CYP2D6 Isoenzyme Research Articles

Bupropion Increased More than Five Times the Systemic Exposure to Aripiprazole: An In Vivo Study in Wistar albino Rats

Background/Objectives: In psychiatric disorders, antipsychotics and antidepressant medication are often administered together. Aripiprazole, a third-generation antipsychotic drug, is extensively metabolized by CYP2D6 and CYP3A4 isoenzymes, while bupropion, used in depressive disorders, is known as a moderate or strong CYP2D6 enzyme inhibitor. This in vivo experiment aimed to assess the presence of a pharmacokinetic drug interaction between aripiprazole and bupropion and its magnitude on the systemic exposure of aripiprazole. Methods: 24 healthy Wistar albino male rats were included in two study groups. A single dose of 8 mg/kg aripiprazole was given to rats in the reference group, while the test group received repeated doses of bupropion for 6 days, followed by a single dose of aripiprazole. An LC-MS/MS method was developed for the concomitant quantification of aripiprazole and its active metabolite, dehydroaripiprazole, and non-compartmental analysis was employed to assess their pharmacokinetic parameters. Results: The mean AUC0-∞ of aripiprazole increased 5.65-fold (1117.34 ± 931.41 vs. 6311.66 ± 2978.71 hr·ng/mL), the mean Cmax increased by 96.76% and the apparent systemic clearance decreased over 9-fold after bupropion repeated doses. The exposure to aripiprazole’s active metabolite increased as well, having a 4-fold increase in the mean AUC0–∞ (from 461.13 ± 339.82 to 1878.66 ± 1446.91 hr·ng/mL) and a 2-fold increase in the mean Cmax. Conclusions: The total exposure to the aripiprazole parent compound and active moiety significantly increased after bupropion pretreatment in this preclinical in vivo experiment. Clinical studies should further establish the significance of this interaction in humans.

Genetic diversity of cytochrome P450 in patients receiving psychiatric care in Greece: a step towards clinical implementation.

Aim: We herein inferred the genetic diversity of CYP450 isoenzymes to predict the percentage of patients who need dose adjustment in drugs used in psychiatry.Materials & methods: Data of 784 Greek patients receiving psychiatric care who were genotyped for CYP2D6, CYP2C19, CYP1A2, CYP3A5 and CYP2C9 isoenzymes were inferred to gene-drug pairs according to the US FDA, Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group annotations and published literature.Results: Atypical metabolism was found for 36.8% of patients in CYP2D6, 49.2% in CYP2C19, 45% in CYP1A2, 16.7% in CYP3A5 and 41.8% in CYP2C9. Dosage adjustment need was estimated for 10.2% of venlafaxine, 10.0% of paroxetine, 6.4% of sertraline, 30.8% of citalopram, 52.1% of escitalopram, 18.2% of fluvoxamine, 54.1% of tricyclic antidepressants, 16.7% of zuclopenthixol, 10.6% of haloperidoland 13.3% of risperidone treated patients.Conclusion: Clinical psychiatric pharmacogenomic implementation holds promise to improve drug effectiveness and safety.

Associations between Selected ADRB1 and CYP2D6 Gene Polymorphisms in Children with Ventricular and Supraventricular Arrhythmias.

Background and Objectives: Tachycardia is a common cardiovascular disease. Drugs blocking β1-adrenergic receptors (ADRB1) are used in the therapy of arrhythmogenic heart diseases. Disease-related polymorphisms can be observed within the ADRB1 gene. The two most important are Ser49Gly and Arg389Gly, and they influence the treatment efficacy. The family of the cytochrome P450 system consists of the isoenzyme CYP2D6 (Debrisoquine 4-hydroxylase), which is involved in phase I metabolism of almost 25% of clinically important drugs, including antiarrhythmic drugs. A study was conducted to detect the ADRB1 and CYP2D6 gene polymorphisms. Materials and Methods: The material for the test was whole blood from 30 patients with ventricular and supraventricular tachycardia and 20 controls. The samples were obtained from the Department of Pediatric Cardiology. The first to be made was the extraction of DNA using a GeneMATRIX Quick Blood DNA Purification Kit from EURx. The selected ADRB1 and CYP2D6 gene polymorphisms were detected by high-resolution melting polymerase chain reaction (HRM-PCR) analysis. Results: Based on the analysis of melt profile data for each PCR product, the identification of polymorphisms was carried out. Heterozygotes and homozygotes were found in the examined alleles. Conclusions: The frequency of the Arg389Gly polymorphism differs statistically significantly between the control group and patients with supraventricular and ventricular arrhythmias, as well as between these two groups of patients. Moreover, the Arg389Gly polymorphism was statistically more prevalent in the group of girls with SVT arrhythmia compared to girls with VT. A few carriers of homozygous and heterozygous systems of the S49G polymorphism were detected among patients with arrhythmias, as well as control group. The percentage of individuals carrying the CYP2D6 4 allele as either homozygous or heterozygous was observed in the study and control groups. The high prevalence of the CYP2D6*4 allele carriers in both groups prompts the optimization of beta-1 blocker therapy.

CLOZAPINE INDUCED EXTRAPYRAMIDAL SYMPTOMS FOLLOWING ALCOHOL CONSUMPTION IN PATIENT WITH SCHIZOPHRENIA AND ALCOHOL DEPENDENCE SYNDROME: A CASE REPORT OF SIALORRHEA, ACUTE AKATHISIA AND DYSTONIA

Clozapine (CLZ), a second-generation or atypical antipsychotic, although not recommended as the first-line drug of choice in the treatment of schizophrenia and schizoaffective disorders; however, it is recommended in the treatment of Treatment-Resistant Schizophrenia and in schizophrenic patients to decrease the recurrent risk of suicidal behavior. For the cytochrome P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4, CLZ serves as a substrate. CLZ also exhibits drug-food interaction with alcohol leading to an increase in the risk of seizures and extrapyramidal symptoms. A case of a 36-year-old male patient with a known history of paranoid schizophrenia and alcohol dependence syndrome came with complaints of dystonia and hypersalivation 1 day following the consumption of alcohol after ingestion of tablet CLZ. After clinical pharmacist intervention, the doses were titrated and the patient improved gradually. With this, it can be postulated that the concomitant use of alcohol with CLZ can be a predisposing factor for drug toxicity in the patients and hence patients should be monitored and counseled to abstain from the use of alcohol while on CLZ therapy.

ANTIOXIDANT ACTIVITY OF QUINOXALYL HYDRAZONES OF 2-HYDROXYIMINO-1,3-DICARBONYL COMPOUNDS

Biosimilarity and pharmacokinetic descriptors were obtained using SwissADME and ADMETlab 2.0 web services. Analysis of the obtained descriptors shows that, according to Lipinski’s rule, quinoxalyl hydrazones of 2-hydroximino-1,3-dioxocompounds may be promising candidates for drug development for oral administration. Analysis of the pharmacokinetic descriptors of the structures studied shows that, according to the in silico predictions, the compounds can penetrate the blood-brain barrier, be absorbed in the gastrointestinal tract, bind to plasma proteins, be rapidly eliminated from target cells and inhibit CYP3A4, CYP1A2, CYP2C19 and CYP2D6 isoenzymes. The antioxidant activity of quinoxalyl hydrazone derivatives with different benzoyl, ester and acetyl moieties has been studied. Pharmacological screening of the obtained compounds was performed in vitro in the model of Fe2+-induced lipid peroxidation. The data of pharmacological screening indicate clearly pronounced inhibition of lipid peroxidation in the system of yolk lipoproteins by the compounds obtained, which indicates a significant contribution of quinoxalone scaffold in the manifestation of antioxidant properties. Variations in the structure of the starting 1,3-dicarbonyl compounds did not result in significant changes in the antioxidant activity of the obtained hydrazones. The compounds obtained can be promising compounds with marked antioxidant activity for further in vivo studies, including investigation of acute and chronic toxicity. The leading compound is tolyl-substituted quinoxalyl hydrazone IIb

Unraveling the In Vitro Toxicity Profile of Psychedelic 2C Phenethylamines and Their N-Benzylphenethylamine (NBOMe) Analogues.

Mescaline derivative (2C phenethylamines) drugs have been modified by the introduction of a N-2-methoxybenzyl group to originate a new series of compounds with recognized and potent psychedelic effects, the NBOMe-drugs. Although they are prevalent in unregulated drug markets, their toxicity profile is still poorly understood, despite several reports highlighting cases of acute intoxication, with brain and liver toxicity. Thus, in this study, mescaline, 2C-N (insertion of a nitro in the para position of the 2C phenethylamines aromatic ring) and 2C-B (insertion of a bromide in the para position of the 2C phenethylamines aromatic ring) and their corresponding NBOMe counterparts, mescaline-NBOMe, 25N-NBOMe and 25B-NBOMe, were synthetized and the in vitro neuro- and hepatocytotoxicity evaluated in differentiated SH-SY5Y and HepG2 cell lines, respectively. Cytotoxicity, oxidative stress, metabolic and energetic studies were performed to evaluate the main pathways involved in their toxicity. Our results demonstrated that the presence of the N-2-methoxybenzyl group significantly increased the in vitro cytotoxicity of 2C phenethylamines drugs in both cell lines, with the NBOMe drugs presenting lower EC50 values when compared to their counterparts. Consistently, our data showed a correlation between the drug's lipophilicity and the EC50 values, except for 2C-B. The 2C-B presented higher cytotoxic effects in both cell lines than mescaline-NBOMe, a result that can be explained by its higher passive permeability. All the NBOMe derivatives were able to cross the blood-brain barrier. Considering metabolic studies, the cytotoxicity of these drugs was shown to be influenced by inhibition of cytochrome P450 (CYP), which suggests a potential role of this enzyme complex, especially CYP3A4 and CYP2D6 isoenzymes in SH-SY5Y cells, in their detoxification or bioactivation. Furthermore, in differentiated SH-SY5Y cells, the drugs were able to induce mitochondrial membrane depolarization, and to disrupt GSH and ATP intracellular levels, these effects being concentration dependent and more pronounced for the NBOMe derivatives. No ROS overproduction was detected for any of the drugs in the tested experimental conditions. A correlation between a drug's lipophilicity and the EC50 values in both cell lines, except for 2C-B, was also obtained. In summary, the introduction of a NBOMe moiety to the parent drugs significantly increases their lipophilicity, brain permeability and cytotoxic effects, with GSH and ATP homeostasis disruption. The inhibition of CYP3A4 and CYP2D6 emphasized that CYP-mediated metabolism impacts the toxicity of these drugs.

CYP2D6 isoenzyme and ABCB1 gene polymorphisms associated with postoperative nausea and vomiting in women undergoing laparoscopic cholecystectomy: a randomized trial

IntroductionPostoperative nausea and vomiting is still a common complication. Serotonin receptor antagonists are commonly used in clinical practice for antiemetic prophylaxis. Interindividual variations in drug response, including single nucleotide polymorphisms, are related to pharmacokinetic and pharmacodynamic changes in these drugs and may lead to a poor therapeutic response. This study aimed to evaluate the influence of CYP2D6 isoenzyme and ABCB1 gene polymorphisms on the frequency of postoperative nausea and vomiting with the use of ondansetron or palonosetron. MethodsA randomized, double-blind clinical trial including 82 women aged 60 years or over undergoing laparoscopic cholecystectomy was conducted. Patients were randomized to receive either ondansetron or palonosetron for postoperative nausea and vomiting prophylaxis. DNA was extracted from saliva. Genetic polymorphisms were analyzed by real-time polymerase chain reaction. The following polymorphisms were analyzed: rs3892097 C/T, rs1128503 A/G, rs16947 A/G, rs1065852 A/G, rs1045642 A/G, rs2032582 C/A, and rs20325821 C/A. ResultsOverall, vomiting, and severe nausea occurred in 22.5% and 57.5% of patients, respectively. In the palonosetron group, patients with the GG genotype (rs16947 A/G) experienced more severe nausea (p = 0.043). In the ondansetron group, patients with the AA genotype (rs16947 A/G) presented mild nausea (p = 0.034), and those with the AA genotype (rs1065852 A/G) experienced more vomiting (p = 0.034). ConclusionA low antiemetic response was observed with ondansetron in the presence of the AA genotype (rs16947 A/G) and the AA genotype (rs1065852 A/G), and a low therapeutic response was found with palonosetron in the presence of the GG genotype (rs16947 A/G) in laparoscopic cholecystectomy. RegisterClinicalTrials.gov.

Alisertib shows negligible potential for perpetrating pharmacokinetic drug-drug interactions on ABCB1, ABCG2 and cytochromes P450, but acts as dual-activity resistance modulator through the inhibition of ABCC1 transporter

Alisertib (MLN8237), a novel Aurora A kinase inhibitor, is currently being clinically tested in late-phase trials for the therapy of various malignancies. In the present work, we describe alisertib's potential to perpetrate pharmacokinetic drug-drug interactions (DDIs) and/or to act as an antagonist of multidrug resistance (MDR). In accumulation assays, alisertib potently inhibited ABCC1 transporter, but not ABCB1 or ABCG2. The results of molecular modeling suggested a bifunctional mechanism for interaction on ABCC1. In addition, alisertib was characterized as a low- to moderate-affinity inhibitor of recombinant CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 isoenzymes, but without potential clinical relevance. Drug combination studies revealed the capability of alisertib to synergistically antagonize ABCC1-mediated resistance to daunorubicin. Although alisertib exhibited substrate characteristics toward ABCB1 transporter in monolayer transport assays, comparative proliferation studies showed lack of its MDR-victim behavior in cells overexpressing ABCB1 as well as ABCG2 and ABCC1. Lastly, alisertib did not affect the expression of ABCC1, ABCG2, ABCB1 transporters and CYP1A2, CYP3A4, CYP2B6 isozymes on mRNA level in various systemic and tumoral models. In conclusion, our study suggests that alisertib is a drug candidate with negligible potential for perpetrating systemic pharmacokinetic DDIs on ABCB1, ABCG2 and cytochromes P450. In addition, we introduce alisertib as an effective dual-activity chemosensitizer whose MDR-antagonistic capacities are not impaired by efflux or effect on MDR phenotype. Our in vitro findings provide important pieces of information for clinicians when introducing alisertib into the clinical area.

Bempedoic acid: A nonstatin drug for the management of hypercholesterolemia.

Bempedoic acid: A nonstatin drug for the management of hypercholesterolemia.

Personalized approach to the administration of haloperidol in patients with acute alcoholic hallucinatie (literature review)

To date, it is known that haloperidol is used to treat productive psychopathological symptoms in acute alcoholic hallucinosis, but its use is associated with a high risk of developing undesirable drug reactions (NLR). A number of isoenzymes of the cytochrome P-450 family take part in the metabolism of haloperidol. The biotransformation of haloperidol occurs with the participation of the CYP2D6 isoenzyme encoded by the gene of the same name. The CYP2D6 gene is highly polymorphic, and this polymorphism can lead to a change in the activity of the encoded isoenzyme. Changes in the rate of biotransformation of haloperidol may affect the profile of its effectiveness and safety. This review is aimed at analyzing the information accumulated in the literature on the role of genetic factors in the formation of an individual response to haloperidol therapy in patients with acute alcoholic hallucinosis.

Pharmacokinetics of Pentanedioic Acid Imidazolyl Ethanamide in Healthy Volunteers

Relevance. Pentanedioic acid imidazolyl ethanamide (PAIE) has been used clinically as an antiviral agent for a long time, however, there is no information in the available literature concerning the dependence of PAIE pharmacokinetics on isoenzymes polymorphism of the cytochrome P450 system (CYP), as well as on the variability of pharmacokinetic parameters in humans. The aim of the study is to determine the main pharmacokinetic parameters of PAIE in healthy volunteers and to assess the contribution of polymorphism of CYP P450 isoenzymes to the variability of pharmacokinetic parameters.Material and methods. The study included 12 healthy volunteers (5 men and 7 women) of the Caucasian race, who took In[1]gavirin® at a dose of 180 mg (2 capsules of 90 mg) on an empty stomach during two dosing periods, separated by a 7-day washout period. Determination of PAIE concentration in blood plasma and urine samples was carried out by high-performance liquid chromatography–mass spectrometry. Polymorphism of CYP genes was analyzed using the polymerase chain re[1]action method in order to analyze the pharmacogenetic features of PAIE metabolism in volunteers during the study.Results. After oral administration, PAIE quickly reached the systemic circulation: the maximum concentration of 578.88±145.21 ng/ml was observed after about 2 hours. Pharmacokinetic parameters of PAIE did not show high intraindividual variability and did not depend on polymorphism of isoenzymes CYP1A1, CYP2C9, and CYP2D6. Within 48 hours after the administration of the studied drug, about half of the taken dose of PAIE was excreted in the urine unchanged, which indicates a significant contribution of the kidneys to the elimination of PAIE. The only adverse event registered in 1 volunteer was a clinically insignificant decrease in the level of leukocytes, which did not require medical intervention and was resolved without consequences.Conclusion. PAIE is characterized by predictable pharmacokinetics, low intraindividual variability of pharmacokinetic parameters, and a favorable safety profile.

Evaluation of the Prescribed Drugs to Elderly in a Tertiary Healthcare Center for Possible Drug Interactions with Investigational Drugs for COVID-19 Treatment.

Objective:Earlier identifying drug interactions may help in risk reduction in elderly patients.Methods:Drug prescription data of 212 elderly patients of tertiary health care center had been analyzed for possible drug interactions with investigational drugs for COVID-19 treatment. Drug interaction had been checked from Stockley's Drug Interaction 2019 and Martindale the Complete Drug Reference 2017 and standard reference books of Pharmacology.Findings:Different types of drugs prescribed in the elderly were 260 and out of which 68 (26.36%) were in the category of fixed-dose combinations. Around 150 (70.75%) elderly patients were having one or more associated comorbidities. Thirty-five drugs prescribed to elderly had been found to cause drug interaction with investigational drugs for COVID-19. Possible drug interactions are mediated through CYP3A4 (eighteen patients), CYP2D6 (seven patients) isoenzymes, or P glycoproteins transporters (three patients).Conclusion:Possible drug interactions predicted in this study suggested need for modification of dose of drug or watchfulness for adverse effects. If these drug interactions are considered beforehand, complications can be prevented on account of these drug interactions in elderly who are suffering from COVID-19.

Efficacy and safety of antipsychotics in adolescents with an acute psychotic episode in relation to the activity of CYP3A and CYP2D6 isoenzymes

Antipsychotics are a first-line treatment for psychotic disorders. The cytochrome P450 isoenzymes CYP3A4/5 and CYP2D6 metabolize most antipsychotics. The activity of these isoenzymes in children changes with maturation, so it is different from that in adults. Objective: to study the associations of CYP3A and CYP2D6 isoenzyme activity parameters with the efficacy and safety of antipsychotics in adolescents with an acute psychotic episode. Patients and methods. The investigation enrolled 53 adolescents with an acute psychotic episode who took antipsychotics. The observation period lasted 14 days. The CGAS, PANSS, UKU SERS, SAS, and BARS scales were used to evaluate the efficiency and safety of the therapy on day 14. The activity of CYP3A and CYP2D6 isoenzymes was measured by determining the metabolic ratios of the concentrations of endogenous substrates of the isoenzymes and their metabolites in a morning urine sample on days 1 and 14 of the study. The activity of CYP3A was assessed by the 6-beta hydroxycortisol/cortisol ratio; that of CYP2D6 was measured by the 6-hydroxy-1,2,3,4-tetrahydro-beta-carboline/pinoline ratio. The influence of carriage of polymorphic variants CYP2D6*4,*9,*10, CYP3A4*22, CYP3A5*3 on the activity of isoenzymes was excluded by removing their carriers from the analysis. Results and discussion. The investigators revealed an association of certain antipsychotic-induced undesirable symptoms with CYP3A and CYP2D6 activity parameters. On day 1, a lower CYP2D6 activity was initially observed in patients with tremor (0.54 [0.34; 1.34] vs 1.25 [0.91; 1.75]; p=0.023). Also, patients with any documented adverse reaction (ARs) to therapy had initially a decreased CYP3A activity (1.2 [0.85; 2.29] vs 2.55 [1.44; 4.83]; p=0.047) and an enhanced CYP3A activity during therapy (the activity difference between day 14 and day 1 was 0.28 [-0.28; 2.32] vs -1.3 [-3.47; 0.66]; p=0.042). Conclusion. The initially reduced activity of CYP2D6 and CYP3A isoenzymes is a significant predictor of antipsychotic-induced ARs in adolescents with an acute psychotic episode. The predictive role of CYP2D6 and CYP3A activity levels in the efficacy of antipsychotics has not been confirmed.

Investigation of MDMA Inhibitory Effect on CytochromeP450 3A4 in Isolated Perfused Rat Liver Model Using Tramadol.

Purpose: MDMA (methylenedioxymethamphetamine) is a synthetic compound, which is a structurally derivative of amphetamine. Also, it acts like an amphetamine, structurally, and functionally. MDMA uses mechanism-based inhibition, to inhibit isoenzyme CYP2D6. It can also inhibit other isoenzymes contributing to its metabolism, including CYP3A4 which is the most important member of the cytochrome P450 superfamily. Since more than 50% of drugs are metabolized by CYP3A4, its inhibition may cause harmful and even lethal drug interactions. Tramadol, as an opioid-like analgesic, is mainly metabolized into O-desmethyl tramadol (M1), by CYP2D6 and undergoes N-demethylation to M2, by CYP2B6 and CYP3A4. Due to the significant potential of abusing tramadol, either alone or in combination with MDMA, the rate of its toxicity and side effects may increase following possible MDMA relevant enzyme inhibition.Methods: Different doses of MDMA (1-10 mg/kg) were intraperitoneally administered to Wistar male rats of both control and treatment groups. Then, after one hour, their isolated livers were perfused by perfusion buffer containing tramadol (1 µg/mL). Afterward, perfusate samples were collected. They were analyzed by HPLC to determine the concentrations of tramadol and its metabolites.Results: MDMA administration in treatment groups reduced M1 production. On the other hand, by following the treatment with different MDMA doses, the M2 metabolic ratio increased by 46 to 101%.Conclusion: it seems that the regular doses of MDMA cannot inhibit the CYP3A4 activity.

Assessment of the clinical utility of pharmacogenetic guidance in a comprehensive medication management service.

Pharmacists are poised to be the health care professionals best suited to provide medication-related consults and services based on a patient's genetics. Despite its potential benefits, the implementation of pharmacogenetic (PGx) testing into primary clinical settings has been slow among medically underserved populations. To our knowledge, this is the first time that PGx-driven recommendations have been incorporated into a Comprehensive Medication Management (CMM) service in a Hispanic population. The aim of this study is to evaluate the clinical utility of adding PGx guidance into pharmacist-driven CMM. This is a pre- and post-interventional design study. Patients were recruited from a psychologist's clinic. A total of 24 patients had a face-to-face interview with a pharmacist to complete a CMM, Personal Medication Record, and Medication-Related Action Plan (MAP) blind to PGx findings. Collected buccal DNA samples were genotyped using drug-metabolizing enzymes and transporters (DMET) Plus Array. The pharmacist generated new MAPs for each patient based on PGx results. Genetic variants that could potentially affect the safety and effectiveness of at least one drug in the pharmacotherapy were identified in 96% of patients, for whom the pharmacist changed the initial recommendations. Polymorphisms in genes encoding for isoenzymes CYP2D6, CYP2C19, and CYP2C9 were identified in 83%, 52%, and 41% of patients, respectively. Pharmacists performing CMM identified 22 additional medication problems after PGx determinations. Moreover, they agreed with the clinical utility of PGx in the studied sample based on perceived value of adding PGx to traditional CMM and its utility in the decision-making process of pharmacists. The study confirmed the critical role to be played by pharmacists in facilitating the clinical usage of relevant genetic information to optimize drug therapy decisions as well as their involvement on many levels of these multidisciplinary implementation efforts, including championing and leading PGx-guided CMM services.

A Herb-drug interaction study: Screen the inhibitory effects of Insulin plant extract on rat liver CYP2D6 isoenzyme upon concurrent administration of Aripiprazole

Aripiprazole belongs to the atypical antipsychotic category of drug. Cytochrome2D6 (CYP2D6) is one of the prominent enzymes that play a key role in the metabolism of Aripiprazole and further formation of an active metabolite, Dehydroaripiprazole takes place. Patients under the treatment with this potent moiety have been reported with the high blood glucose level as a side effect. In addition to this, literature suggests that the leaves of Insulin plant (Costus igneus) are usually administered by diabetic patients (2-3 times) to manage the sugar level without concerning to the physicians. There might be probability while concurrent administration of (Aripiprazole and Insulin plant leaves), leaves inhibit the enzyme and ultimately Dehydroaripiprazole exhibit poor pharmacological action. Hence, the present work was done to investigate the inhibitory effect of Insulin plant extract (IPE) on CYP2D6, with the co-administration of Aripiprazole (to examine the changes in a metabolite of Aripiprazole). In order to carry out this protocol firstly, IPE was prepared by the successive extraction method. Methanolic extract of Insulin plant was found enriched with the Quercetin, which was used as a marker to carry out this study. Presence of Quercetin was confirmed with the Ultra-violet spectroscopy (UV) and High-performance liquid chromatography (HPLC) analytical methods. Characterization of Aripiprazole was done with the help of different analytical tools such as: HPLC, melting point, and UV. Aripiprazole alone and with the several dilutions of IPE were incubated using isolated rat liver microsome (RLM) and analyzed using HPLC. HPLC data demonstrated that the, mixture of IPE+Aripiprazole (herb and drug in liver microsomes), in comparison to Aripiprazole+RLM (alone drug in liver microsomes) has not shown any significant inhibition of the enzyme, and inhibitory concentration (IC50) value found to be 4.49µg/ml. Therefore this study concluded that IPE has shown safe results even at the highest clinical dose after oral administration i.e., 20-1000µg/ml and did not show any significant CYP2D6 inhibition. Nevertheless, to confirm these observations, inclusion of in vivo studies will be advantageous. As per our knowledge, this is the first attempt made on the detection of Herb- Drug interactions (HDI’S) between Insulin plant and Aripiprazole.

No association of rs1065852 and rs3892097 polymorphisms gene CYP2D6 with treatment resistant schizophrenia

According to modern data, about a third of patients suffering from schizophrenia are considered treatment resistant. The metabolism of about 20% of medicines and mainly psychotropic drugs is caused by the isoenzyme CYP2D6. This article presents the data of the CYP2D6 gene study as biomarkers for the treatment resistant schizophrenia. The study included 130 patients, men (65.4%) and women (34.6%) aged 18 to 60 years with schizophrenia. Based on the results, we found no effect of rs1065852 and rs3892097 polymorphisms gene CYP2D6 on treatment resistant schizophrenia.

Effects of Pharmacogenetic Screening for CYP2D6 Among Elderly Starting Therapy With Nortriptyline or Venlafaxine: A Pragmatic Randomized Controlled Trial (CYSCE Trial).

The duration of untreated depression is a predictor for poor future prognosis, making rapid dose finding essential. Genetic variation of the CYP2D6 isoenzyme can influence the optimal dosage needed for individual patients. The aim of this study was to determine the effectiveness of CYP2D6 pharmacogenetic screening to accelerate drug dosing in older patients with depression initiating nortriptyline or venlafaxine. In this randomized controlled trial, patients were randomly allocated to one of the study arms. In the intervention arm (DG-I), the specific genotype accompanied by a standardized dosing recommendation based on the patients' genotype and the prescribed drug was directly communicated to the physician of the participant. In both the deviating genotype control arm (DG-C) and the nonrandomized control arm, the physician of the participants was not informed about the genotype and the associated dosing advise. The primary outcome was the time needed to reach adequate drug levels: (1) blood levels within the therapeutic range and (2) no dose adjustments within the previous 3 weeks. No significant difference was observed in mean time to reach adequate dose or time to adequate dose between DG-I and DG-C. Compared with the nonrandomized control arm group, adequate drug levels were reached significantly faster in the DG-I group (log-rank test; P = 0.004), and there was a similar nonsignificant trend for the DG-C group (log-rank test; P = 0.087). The results of this study do not support pharmacogenetic CYP2D6 screening to accelerate dose adjustment for nortriptyline and venlafaxine in older patients with depression.

Investigation of metabolism of HN-1 isolated from Millettia pachyloba in vivo and in vitro

Ultra-fast performance liquid chromatography-mass spectrometry( UFLC-MS/MS) was used to study the anti-inflammatory active ingredient of Millettia pachyloba,6-methoxy-8,8-dimethyl-3-( 2,4,5-trimethoxyphenyl)-4 H,8 H-pyrano[2,3-f]chromen-4-one( HN-1),in liver microsomes of rats,mice,rhesus monkeys,Beagle dogs and humans metabolic stability,and compare the metabolic differences between different species. The metabolic phenotype in human liver microsomes was determined by chemical inhibitor method. Using UPLC-Q-TOF-MS/MS detection method,the in vitro metabolites of various liver microsomes were preliminarily inferred by comparing the samples incubated for 0 min and 60 min in vitro. The metabolites of HN-1 in SD rats were presumed by comparing feces,urine,plasma blanks and samples after administration. The results showed that the metabolism of HN-1 in various liver microsomes was stable,and the metabolic properties of dog and human liver microsomes were the closest. It is mainly catabolized by CYP1 A1,CYP2 D6 and CYP3 A4 isoenzymes in human liver microsomes. The metabolites of HN-1 in vitro and in vivo,including 3 in vitro metabolites and5 in vivo metabolites,were preliminarily estimated. The results laid the foundation for further pharmacological studies of HN-1.

In vitro metabolic profiling of synthetic cannabinoids by pooled human liver microsomes, cytochrome P450 isoenzymes, and Cunninghamella elegans and their detection in urine samples.

As synthetic cannabinoids are extensively metabolized, there is an urgent need for data on which metabolites can be used for successful urine screening. This study examines the in vitro metabolism of EG-018 and its 5F-analogue EG-2201 by means of comparing three different in vitro models: pooled human liver microsomes, cytochrome P450 isoenzymes, and a fungal approach utilizing the filamentous fungus Cunninghamella elegans LENDNER, which is known for its ability to mimic human biotransformation of xenobiotics. In addition, this study includes the screening of two authentic urine samples from individuals with proven EG-018 consumption, for the evaluation of in vitro-in vivo extrapolations made in the study. Incubation with pooled human liver microsomes yielded 15 metabolites of EG-018 belonging to six different metabolite subgroups, and 21 metabolites of EG-2201 belonging to seven different metabolite subgroups, respectively. Incubation with cytochrome P450 isoenzymes incubation yielded a further three EG-018 and five EG-2201 metabolites. With reference to their summed metabolite peak abundancies, the isoenzymes CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were shown to contribute most to the microsomal metabolism of EG-018 and EG-2201. CYP2B6 was shown to make the lowest contribution, by far. As the phase I metabolism of both synthetic cannabinoids was shown to be distributed over a substantial number of different cytochrome P450 isoenzymes, it was concluded that it is likely to not be significantly affected by co-consumption of other drugs. Although fungal incubation with Cunninghamella elegans yielded an additional three EG-018 and four EG-2201 metabolites not observed after microsomal incubation, metabolites generated by Cunninghamella elegans were in good correlation with those generated by microsomal incubations. The fungal model demonstrated its ability to be an independent in vitro model in synthetic cannabinoid metabolism research. The three tested in vitro models enable sufficient predictive in vitro-in vivo extrapolations, comparable to those obtained from hepatocyte incubation published in the literature. In addition, with regard to the screening of authentic urine samples and comparison with the literature, one monohydroxylated EG-018 metabolite and two monohydroxylated EG-2201 metabolites can be recommended as urinary targets, on the basis of the tested in vitro models. Graphical abstract.