Solanidine is a sensitive and specific dietary biomarker for CYP2D6 activity.

BACKGROUND: Individual assessment of CYP enzyme activities can be challenging. Recently, the potato alkaloid solanidine was suggested as a biomarker for CYP2D6 activity. Here, we aimed to characterize the sensitivity and specificity of solanidine as a CYP2D6 biomarker among Finnish volunteers with known CYP2D6 genotypes. RESULTS: Using non-targeted metabolomics analysis, we identified 9152 metabolite features in the fasting plasma samples of 356 healthy volunteers. Machine learning models suggested strong association between CYP2D6 genotype-based phenotype classes with a metabolite feature identified as solanidine. Plasma solanidine concentration was 1887% higher in genetically poor CYP2D6 metabolizers (gPM) (n = 9; 95% confidence interval 755%, 4515%; P = 1.88 × 10-11), 74% higher in intermediate CYP2D6 metabolizers (gIM) (n = 89; 27%, 138%; P = 6.40 × 10-4), and 35% lower in ultrarapid CYP2D6 metabolizers (gUM) (n = 20; 64%, - 17%; P = 0.151) than in genetically normal CYP2D6 metabolizers (gNM; n = 196). The solanidine metabolites m/z 444 and 430 to solanidine concentration ratios showed even stronger associations with CYP2D6 phenotypes. Furthermore, the areas under the receiver operating characteristic and precision-recall curves for these metabolic ratios showed equal or better performances for identifying the gPM, gIM, and gUM phenotype groups than the other metabolites, their ratios to solanidine, or solanidine alone. In vitro studies with human recombinant CYP enzymes showed that solanidine was metabolized mainly by CYP2D6, with a minor contribution from CYP3A4/5. In human liver microsomes, the CYP2D6 inhibitor paroxetine nearly completely (95%) inhibited the metabolism of solanidine. In a genome-wide association study, several variants near the CYP2D6 gene associated with plasma solanidine metabolite ratios. CONCLUSIONS: These results are in line with earlier studies and further indicate that solanidine and its metabolites are sensitive and specific biomarkers for measuring CYP2D6 activity. Since potato consumption is common worldwide, this biomarker could be useful for evaluating CYP2D6-mediated drug-drug interactions and to improve prediction of CYP2D6 activity in addition to genotyping.

Delayed gametocyte clearance in Plasmodium vivax malaria is associated with polymorphisms in the cytochrome P450 reductase (CPR).

Primaquine (PQ) is the main drug used to eliminate dormant liver stages and prevent relapses in Plasmodium vivax malaria. It also has an effect on the gametocytes of Plasmodium falciparum; however, it is unclear to what extent PQ affects P. vivax gametocytes. PQ metabolism involves multiple enzymes, including the highly polymorphic CYP2D6 and the cytochrome P450 reductase (CPR). Since genetic variability can impact drug metabolism, we conducted an evaluation of the effect of CYP2D6 and CPR variants on PQ gametocytocidal activity in 100 subjects with P. vivax malaria. To determine gametocyte density, we measured the levels of pvs25 transcripts in samples taken before treatment (D0) and 72 hours after treatment (D3). Generalized estimating equations (GEEs) were used to examine the effects of enzyme variants on gametocyte densities, adjusting for potential confounding factors. Linear regression models were adjusted to explore the predictors of PQ blood levels measured on D3. Individuals with the CPR mutation showed a smaller decrease in gametocyte transcript levels on D3 compared to those without the mutation (P = 0.02, by GEE). Consistent with this, higher PQ blood levels on D3 were associated with a lower reduction in pvs25 transcripts. Based on our findings, the CPR variant plays a role in the persistence of gametocyte density in P. vivax malaria. Conceptually, our work points to pharmacogenetics as a non-negligible factor to define potential host reservoirs with the propensity to contribute to transmission in the first days of CQ-PQ treatment, particularly in settings and seasons of high Anopheles human-biting rates.

Impact of pharmacogenomic profiles on post-surgical pain following laparotomy for gynecologic pathology.

OBJECTIVES: The aim of this prospective study was to compare perioperative opioid use in women by status of CYP2D6, a highly polymorphic pharmacogene relevant to opioid metabolism. METHODS: Patients undergoing laparotomy were prospectively recruited and provided a preoperative saliva swab for a pharmacogenomic (PGx) gene panel. Postoperative opioid usage and pain scores were evaluated via chart review and a phone survey. Pharmacogenes known to be relevant to opioid metabolism were genotyped, and opioid metabolizing activity predicted by CYP2D6 genotyping. Patient and procedural factors were compared using Fisher's exact and Kruskal-Wallis tests. RESULTS: The 96 enrolled patients were classified as ultra-rapid (N = 3, 3%), normal (58, 60%), intermediate (27, 28%), and poor (8, 8%) opioid metabolizers. There was no difference in surgical complexity across CYP2D6 categories (p = 0.61). Morphine Milligram Equivalents (MME) consumed during the first 24 h after peri-operative suite exit were significantly different between groups: ultrarapid metabolizers had the highest median MME (75, IQR 45-88) compared to the other three groups (normal metabolizers 23 [8-45], intermediate metabolizers 48 [20-63], poor metabolizers 31 [12-53], p = 0.03). Opioid requirements were clinically greater in ultrarapid metabolizers during the second 24 h and last 24 h but were statistically similar (p = 0.07). There was no difference in MME prescribed at discharge (p = 0.22) or patient satisfaction with pain control (p = 0.64) between groups. CONCLUSIONS: A positive association existed between increased CYP2D6 activity and in-hospital opioid requirements, especially in the first 24 h after surgery. This provides important information to further individualize opioid prescriptions for patients undergoing laparotomy for gynecologic pathology.

Evidence for solanidine as a dietary CYP2D6 biomarker: Significant correlation with risperidone metabolism.

AIMS: The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism. The aim of this study was to investigate the correlation between solanidine metabolism and the CYP2D6-mediated metabolism of risperidone in patients with known CYP2D6 genotypes. METHODS: The study included therapeutic drug monitoring (TDM) data from CYP2D6-genotyped patients treated with risperidone. Risperidone and 9-hydroxyrisperidone levels were determined during TDM, and reprocessing of the respective TDM full-scan high-resolution mass spectrometry files was applied for semi-quantitative measurements of solanidine and five metabolites (M402, M414, M416, M440 and M444). Spearman's tests determined the correlations between solanidine metabolic ratios (MRs) and the 9-hydroxyrisperidone-to-risperidone ratio. RESULTS: A total of 229 patients were included. Highly significant, positive correlationswere observed between all solanidine MRs and the 9-hydroxyrisperidone-to-risperidone ratio (ρ > 0.6, P < .0001). The strongest correlation was observed for the M444-to-solanidine MR in patients with functional CYP2D6 metabolism, i.e., genotype activity scores of 1 and 1.5 (ρ 0.72-0.77, P < .0001). CONCLUSION: The present study shows strong, positive correlations between solanidine metabolism and CYP2D6-mediated risperidone metabolism. The strong correlation within patients carrying CYP2D6 genotypes encoding functional CYP2D6 metabolism suggests that solanidine metabolism may predict individual CYP2D6 metabolism, and hence potentially improve personalized dosing of drugs metabolized by CYP2D6.

Effect of isotretinoin on CYP2D6 and CYP3A activity in patients with severe acne.

AIMS: Previously, retinoids have decreased CYP2D6 mRNA expression in vitro and induced CYP3A4 in vitro and in vivo. This study aimed to determine whether isotretinoin administration changes CYP2D6 and CYP3A activities in patients with severe acne. METHODS: Thirty-three patients (22 females and 11 males, 23.5 ± 6.0 years old) expected to receive isotretinoin treatment completed the study. All participants were genotyped for CYP2D6 and CYP3A5. Participants received dextromethorphan (DM) 30 mg orally as a dual-probe substrate of CYP2D6 and CYP3A activity at two study timepoints: pre-isotretinoin treatment and with isotretinoin for at least 1 week. The concentrations of isotretinoin, DM and their metabolites were measured in 2-h postdose plasma samples and in cumulative 0-4-h urine collections using liquid chromatography-mass spectrometry. RESULTS: In CYP2D6 extensive metabolizers, the urinary dextrorphan (DX)/DM metabolic ratio (MR) (CYP2D6 activity marker) was numerically, but not significantly, lower with isotretinoin administration compared to pre-isotretinoin (geometric mean ratio [GMR] [90% confidence interval (CI)] 0.78 [0.55, 1.11]). The urinary 3-hydroxymorphinan (3HM)/DX MR (CYP3A activity marker) was increased (GMR 1.18 [1.03, 1.35]) and the urinary DX-O-glucuronide/DX MR (proposed UGT2B marker) was increased (GMR 1.22 [1.06, 1.39]) with isotretinoin administration compared to pre-isotretinoin. CONCLUSIONS: Administration of isotretinoin did not significantly reduce CYP2D6 activity in extensive metabolizers, suggesting that the predicted downregulation of CYP2D6 based on in vitro data does not translate into humans. We observed a modest increase in CYP3A activity (predominantly CYP3A4) with isotretinoin treatment. The data also suggest that DX glucuronidation is increased following isotretinoin administration.

Combined effect of CYP2C19 and CYP2D6 genotypes on escitalopram serum concentration and its metabolic ratio in a European patient population.

AIMS: The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real-world population. METHODS: Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N-desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype-predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration-to-dose (CD) ratio and metabolite-to-parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal-Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. RESULTS: A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P < .001), 28% in CYP2C19 IMs (P < .001) and 31% in CYP2C19 PMs (P = .04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. CONCLUSIONS: CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone.

Impact of CYP2D6*2A, CYP2D6*4 and CYP3A5*3 genetic polymorphisms on Bisoprolol peak concentration and clinical response in acute coronary syndrome patients.

AIMS: Acute coronary syndrome (ACS) represents a major cause of death. Bisoprolol is commonly used in the management of ACS. This study aims to investigate the impact of CYP2D6*2A, CYP2D6*4 and CYP3A5*3 genetic polymorphisms on pharmacokinetics and clinical response of bisoprolol in ACS patients. METHODS: This is an open-label cohort study that included 127 ACS patients and studied the effect of CYP3A5*3, CYP2D6*2A and CYP2D6*4 genotyping using real-time polymerase chain reaction on steady state bisoprolol plasma peak concentration analysed by high performance liquid chromatography-fluorescence detector. RESULTS: Regarding CYP3A5*3, the mean peak bisoprolol concentration for CC, CT and TT genotypes were 4.25 ± 1.20, 3.93 ± 1.10 and 1.79 ± 0.69 ng/mL, respectively (P < .001). Higher systolic (126 ± 5.47 mmHg), diastolic blood pressure (82 ± 2.73 mmHg) and heart rate (97.80 ± 3.03 beats/min) were also observed in CYP3A5*3 TT carriers (P < .05). In CYP2D6*2A, the peak concentration of bisoprolol was lower in CC carriers (3.54 ± 1 ng/mL) compared to GG (4.38 ± 1.25 ng/mL) and GC carriers (4.07 ± 1.29 ng/mL, P = .019). In CYP2D6*4, the mean bisoprolol peak concentration in CC carriers was 3.98 ± 1.31 ng/mL, which was lower than T allele carriers (4.5 ± 0.8, P = .02). No differences in heart rate, systolic, diastolic blood pressure or bisoprolol dose were observed among CYP2D6*2A or CYP2D6*4 variants. Smokers exhibited lower bisoprolol peak concentration (3.96 ± 1.2 ng/mL) compared to nonsmokers (4.55 ± 1.34 ng/mL, P = .037). CONCLUSION: There is an association between CYP3A5*3, CYP2D6*4, CYP2D6*2A variants and bisoprolol peak concentration, which may serve as a guide in the future in choosing the optimum dose of bisoprolol in ACS patients.

Physiologically Based Pharmacokinetic Modeling to Unravel the Drug-gene Interactions of Venlafaxine: Based on Activity Score-dependent Metabolism by CYP2D6 and CYP2C19 Polymorphisms.

BACKGROUND: Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable variations in plasma concentrations across different phenotypes. This divergence in phenotypic responses leads to notable differences in both the efficacy and tolerance of the drug. PURPOSE: A physiologically based pharmacokinetic (PBPK) model for VEN and its metabolite O-desmethylvenlafaxine (ODV) to predict the impact of CYP2D6 and CYP2C19 gene polymorphisms on VEN pharmacokinetics (PK). METHODS: The parent-metabolite PBPK models for VEN and ODV were developed using PK-Sim® and MoBi®. Leveraging prior research, derived and implemented CYP2D6 and CYP2C19 activity score (AS)-dependent metabolism to simulate exposure in the drug-gene interactions (DGIs) scenarios. The model's performance was evaluated by comparing predicted and observed values of plasma concentration-time (PCT) curves and PK parameters values. RESULTS: In the base models, 91.1%, 94.8%, and 94.6% of the predicted plasma concentrations for VEN, ODV, and VEN + ODV, respectively, fell within a twofold error range of the corresponding observed concentrations. For DGI scenarios, these values were 81.4% and 85% for VEN and ODV, respectively. Comparing CYP2D6 AS = 2 (normal metabolizers, NM) populations to AS = 0 (poor metabolizers, PM), 0.25, 0.5, 0.75, 1.0 (intermediate metabolizers, IM), 1.25, 1.5 (NM), and 3.0 (ultrarapid metabolizers, UM) populations in CYP2C19 AS = 2.0 group, the predicted DGI AUC0-96 h ratios for VEN were 3.65, 3.09, 2.60, 2.18, 1.84, 1.56, 1.34, 0.61, and for ODV, they were 0.17, 0.35, 0.51, 0.64, 0.75, 0.83, 0.90, 1.11, and the results were similar in other CYP2C19 groups. It should be noted that PK differences in CYP2C19 phenotypes were not similar across different CYP2D6 groups. CONCLUSIONS: In clinical practice, the impact of genotyping on the in vivo disposition process of VEN should be considered to ensure the safety and efficacy of treatment.

Inhibition Effect of Okanin Toward Human Cytochrome P450 3A4 and 2D6 with Multi-spectroscopic Studies and Molecular Docking.

Okanin, a major flavonoid of a popular herb tea, Coreopsis tinctoria Nutt., showed strong inhibition on CYP3A4 and CYP2D6. The strong interaction between okanin and CYPs were determined by enzyme kinetics, multispectral technique and molecular docking. The inhibition type of two enzymes, CYP3A4 and CYP2D6, by okanin are mixed and non-competitive inhibition type, respectively. The IC50 values and the binding constant of okanin to CYP3A4 can be deduced that the interaction was stronger than that of CYP2D6. The Conformations of CYP3A4 and CYP2D6 were changed by okanin. The evidence from fluorescence measurement along with molecular docking verified that these two CYPs were bound with okanin by hydrogen bonds and hydrophobic forces. Our investigation suggested that okanin may lead to interactions between herb and drug by inhibiting CYP3A4 and CYP2D6 activities, thus its consumption should be taken with caution.

Drug-drug interaction perpetrators of oxycodone in patients with cancer: frequency and clinical relevance.

AIM: Oxycodone is known to have numerous drug-drug interactions (DDIs) that can potentially decrease efficacy or lead to adverse drug reactions (ADRs). However, there is limited research on the frequency of DDIs associated with oxycodone, which is important in optimising pharmacovigilance and the need for additional research on certain DDIs. In this study, the frequency of pharmacologically and clinically relevant DDI perpetrators was studied in patients with cancer. METHODS: This was a cross-sectional study using hospital pharmacy records of patients with cancer who were prescribed oxycodone between September 2021 and September 2022. Medication records of patients prescribed oxycodone during a period of ≥ 5 consecutive days (= oxycodone treatment episodes) were reviewed to identify the concomitant use of pharmacologically relevant perpetrators, based on reference sources (Lexicomp®, Micromedex®, the Dutch Kennisbank and the Dutch Commentaren Medicatiebewaking). The clinical relevance was examined by a clinical pharmacologist and a medical oncologist. Additionally, the frequency of double interactions-concomitant oxycodone use with two CYP3A4 and / or CYP2D6 perpetrators-was studied. RESULTS: Overall, 254 oxycodone treatment episodes were included, of which 227 (89.4%) were found to contain at least one pharmacologically relevant DDI perpetrator. Of these, 210 (82.7%) were considered to be clinically relevant. A total of 80 different pharmacologically relevant perpetrators were identified, with 65 (81.3%) being considered clinically relevant. Double interactions were observed in 21 (8.3%) oxycodone treatment episodes. CONCLUSION: A high frequency of pharmacologically and clinically relevant perpetrators of oxycodone was observed in our cohort. Moreover, a high number of double interactions involving oxycodone was registered. More intense monitoring of DDIs may be needed to improve medication safety of patients with cancer taking oxycodone.

Evaluation of SLC6A2 and CYP2D6 polymorphisms' effects on atomoxetine treatment in attention deficit and hyperactivity disorder.

BACKGROUND: There is insufficient replicated data to establish a relationship between the polymorphisms of SLC6A2 and CYP2D6 and the treatment responses of atomoxetine (ATX) in ADHD. We focused on evaluating the effect of top-line single nucleotide polymorphisms (SNPs) in SLC6A2 and CYP2D6 on the ATX treatment response in attention deficit and hyperactivity disorder (ADHD). METHODS: Of 160 patient records, 34 patients who met the inclusion criteria were evaluated to determine the relationship between genotypes of ten SNPs (six of SLC6A2 and four of CYP2D6) and ATX treatment response. Additionally, the connection between SNPs of CYP2D6 and the severity of side effects associated with ATX was analyzed in 37 patients, including the 34 study patients, and three patients discontinued because of ATX-dependent side effects. RESULTS: All six polymorphisms we studied in SLC6A2 were associated with the treatment response of ATX. Clinical improvement in oppositional defiant disorder symptoms of patients with ADHD was only observed in carriers of the homozygous "C" allele of rs3785143 (podd = 0.026). We detected an association between higher CGI-side-effect severity scores and the "TT" genotype of rs1065852 polymorphism in CYP2D6 (p = 0.043). CONCLUSIONS: The findings of this study suggest that genotypes of polymorphisms within the SLC6A2 and CYP2D6 may play an influential role in treatment response or the severity of side effects associated with ATX in ADHD patients.

Association of CYP2D6 and CYP2C19 metabolizer status with switching and discontinuing antidepressant drugs: an exploratory study.

BACKGROUND: Tailoring antidepressant drugs (AD) to patients' genetic drug-metabolism profile is promising. However, literature regarding associations of ADs' treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses. METHODS: Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann-Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses. RESULTS: No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects. CONCLUSIONS: We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.

Risperidone plasma level, and its correlation with CYP2D6 gene polymorphism, clinical response and side effects in chronic schizophrenia patients.

BACKGROUND: To explore the influence of CYP2D6 genetic polymorphism on risperidone metabolism, thereby affecting risperidone's effects and safeties in patients with chronic schizophrenia. METHODS: Sixty-nine subjects with chronic schizophrenia treated with risperidone were recruited. CYP2D6 genotypes was determined using targeted sequencing and translated into phenotype using activity system. Risperidone plasma concentrations were measured using HPLC. Positive and Negative Symptom Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) were used to evaluate the existence and severity of psychiatric symptoms, Barnes Akathisia Scale (BAS) and Extrapyramidal Symptom Rating Scale (ESRS) for neurological side effects. Metabolic and endocrine status assess were also included. RESULTS: The plasma drug concentrations varied hugely among individuals. Intermediate metabolizer (IM) group had higher plasma levels of RIP and dose corrected RIP concentration, RIP/9-OH-RIP ratio and C/D ratio than normal metabolizer (NM) group (p < 0.01). There was no statistic difference between responders and non-responders in dose-adjusted plasma concentrations and ratios of RIP/9-OH-RIP and C/D. The occurrence of EPS was related to active moiety levels in 4th week (p < 0.05). The prolactin (PRL) levels in two follow-ups were both significantly higher than baseline (p < 0.01). PRL change from baseline to week 4 and week 8 were both positively associated with active moiety concentration detected in week 4 (p < 0.05). CONCLUSIONS: The risperidone plasma levels have great inter- and intraindividual variations, and are associated with the CYP2D6 phenotypes, as well as the changes in serum prolactin in patients diagnosed with chronic schizophrenia.

Refining Hepatocyte Models to Capture the Impact of CYP2D6*10 Utilizing a PITCh System.

CYP2D6 variants contain various single nucleotide polymorphisms as well as differing levels of metabolic activity. Among these, one of the less active variants CYP2D6*10 (100C > T) is the most prevalent mutation in East Asians, including Japanese. This mutation leads to an amino acid substitution from proline to serine, which reduces the stability of CYP2D6 and consequently decreases its metabolic activity. In this study, we used a genome editing technology called the Precise Integration into Target Chromosome (PITCh) system to stably express six drug-metabolizing enzymes (CYP3A4, POR, uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), CYP1A2, CYP2C19, CYP2C9, and CYP2D6*10) in HepG2 (CYP2D6*10 KI-HepG2) cells to examine the effect of CYP2D6*10 on drug metabolism prediction. The protein expression levels of CYP2D6 in CYP2D6*10 KI-HepG2 cells were reduced relative to those in the CYP3A4-POR-UGT1A1-CYP1A2-CYP2C19-CYP2C9-CYP2D6 knock-in-HepG2 (CYPs-UGT1A1 KI-HepG2) cells. Consistent with the CYP2D6 protein expression results, CYP2D6 metabolic activity in CYP2D6*10 KI-HepG2 cells was reduced relative to CYPs-UGT1A1 KI-HepG2 cells. We successfully generated CYP2D6*10 KI-HepG2 cells with highly expressed, functional CYP2D6*10, as well as CYP1A2, 2C9, 2C19 and 3A4. CYP2D6*10 KI-HepG2 cells could be an invaluable model for hepatic metabolism and hepatotoxicity studies in East Asians, including Japanese.

Prediction of combination effect of quinidine on the pharmacokinetics of tipepidine using a physiologically based pharmacokinetic model.

Tipepidine, an antitussive drug, has been reported to have central pharmacological effects and can be expected to be safely repositioned as treatment for psychiatric disorders. Since tipepidine requires three doses per day, development of a once-daily medication would be highly beneficial. Previously, we reported that combination use with quinidine, a CYP2D6 inhibitor, prolongs the half-life of tipepidine in chimeric mice with humanised liver.In this study, to predict this combination effect in humans, a physiologically based pharmacokinetic (PBPK) model was developed, and quantitative simulation was conducted. The simulation results indicated that concomitant administration of tipepidine with quinidine increased the predicted Cmax, AUC, and t1/2 of tipepidine in the Japanese population by 3.4-, 6.6-, and 2.4-fold, respectively.Furthermore, to compare with another approach that aims to prolong the half-life, the PK profile of tipepidine administered in hypothetical extended-release form was simulated. Extended-release form was predicted to be more influenced by CYP2D6 genotype than combination with quinidine, and the predicted plasma exposure was markedly increased in poor metabolizers, potentially leading to adverse effects.In conclusion, quantitative simulation using the PBPK model suggests the feasibility of the safe repositioning of tipepidine as a once-daily medication in combination with quinidine.

Influence of CYP2C19, CYP2D6, and ABCB1 Gene Variants and Serum Levels of Escitalopram and Aripiprazole on Treatment-Emergent Sexual Dysfunction: A Canadian Biomarker Integration Network in Depression 1 (CAN-BIND 1) Study.

OBJECTIVES: Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19 and CYP2D6, and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample. METHODS: A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0-8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n = 91), while responders continued ESC (i.e., ESC-Only, n = 80) from weeks 8-16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0-8 and 8-16, using repeated measures mixed-effects models. RESULTS: In ESC-Only, CYP2C19 intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8-16, relative to CYP2C19 normal metabolizers (NMs) who showed a decline, F(2,54) = 8.00, p < 0.001, q = 0.048. Specifically, CYP2C19 IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF (r = -0.42, p = 0.004, q = 0.034) and SS (r = -0.43, p = 0.003, q = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction (r = -0.39, p = 0.009, q = 0.052). CONCLUSIONS: CYP2C19 metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19 may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.

Interactions studies of CYP2D6 with quercetin and hyperoside by spectral analysis and molecular dynamics simulations.

Some ingredients from herbal medicine can significantly affect the activity of CYP2D6, thus leading to serious interactions between herbs and drugs. Quercetin and hyperoside are active ingredients widely found in vegetables, fruits, and herbal medicines. Quercetin and hyperoside have many biological activities. In this work, the characteristic bindings of CYP2D6 with quercetin/hyperoside are revealed by multi-spectroscopy analysis, molecular docking, and molecular dynamics simulations. The fluorescence of CYP2D6 is statically quenched by quercetin and hyperoside. The binding constant (Ka ) values of CYP2D6-quercetin/hyperoside range from 104 L mol-1 , which indicates that these two flavonoids bind moderately to CYP2D6. Meanwhile, quercetin has a stronger quenching ability to CYP2D6 than that of hyperoside. The secondary structure of CYP2D6 is obviously changed by binding with quercetin/hyperoside. The docking results reveal that the quercetin/hyperoside enters the active site of CYP2D6 near heme and binds to CYP2D6 by hydrogen bonds and van der Waals forces. The molecular dynamics simulation results indicate that the binding of quercetin/hyperoside can stabilize the two complexes, enhance the flexibility of CYP2D6 backbone atoms, and make a more unfolded and looser structure of CYP2D6.

Design, synthesis, and in-silico study of novel triarylethylene analogs with dual anti-estrogenic and serotonergic activity.

Estrogen receptor is an important target in breast cancer. Serotonin receptors (5-HT2A and 5-HT2C , in particular) were investigated for a potential role in development and progression of breast cancer. Ligands that interact with estrogenic receptors influence the emotional state of females. Thus, designing selective estrogen receptor modulator (SERM) analogs with potential serotonergic activity is a plausible approach. The dual ligands can augment cytotoxic effect of SERMs, help in both physical and emotional menopausal symptom relief, enhance cognitive function and support bone health. Herein, we report triarylethylene analogs as potential candidates for treatment of breast cancer. Compound 2e showed (ERα relative ß- galactosidase activity = 0.70), 5-HT2A (Ki = 0.97 µM), and 5-HT2C (Ki = 3.86 µM). It was more potent on both MCF-7 (GI50 = 0.27 µM) and on MDA-MB-231 (GI50 = 1.86 µM) compared to tamoxifen (TAM). Compound 4e showed 40 times higher antiproliferative activity on MCF-7 and 15 times on MDA-MBA compared to TAM. Compound 4e had higher average potency than TAM on all nine tested cell line panels. Our in-silico model revealed the binding interactions of compounds 2 and 2e in the three receptors; further structural modifications are suggested to optimize binding to the ERα, 5-HT2A , and 5-HT2C .

Into a Deeper Understanding of CYP2D6's Role in Risperidone Monotherapy and the Potential Side Effects in Schizophrenia Spectrum Disorders.

Schizophrenia spectrum disorders (SSD) are a group of diseases characterized by one or more abnormal features in perception, thought processing and behavior. Patients suffering from SSD are at risk of developing life-threatening complications. Pharmacogenetic studies have shown promising results on personalized treatment of psychosis. In the current study, 103 patients diagnosed with SSD treated with risperidone as antipsychotic monotherapy were enrolled. Socio-demographics and clinical data were recorded, and laboratory tests and genotyping standard procedure for cytochrome P450 (CYP) 2D6*4 were performed. Patients were evaluated by the Positive and Negative Syndrome Scale (PANSS) on admission and at discharge. Based on the reduction in the PANSS total score, subjects were divided into non-responders, partial responders and full responders. Only 11 subjects had a full response to risperidone (10.67%), 53 subjects (51.45%) had a partial response, and 39 participants (37.86%) were non-responders. Patients at first episode psychosis showed significantly higher levels of blood glucose and prolactin levels, while chronic patients showed significantly higher LDL levels. Adverse drug reactions (ADR) such as tremor and stiffness significantly correlated with genetic phenotypes (p = 0.0145). While CYP2D6 showed no impact on treatment response, ADR were significantly more frequent among poor and intermediate metabolizers.

Pharmacogenetic Approach to Tramadol Use in the Arab Population.

Tramdol is one of most popular opioids used for postoperative analgesia worldwide. Among Arabic countries, there are reports that its dosage is not appropriate due to cultural background. To provide theoretical background of the proper usage of tramadol, this study analyzed the association between several genetic polymorphisms (CYP2D6/OPRM1) and the effect of tramadol. A total of 39 patients who took tramadol for postoperative analgesia were recruited, samples were obtained, and their DNA was extracted for polymerase chain reaction products analysis followed by allelic variations of CYP2D6 and OPRM A118G determination. Numerical pain scales were measured before and 1 h after taking tramadol. The effect of tramadol was defined by the difference between these scales. We concluded that CYP2D6 and OPRM1 A118G single nucleotide polymorphisms may serve as crucial determinants in predicting tramadol efficacy and susceptibility to post-surgical pain. Further validation of personalized prescription practices based on these genetic polymorphisms could provide valuable insights for the development of clinical guidelines tailored to post-surgical tramadol use in the Arabic population.