an NHS hospital pain service from GPs over a 3-month period was undertaken. Information about current and concomitant medications was analysed to identify the potential for CYP2D6 inhibition and adverse events. Letters failed to provide information about current pain medication for 20 (8%) patients or non-pain concomitant medication for 54 (21.6%) patients. Of 176 patients, 52 (29.5%) patients with information about non-pain concomitant medication had been prescribed at least one known CYP2D6 inhibitor. A total of 35 (19.9%) patients were identified as being at risk of an adverse drug reaction and 33 (18.75%) patients at risk of suboptimal analgesic response due to co-administration of CYP2D6 inhibitors. The review revealed the need for improved detail in GP referral letters used to transfer care to UK NHS hospital pain clinics. There is a need to consider an individual's CYP2D6 phenotype when prescribing analgesic prodrugs to manage persistent pain. Caution is needed when patients are co-prescribed codeine or tramadol with selective serotonin reuptake inhibitors (SSRIs).

Prediction of CYP2D6 phenotype from genotype across world populations

Purpose:Owing to its highly polymorphic nature and major contribution to the metabolism and bioactivation of numerous clinically used drugs, CYP2D6 is one of the most extensively studied drug-metabolizing enzymes and pharmacogenes. CYP2D6 alleles confer no, decreased, normal, or increased activity and cause a wide range of activity among individuals and between populations. However, there is no standard approach to translate diplotypes into predicted phenotype.Methods:We exploited CYP2D6 allele-frequency data that have been compiled for Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines (>60,000 subjects, 173 reports) in order to estimate genotype-predicted phenotype status across major world populations based on activity score (AS) assignments.Results:Allele frequencies vary considerably across the major ethnic groups predicting poor metabolizer status (AS = 0) between 0.4 and 5.4% across world populations. The prevalence of genotypic intermediate (AS = 0.5) and normal (AS = 1, 1.5, or 2) metabolizers ranges between 0.4 and 11% and between 67 and 90%, respectively. Finally, 1 to 21% of subjects (AS >2) are predicted to have ultrarapid metabolizer status.Conclusions:This comprehensive study summarizes allele frequencies, diplotypes, and predicted phenotype across major populations, providing a rich data resource for clinicians and researchers. Challenges of phenotype prediction from genotype data are highlighted and discussed.Genet Med19 1, 69–76.

Multigene and Drug Interaction Approach for Tamoxifen Metabolite Patterns Reveals Possible Involvement of CYP2C9, CYP2C19, and ABCB1.

Tamoxifen is metabolically activated to 4-hydroxytamoxifen and endoxifen by cytochrome P450 (CYP). CYP phenotypes have been correlated to tamoxifen outcomes, but few have considered drug interactions or combinations of genes. Fewer still have considered ABCB1, which encodes P-glycoprotein and transports active tamoxifen metabolites. We compared the concentrations of tamoxifen and metabolites in 116 breast cancer patients with predicted phenotypes for CYP2D6, CYP3A4, CYP3A5, CYP2C9, CYP2C19, and ABCB1 genotypes. A significant correlation between CYP2D6 phenotypes and tamoxifen metabolites was seen, strongest for endoxifen (P<.0001). Statistical fit of the data improved when using gene activity scores adjusted for known drug interactions. Concentration of tamoxifen was significantly higher (P = .02) for patients taking a CYP2C19 inhibitor. No significant relationships were found for other genes unless patients were subgrouped according to CYP2D6 phenotypes or ABCB1 genotypes. Lower concentrations of endoxifen and endoxifen/4-hydroxytamoxifen ratios were seen with impaired CYP2C9 (P = .05 and P = .03, respectively) if patients had the same CYP2D6 phenotype and were not taking a CYP2D6 or CYP2C19 inhibitor. Lower concentrations of 4-hydroxytamoxifen were seen for impaired CYP2C19 when ABCB1 SNP3435 was nonvariant (P = .04). With 3 impaired CYP phenotypes, endoxifen concentrations were lower than if only CYP2D6 was impaired (P = .05). When CYP2D6 was impaired, ABCB1 3435 CC (rs1045642) was associated with significantly higher endoxifen (P = .03). Thus, impairment in CYP2C9, CYP2C19, or ABCB1 contributes to a lower steady-state endoxifen concentration at the dose studied. These studies represent an improved way of examining relationships between pharmacogenetics, drug concentrations, and clinical outcomes and warrants study in larger populations.

Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity.

Polymorphic CYP2D6 is primarily responsible for metabolic activation of tamoxifen to endoxifen. We previously reported that by increasing the daily tamoxifen dose to 40 mg/day in CYP2D6 intermediate metabolizer (IM), but not poor metabolizer (PM), patients achieve endoxifen concentrations similar to those of extensive metabolizer patients on 20 mg/day. We expanded enrollment to assess the safety of CYP2D6 genotype-guided dose escalation and investigate concentration differences between races. PM and IM breast cancer patients currently receiving tamoxifen at 20 mg/day were enrolled for genotype-guided escalation to 40 mg/day. Endoxifen was measured at baseline and after 4 months. Quality-of-life data were collected using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and Breast Cancer Prevention Trial Menopausal Symptom Scale at baseline and after 4 months. In 353 newly enrolled patients, genotype-guided dose escalation eliminated baseline concentration differences in IM (p = .08), but not PM (p = .009), patients. Endoxifen concentrations were similar in black and white patients overall (p = .63) and within CYP2D6 phenotype groups (p > .05). In the quality-of-life analysis of 480 patients, dose escalation did not meaningfully diminish quality of life; in fact, improvements were seen in several measures including the FACT Breast Cancer subscale (p = .004) and limitations in range of motion (p < .0001) in IM patients. Differences in endoxifen concentration during treatment can be eliminated by doubling the tamoxifen dose in IM patients, without an appreciable effect on quality of life. Validation of the association between endoxifen concentration and efficacy or prospective demonstration of improved efficacy is necessary to warrant clinical uptake of this personalized treatment strategy. This secondary analysis of a prospective CYP2D6 genotype-guided tamoxifen dose escalation study confirms that escalation to 40 mg/day in patients with low-activity CYP2D6 phenotypes (poor or intermediate metabolizers) increases endoxifen concentrations without any obvious increases in treatment-related toxicity. It remains unknown whether endoxifen concentration is a useful predictor of tamoxifen efficacy, and thus, there is no current role in clinical practice for CYP2D6 genotype-guided tamoxifen dose adjustment. If future studies confirm the importance of endoxifen concentrations for tamoxifen efficacy and report a target concentration, this study provides guidance for a dose-adjustment approach that could maximize efficacy while maintaining patient quality of life.

Simplified CYP2D6 metabolizer phenotype categorization of patients treated with tamoxifen: Role for endoxifen level monitoring?

536Background: Classifications for CYP2D6 phenotypes are established for debrisoquine, sparteine and codeine, but not for tamoxifen. CYP2D6 protein activity can be inferred from the ratio of N-desmethyl-tamoxifen (NDMT) to endoxifen (EDF). CYP2D6polymorphisms are common and can affect CYP2D6 protein activity and EDF level. Retrospective analyses of two breast cancer studies indicate that EDF levels below 15nM may relate to worse outcome. Methods: A target NDMT/EDF ratio was defined as that which was associated with an EDF level of 15nM in 108 Australian tamoxifen-treated patients (pts), dichotomizing the group into ‘Normal’ (NM) and ‘Slow’ CYP2D6 metabolizer groups (SM). Pts were classified according to genotype based on Crews et al Clin Pharmacol Ther 95, 376, 2014 (ultrarapid/extensive, intermediate or poor metabolizers; UM/EM, IM, PM) or a simplified system based on whether anyvariant allele was present. The following alleles were measured: *2, *3, *4, *5, *6, *8, *9, *10, *14, *17, *39, *41, 1N and 2N...

High Frequency of CYP2D6 Ultrarapid Metabolizer Genotype in the Finnish Population.

CYP2D6 participates in the biotransformation of many commonly used drugs. Large genetic variability in CYP2D6 results in a wide interindividual variability in the response to CYP2D6 substrate drugs. Previous studies have assessed the phenotype and genotype distributions of CYP2D6 in relatively small Finnish population samples. The aim of our study was to investigate the frequencies of CYP2D6 genotypes in a larger Finnish population cohort of 857 healthy volunteers. The volunteers were genotyped for 10 CYP2D6 genetic variants (*2, *3, *4, *5, *6, *9, *10, *17, *39, *41) and copy number variation performed with TaqMan genotyping assays and copy number assay targeting exon 9. CYP2D6 phenotypes were inferred from the genotype data with the classical and activity score methods. According to the classical method, a large majority of the study cases were extensive metabolizers (EM; 87.3%; 95% confidence interval 84.9-89.3) and the second largest group was ultrarapid metabolizers (UM; 7.2%; 5.7-9.2%). Intermediate (IM) and poor metabolizers (PM) were in clear minority (3.0%; 2.1-4.4% and 2.3%; 1.5-3.6%, respectively). The activity score method yielded similar phenotype predictions. These results show that the frequency of UM genotype is higher and that of PM and IM genotype is lower in the Finnish population than in other North European populations. Accordingly, CYP2D6 genetic profile of the Finnish population differs from its geographically close neighbours, which has implications for the effective and safe use of drugs metabolized by CYP2D6.

Relation between CYP2D6 Genotype, Phenotype and Therapeutic Drug Concentrations among Nortriptyline and Venlafaxine Users in Old Age Psychiatry.

Objectives: To determine relations between drug concentrations and the cytochrome P450-CYP2D6 genotype or phenotype among elderly patients treated with nortriptyline or venlafaxine. Methods: A post-hoc analysis of a clinical trial was performed. Patients were grouped into phenotypes according to the metabolite/mother compound ratio. Genotypes were assessed by the CYP2D6 *3 and *4 alleles. Results: Data was available from 81 patients (41 nortriptyline, 40 venlafaxine) with a mean age of 72 years. No phenoconversion from poor metabolizers (PM) to extensive metabolizers (EM), or vice versa, was found. However, we did find phenoconversion from PM to intermediate metabolizers (IM), IM to EM, or vice versa in 36% of observations. Among nortriptyline users, patients with a PM or IM genotype had more supra-therapeutic blood levels, although this did not reach statistical significance. In exploratory analyses we found men were more likely (RR: 2.4; 95% CI: 1.14-5.07) to display phenoconversion from an IM genotype to EM phenotype. In addition, compared to non-PMs, PMs were found to have higher risk (RR: 1.56; 95% CI: 1.03-2.37) on non-response, although this was only significant when response was measured on the Hamilton Rating Scale for Depression and not on the Montgomery Åsberg Depression Rating Scale. Conclusion: Patients phenoconversed, but we did not observe phenoconversion from PM to EM or vice versa. Genotype information could be used as a valuable tool, in addition to therapeutic drug monitoring, to prevent supratherapeutic drug levels of nortriptyline or venlafaxine in elderly patients with a PM genotype.

Impact of Cytochrome P450 2D6 Function on the Chiral Blood Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine (MDMA) and Its Phase I and II Metabolites in Humans.

3,4-methylenedioxymethamphetamine (MDMA; ecstasy) metabolism is known to be stereoselective, with preference for S-stereoisomers. Its major metabolic step involves CYP2D6-catalyzed demethylenation to 3,4-dihydroxymethamphetamine (DHMA), followed by methylation and conjugation. Alterations in CYP2D6 genotype and/or phenotype have been associated with higher toxicity. Therefore, the impact of CYP2D6 function on the plasma pharmacokinetics of MDMA and its phase I and II metabolites was tested by comparing extensive metabolizers (EMs), intermediate metabolizers (IMs), and EMs that were pretreated with bupropion as a metabolic inhibitor in a controlled MDMA administration study. Blood plasma samples were collected from 16 healthy participants (13 EMs and three IMs) up to 24 h after MDMA administration in a double-blind, placebo-controlled, four-period, cross-over design, with subjects receiving 1 week placebo or bupropion pretreatment followed by a single placebo or MDMA (125 mg) dose. Bupropion pretreatment increased the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC24) of R-MDMA (9% and 25%, respectively) and S-MDMA (16% and 38%, respectively). Bupropion reduced the Cmax and AUC24 of the CYP2D6-dependently formed metabolite stereoisomers of DHMA 3-sulfate, DHMA 4-sulfate, and 4-hydroxy-3-methoxymethamphetamine (HMMA sulfate and HMMA glucuronide) by approximately 40%. The changes that were observed in IMs were generally comparable to bupropion-pretreated EMs. Although changes in stereoselectivity based on CYP2D6 activity were observed, these likely have low clinical relevance. Bupropion and hydroxybupropion stereoisomer pharmacokinetics were unaltered by MDMA co-administration. The present data might aid further interpretations of toxicity based on CYP2D6-dependent MDMA metabolism.

Abstract P5-12-06: Comprehensive assessment of the effect of genetic polymorphisms in drug metabolizing enzymes and transporters on tamoxifen activation to endoxifen

Abstract Background: Tamoxifen is the most commonly prescribed hormonal drug for estrogen receptor positive breast cancer treatment. Tamoxifen itself has weak anti-estrogenic activity, but is bioactivated to the more potent inhibitor endoxifen. Recent data suggest inferior efficacy of tamoxifen treatment in patients who have low systemic endoxifen concentration. Genetic variability in drug metabolizing enzymes and transporters, particularly CYP2D6, are known to effect serum endoxifen concentration. The association of CYP2D6 genotype and endoxifen concentration is well established; however, there is a paucity of data regarding the effects of genetic variants in other drug metabolizing enzymes and transporters on endoxifen concentrations. The objective of our study was to comprehensively screen known, functionally consequential polymorphisms and copy number variations in genes of interest to detect additional pharmacogenetic predictors of endoxifen concentration during tamoxifen treatment. Methods: This analysis includes patients prospectively enrolled on the Lineberger Comprehensive Cancer Center 0801 trial. Patients had received tamoxifen for a minimum of 4 months prior to enrollment and were not concurrently taking strong or moderate CYP2D6 inhibitors. Samples were collected at enrollment for measurement of steady state endoxifen level and collection of germline DNA. Genotyping was performed for CYP2D6 using the Amplichip® CYP450 test (Roche Diagnostics) and for other candidate genes (CYP2C9, CYP3A4, CYP3A5, ABCB1, SLCO1B1, SULT1A1, SULT1A2, and UGT2B7) using the iPLEX® ADME PGx Pro Panel (Agena Bioscience). Activity phenotype for each gene was inferred from genotype data based on known activity of variant alleles or copy numbers. Metabolite concentrations were measured via LC/MS-MS assay at Indiana University and square root transformed prior to analysis to improve normality. Linear regression models were used to evaluate the association of each gene individually with endoxifen concentration, assuming an additive pharmacogenetic effect, after adjustment for CYP2D6 phenotype (EM/UM, IM or PM). Results: 304 Patients with steady-state endoxifen concentration and successful genotyping were included in the analysis. After transformation and adjustment, endoxifen concentration was significantly associated with carrying low-activity CYP2C9 variant alleles (*2, *3, *5, *6, *8, *11, *12) (p=0.016). Predicted endoxifen concentration based on CYP2C9 and CYP2D6 genotype can be found in. Predicted endoxifen concentration (ng/mL) based on CYP2C9 and CYP2D6 Phenotype CYP2D6 EM/UMCYP2D6 IMCYP2D6 PMCYP2C9 WT/WT9.716.553.41CYP2C9 WT/Var8.375.482.63CYP2C9 Var/Var7.134.481.96Abbreviations: WT= wild-type, Var=Variant allele for CYP2C9 Phenotype activity of other enzymes and transporters was not associated with endoxifen concentration (all p&amp;gt;0.05). Conclusions: Polymorphisms in CYP2C9 and CYP2D6, but not other enzymes or transporters, contribute to variation in endoxifen exposure. If endoxifen exposure is validated to predict tamoxifen efficacy, personalized tamoxifen dosing algorithms should include CYP2C9, in addition to CYP2D6 and clinical factors, to improve efficacy and minimize side effects. Citation Format: Hertz DL, Danko W, Deal A, Walko CM, Flockhart DA, McLeod HL, Ibrahim JG, Irvin Jr WJ. Comprehensive assessment of the effect of genetic polymorphisms in drug metabolizing enzymes and transporters on tamoxifen activation to endoxifen. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-06.

Detection of CYP2D6 polymorphism using Luminex xTAG technology in autism spectrum disorder: CYP2D6 activity score and its association with risperidone levels

CYP2D6 is involved in the biotransformation of a large number of drugs, including risperidone. This study was designed to detect CYP2D6 polymorphisms with a Luminex assay, including assessment the relationship of CYP2D6 polymorphisms and risperidone plasma concentration in autism spectrum disorder children (ASD) treated with risperidone. All 84 ASD patients included in this study had been receiving risperidone at least for 1 month. The CYP2D6 genotypes were determined by Luminex assay. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Among the 84 patients, there were 46 (55.42%) classified as EM, 33 (39.76%) as IM, and 4(4.82%) as UM. The plasma concentration of risperidone and risperidone/9-hydroxyrisperidone ratio in the patients were significant differences among the CYP2D6 predicted phenotype group (P = 0.001 and P < 0.0001 respectively). Moreover, the plasma concentration of risperidone and risperidone/9-hydroxyrisperidone ratio in the patients with CYP2D6 activity score 0.5 were significantly higher than those with the CYP2D6 activity score 2.0 (P = 0.004 and P = 0.002 respectively). These findings suggested that the determination of the accurate CYP2D6 genotype-predicted phenotype is essential in the clinical setting and individualization of drug therapy. The use of the Luminex assay for detection of CYP2D6 polymorphisms could help us more accurately identify an individual's CYP2D6 phenotype.

Is It Truly the Answer? Personalized Oxycodone Dosing Based on Pharmacogenetic Testing and the Corresponding Pharmacokinetics

Dear Editor, It is with great interest that we read the article by Linares and colleagues, “Personalized oxycodone dosing: using pharmacogenetic testing and clinical pharmacokinetics to reduce toxicity risk and increase effectiveness”, published in the April 2014 issue of Pain Medicine [1]. In this study, a randomized, crossover, double-blind, placebo-controlled investigation was conducted, with a total of 15 healthy male subjects phenotyped as CYP2D6 ultra-rapid metabolizer (UM), extensive metabolizer (EM), or poor metabolizer (PM) to obtain mean plasma oxycodone concentrations at each time point in each phenotype, and subsequently to be used to generate the phenotype-specific drug clearance parameter, in an attempt to “develop a frame for integrating pharmacogenetics with clinical pharmacokinetics for personalized oxycodone dosing based on a patient’s CYP2D6 phenotype.” The authors utilized a plethora of complicated computational formulae in advanced pharmacokinetics, and applied them to the subjects whose CYP2D6 polymorphisms were known, via genetic testing, to determine the target therapeutic plasma oxycodone concentrations, and finally determined the personalized oxycodone dose with the utilization of “phenotype-specific clinical pharmacokinetics” after repeated pharmacokinetic computations. The authors concluded that “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”. We respect the painstaking effort of the Linares and colleagues devoted to this highly technical 16-page work …

Influence of CYP2D6 and CYP3A4 Phenotypes, Drug Interactions, and Vitamin D Status on Tamoxifen Biotransformation

In view of the large variability on therapeutic response and the multiple factors associated to tamoxifen (TAM) metabolic activation, this study aimed to evaluate the effect of CYP2D6 and CYP3A4 phenotypes, drug interactions, and vitamin D exposure on TAM metabolism in a group of breast cancer patients. Trough blood samples were collected from 116 patients. TAM and metabolites endoxifen (EDF), N-desmethyltamoxifen, and 4-hydroxytamoxifen (HTF) were measured in plasma by liquid chromatography-tandem mass spectrometry. CYP2D6 and CYP3A4 phenotyping were obtained according to [dextromethorphan]/[dextrorphan] and [omeprazole]/[omeprazole sulfone] metabolic ratios, measured by high-performance liquid chromatography in plasma collected 3 hours after oral administration of 33 mg of dextromethorphan and 20 mg of omeprazole. Vitamin D3 was measured in plasma by high-performance liquid chromatography-ultraviolet. Data on concomitant use of drug considered as CYP2D6 and CYP3A4 inhibitor or inducer and vitamin D supplementation were recorded. About 20% of patients had reduced CYP2D6 metabolic activity and 7% CYP3A4 impaired metabolism. EDF levels diminished proportionally to the reduction of CYP2D6 metabolic activity (poor metabolizer 2.79 ng·mL, intermediate metabolizer (IM) 5.36 ng·mL, and extensive metabolizer 10.65 ng·mL, P < 0.01). Median plasma levels of TAM (161.50 ng·mL) and HTF (1.32 ng·mL) in CYP2D6 IM/CYP3A4 poor metabolizer patients were higher (P < 0.05) than those from CYP2D6 IM/CYP3A4 extensive metabolizer patients (122.07 ng·mL and 0.61 ng·mL, respectively). Seasons contributed to the interpatient variability of EDF and HTF levels; summer concentrations were 24% and 42% higher compared with winter. Vitamin D3 was not associated to CYP3A4 metabolic activity, indicating that other mechanisms might be involved in the relation between TAM metabolism and vitamin D exposure. CYP3A4 contributes to the bioactivation of TAM through formation of HTF and becomes increasingly important in case of reduced or absent CYP2D6 activity. EDF and HTF exposure were associated to seasonal variations, with considerable higher plasma concentrations during summer.

Individualized Hydrocodone Therapy Based on Phenotype, Pharmacogenetics, and Pharmacokinetic Dosing

(1) To quantify hydrocodone (HC) and hydromorphone (HM) metabolite pharmacokinetics with pharmacogenetics in CYP2D6 ultra-rapid metabolizer (UM), extensive metabolizer (EM), and poor metabolizer (PM) metabolizer phenotypes. (2) To develop an HC phenotype-specific dosing strategy for HC that accounts for HM production using clinical pharmacokinetics integrated with pharmacogenetics for patient safety. In silico clinical trial simulation. Healthy white men and women without comorbidities or history of opioid, or any other drug or nutraceutical use, age 26.3±5.7 years (mean±SD; range, 19 to 36 y) and weight 71.9±16.8 kg (range, 50 to 108 kg). CYP2D6 phenotype-specific HC clinical pharmacokinetic parameter estimates and phenotype-specific percentages of HM formed from HC. PMs had lower indices of HC disposition compared with UMs and EMs. Clearance was reduced by nearly 60% and the t1/2 was increased by about 68% compared with EMs. The canonical order for HC clearance was UM>EM>PM. HC elimination mainly by the liver, represented by ke, was reduced about 70% in PM. However, HC's apparent Vd was not significantly different among UMs, EMs, and PM. The canonical order of predicted plasma HM concentrations was UM>EM>PM. For each of the CYP2D6 phenotypes, the mean predicted HM levels were within HM's therapeutic range, which indicates HC has significant phenotype-dependent pro-drug effects. Our results demonstrate that pharmacogenetics afford clinicians an opportunity to individualize HC dosing, while adding enhanced opportunity to account for its conversion to HM in the body.

CYP2D6 Metabolism in Frail Elderly Compared to Non-Frail Elderly: A Pilot Feasibility Study.

BackgroundFrailty is a clinical phenotype that is associated with adverse health outcomes. Since frail patients may be more prone for adverse drug events and about 15–20 % of commonly prescribed drugs are metabolized by CYP2D6, we hypothesized that CYP2D6 metabolism is decreased in frail patients compared with healthy subjects.MethodsThe 13C-dextromethorphan breath test (DM-BT) was used to determine CYP2D6 phenotype using 13C-dextromethorphan (13C-DM) as a probe. Eleven frail and 22 non-frail (according to the Fried criteria) subjects aged 70–85 years were phenotyped for CYP2D6.ResultsDespite inequalities in CYP2D6 genotype between frail and non-frail subjects, the CYP2D6 gene activity score was equally distributed between the two groups (1.33 ± 0.50 vs. 1.28 ± 0.752). In male patients, no difference in total and free serum testosterone levels was observed between frail and non-frail men. Serum dehydroepiandrostenedione sulfate (DHEAS) levels were lower in frail subjects (1.56 μmol/L) compared with non-frail subjects (2.36 μmol/L), but the difference was not significant (p = 0.15). Body mass index was significantly correlated to CYP2D6 phenotype, whereas frailty score and individual parameters of frailty, Karnofsky score, and activities of daily living score were not significantly correlated to CYP2D6 phenotype. Although there was no difference in CYP2D6 phenotype observed between frail mean ± standard deviation (mean ± SD) area under the curve for delta over baseline values (0–2 h) (AUCDOB2h) 319 ± 169 ‰ min] and non-frail subjects (mean ± SD AUCDOB2h 298 ± 159 ‰ min), the present sample size is considered too small to draw any firm conclusions regarding a potential phenoconversion of CYP2D6 in frail elderly as compared with healthy subjects.ConclusionFrail and non-frail subjects did not differ in CYP2D6 phenotype, taking into account that the precalculated sample size was not achieved. Further studies with more patients are needed in order to adequately understand a possible correlation.

The relationship between African-American women's health discussion networks & HIV risk behaviors

s / Drug and Alcohol Dependence 156 (2015) e102–e182 e167 Methods: Healthy volunteers (18–50 yrs), stratified by CYP2D6 phenotype (extensive (EMs) vs poor (PMs)metabolizers) after an 8h debrisoquine urinary recovery ratio test, underwent five sessions inwhichMA (10 and15mg), caffeine (500mg), codeine (120mg) or placebo was administered in random order. Subjective and cardiovascular measures were obtained preand at 30, 60, 90, 120, 180, 240, 300 and 360min post-drug. For eachmeasure, AUCwas generated within each session. Data were entered separately for placebo and each drug into mixed models ANOVA with CYP2D6 phenotype and dose (e.g., placebo, MA10, MA15; placebo, caffeine; placebo, codeine) as factors. Results: Thus far, 5 EMs and 2 PMs at CYP2D6 have completed all sessions and 2 PM are actively participating. Preliminary AUC change fromplacebo data showed severalmain effects forMA, such thatMA at 15mg increased ratings of arousal (t=2.71, p<0.03) and vigor (t=2.33, p<0.05) on the POMS and systolic (t=2.30, p<0.05) and diastolic (t=2.86, p<0.02) blood pressure relative to placebo regardless ofmetabolizer status.MA-induced ratings of on theMBG subscale of the ARCI relative to placebo were significantly greater for EMs than PMs (t=2.92, p<0.02). No significant main effects or interactions have occurred with caffeine or codeine. Conclusions: These preliminary results suggest that MAinduced euphoric-like effects may differ depending on CYP2D6 phenotype. The lack of caffeineor codeine-induced main effects or interactions may be due to the doses not being high enough. Financial support: Supported by R21DA031837. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.453 The relationship between African-American women’s health discussion networks & HIV risk behaviors Carrie B. Oser1, Kate Eddens1, Erin Pullen1, Brea Perry2, Richard Crosby1 1 Univ of Kentucky, Lexington, KY, United States 2 Indiana University, Bloomington, IN, United States Aims: HIV is an epidemic in the African American community, where personal relationships are salient and can influence health behaviors. Yet, there is limited research examining egocentric social networks and African American women’s HIV risk behaviors. This study examines the relationship between African American women’s health discussion networks (size, composition, strength, and function) and HIV risk behaviors. Methods: Using data from the Black Women in the Study of Epidemics (B-WISE, n=344), multivariate models investigated associations between characteristics of health discussion networks and two risk behaviors: a positive drug screen and unprotected vaginal sex. Results:Theaverageparticipantwas single, 35yearsold, and the number of health discussion networkmembers ranged from 0 to 5, with 22% having no one to talk to about their health (mean=1.39, S.D. = 1.10). African American women were less likely to use drugs when they reported larger (AOR= .71; 95% CI: .55–.92) or closer (AOR= .79; 95% CI: .68–.92) networks, as well as those comprised of people who provided a variety of support functions including instrumental (AOR= .52; 95% CI: .31–.88) or financial (AOR= .59; 95% CI: .34–.99) support, health information (AOR= .44; 95% CI: .25–.78), and discussing health (AOR= .51; 95% CI: .28–.90). In contrast, health discussion network variableswere not associatedwith unprotected sex. Conclusions: It is concerning that almost one-quarter ofwomen had no one to talk to about their health considering that larger, closer-knit, and more supportive networks are protective against drug use for African American women. Risky sexual behaviors are challenging to change, which is problematic as most new HIV infectionsamongAfricanAmericanwomenareacquiredviaheterosexual contact. Future research should examine the characteristics of African American women’s health discussion networks as predictors of drug treatment and include health discussion networks in HIV interventions. Financial support: This research is funded by NIDA (R01DA022967 and K02-DA35116, PI: Oser). http://dx.doi.org/10.1016/j.drugalcdep.2015.07.454 Drug use and injection practices in Tajikistan: Qualitative study in Kulob and Khorog David Otiashvili 1, Alisher Latypov2, Umedjon Ibragimov3, Irma Kirtadze1, William Zule4 1 Addiction Research Center, Alternative Georgia, Tbilisi, Georgia 2 Management Sciences for Health, Leadership, Management and Governance, Kiev, Ukraine 3 Laney Graduate School, Emory University, Atlanta, GA, United States 4 RTI International, Research Triangle Park, NC,

Impact of CYP2D6 phenotype on response to methamphetamine in healthy volunteers

Impact of CYP2D6 phenotype on response to methamphetamine in healthy volunteers

CYP2D6 Genetic Polymorphisms and Phenotypes in Different Ethnicities of Malaysian Breast Cancer Patients.

The cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) is an enzyme that is predominantly involved in the metabolism of tamoxifen. Genetic polymorphisms of the CYP2D6 gene may contribute to inter-individual variability in tamoxifen metabolism, which leads to the differences in clinical response to tamoxifen among breast cancer patients. In Malaysia, the knowledge on CYP2D6 genetic polymorphisms as well as metabolizer status in Malaysian breast cancer patients remains unknown. Hence, this study aimed to comprehensively identify CYP2D6 genetic polymorphisms among 80 Malaysian breast cancer patients. The genetic polymorphisms of all the 9 exons of CYP2D6 gene were identified using high-resolution melting analysis and confirmed by DNA sequencing. Seven CYP2D6 alleles consisting of CYP2D6*1, CYP2D6*2, CYP2D6*4, CYP2D6*10, CYP2D6*39, CYP2D6*49, and CYP2D6*75 were identified in this study. Among these alleles, CYP2D6*10 is the most common allele in both Malaysian Malay (54.8%) and Chinese (71.4%) breast cancer patients, whereas CYP2D6*4 in Malaysian Indian (28.6%) breast cancer patients. In relation to CYP2D6 genotype, CYP2D6*10/*10 is more frequently observed in both Malaysian Malay (28.9%) and Chinese (57.1%) breast cancer patients, whereas CYP2D6*4/*10 is more frequently observed in Malaysian Indian (42.8%) breast cancer patients. In terms of CYP2D6 phenotype, 61.5% of Malaysian Malay breast cancer patients are predicted as extensive metabolizers in which they are most likely to respond well to tamoxifen therapy. However, 57.1% of Chinese as well as Indian breast cancer patients are predicted as intermediate metabolizers and they are less likely to gain optimal benefit from the tamoxifen therapy. This is the first report of CYP2D6 genetic polymorphisms and phenotypes in Malaysian breast cancer patients for different ethnicities. These data may aid clinicians in selecting an optimal drug therapy for Malaysian breast cancer patients, hence improve the clinical outcome of the patients.

Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort.

The relationship between genetic variation in CYP2D6 and variable drug response represents a potentially powerful pharmacogenetic tool. However, little is known regarding this relationship in the genetically diverse South African population. The aim was therefore to evaluate the relationship between predicted and measured CYP2D6 phenotype. An XL-PCR+Sequencing approach was used to determine CYP2D6 genotype in 100 healthy volunteers and phenotype was predicted using activity scores. With dextromethorphan as the probe drug, metabolic ratios served as a surrogate measure of in vivo CYP2D6 activity. Three-hour plasma metabolic ratios of dextrorphan/dextromethorphan were measured simultaneously using semi-automated online solid phase extraction coupled with tandem mass spectrometry. Partial adaptation of the activity score system demonstrated a strong association between genotype and phenotype, as illustrated by a kappa value of 0.792, inter-rater discrepancy of 0.051 and sensitivity of 72.7%. Predicted phenotype frequencies using the modified activity score were 1.3% for poor metabolisers (PM), 7.6% for intermediate metabolisers (IM) and 87.3% for extensive metabolisers (EM). Measured phenotype frequencies were 1.3% for PM, 13.9% for IM and 84.8% for EM. Comprehensive CYP2D6 genotyping reliably predicts CYP2D6 activity in this South African cohort and can be utilised as a valuable pharmacogenetic tool.

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.