CYP2C19 Enzyme Research Articles

CYP2C19 genetic variation and individualized clopidogrel prescription in a cardiology clinic

ABSTRACTBackground: Clopidogrel (Plavix) is an antiplatelet medication that is routinely used in patients with cardiovascular disease. Cytochrome P2C19 enzymes play a major role in its metabolism, which determines its varied therapeutic level and its effectiveness.Objectives: To customize clopidogrel therapy and evaluate its efficacy by using CYP2C19 genotypic and phenotypic information to improve clinical outcomes in patients.Methods: A total of 465 patients with underlying cardiovascular disease were selected from our out-patient cardiology clinic. DNA sequences of CYP2C19 were analyzed in 465 patients.Results: Of 465 patients, 183 were wild-type homozygous (*1/*1) and 18.8% gain-of function and 19.8% loss-of-function alleles in our patient population The following changes were made: 1) Switching to prasugrel in patients whose genotype noted them to be “Slow metabolizers. This medication adjustment improved clinical outcomes in this patient group.2) Discontinuing or lowering clopidogrel doses in patients whose genotypes noted them to be “Fast or ultra-fast metabolizes” to decrease bleeding risk. For those who were not on clopidogrel but carried abnormal allele(s), “clopidogrel caution” was documented. These individuals were followed up for 3 years and there has not been any cardiac clinical symptoms, cardiac death or excessive bleeding reported.Conclusions: Given the varied effectiveness of clopidogrel due to its metabolism by CYP2C19 enzyme, and the relatively high frequency of both gain-of-function (18.8%) and loss-of-function (19.8%) alleles in our patient population, we believe that genotyping CYP2C19 is clinically important in order to improve patient outcomes and minimize patient risk.

Abstract 5031: Distribution of single nucleotide polymorphisms related to paclitaxel and carboplatin toxicity in ovarian cancer patients

Abstract Introduction: Standard first-line treatment for ovarian cancer consists in the combined use of taxanes and platinum, with neuropathies and neutropenia the most frequent and complex adverse drug reactions (ADRs) requiring clinical management. These adverse effects may be related to differing levels of drug transport and metabolism brought about by intrinsic genetic characteristics of the patients. Single nucleotide polymorphisms (SNPs) are now recognized as key factors in the variability of drug response. In a cohort of Chilean ovarian cancer patients we analyzed the frequencies of several SNPs previously reported to be associated with paclitaxel and carboplatin ADRs. Methods: Blood samples were obtained with informed consent from adult ovarian cancer patients (n = 120). DNA was extracted and SNPs within the ABC transporter and CYP P450 gene families were genotyped. High specificity Taqman probes were used. Results: Four SNPs associated with risk of ADR within the ABC transporter family showed genotypic frequencies ranging between 0 - 23%. Frequencies for the ADR-associated variants in the CYP P450 family were 4 - 90%. Finally, for the CYP2C8 enzyme, whose function is essential in paclitaxel metabolism, the frequencies of risk-associated SNPs ranged from 2.10% to 13.6%. Conclusions: SNPs associated with paclitaxel and carboplatin ADRs are highly prevalent in the Chilean population of ovarian cancer patients studied. The identification of these variants may help avoid severe ADRs associated with chemotherapy regimes. Funding: CORFO 13CTI21526-P6 & 13IDL2-18608 Citation Format: Miguel Cordova, Maria L. Bravo, Isidora Arriagada, Elisa Cumsille, Luis Quiñones, Erasmo Bravo, Raimundo Correa, Juan E. Leiva, Cesar Paredes, Mauricio Cuello, Carolina Ibañez, Marcelo Garrido, Gareth I. Owen. Distribution of single nucleotide polymorphisms related to paclitaxel and carboplatin toxicity in ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5031. doi:10.1158/1538-7445.AM2017-5031

Effects of obesity on liver cytochromes P450 in various animal models.

The prevalence of obesity and other obesity-related diseases is increasing worldwide. Obesity is a disease characterized by increased body weight, or a condition resulting from excessive accumulation of body fat. Due to increased body fat deposits, obesity has also been associated with increased mortality resulting from higher incidence rates of hypertension, diabetes, or various types of cancer, such as breast, colorectal, cervical and prostate cancer. Physiological changes associated with obesity are likely to result in altered drug biotransformation. The main enzymes enabling the oxidative biotransformation of most drugs are cytochromes P450 (CYPs). The review summarizes how pathophysiological factors, especially obesity, affect properties (e.g. enzyme activity, protein expression, gene expression) of CYP enzymes in various experimental models of human obesity. Results reported by various authors suggest that obesity is associated with a decrease of CYP activities (except for the CYP2C and CYP2E1 enzymes). The only exception is mouse obesity induced by monosodium glutamate (administered to newborn mice) as it usually leads to increased CYP expression. Selecting an animal model that is as close as possible to the properties of human obesity is of paramount importance.

Actividad de CYP2C19 y factores de riesgo cardiovascular en pacientes con síndrome coronario agudo

IntroductionCYP2C19 is a major isoform of cytochrome P450 that metabolizes a number of drugs and is involved in the glucocorticoids synthesis. CYP2C19 polymorphisms have been associated with the genetic risk for type 2 diabetes. MethodsFive hundred and three patients with an acute coronary event were studied to assess the association between the CYP2C19 activity (CYP2C19*2, CYP2C19*3 and CYP2C19*17 variants) and the type of acute coronary syndrome, cardiovascular risk factors (arterial systemic hypertension, diabetes mellitus, dyslipidemia and smoking), analytical parameters and the extent and severity of coronary atherosclerosis. ResultsGenotype distribution in our series was similar to that expected in the Caucasian population. Among the traditional cardiovascular risk factors, very poor metabolizer patients (*2/*2, *3/*3 or *2/*3) had a greater tendency to present diabetes mellitus needing insuline (P=.067). Conversely, when we compared very poor, poor and normal metabolizers vs. rapid and ultrarapid metabolizers we found significant differences in those diabetic patients under insulin treatment (64 patients [18%] vs. 17 patients [11%]; P=.032). On the contrary, analytical parameters, systemic arterial hypertension, dyslipidemia, smoking or the personal/family history of coronary artery disease did not reach statistical significance regardless of CYP2C19 activity. Similarly, the number and the type of coronary disease (thrombotic, fibrotic or both) did not differ between patients with different CYP2C19 enzyme activity. ConclusionPatients with an acute coronary event and a very poor, poor and normal CYP2C19 metabolizer genotype have a higher prevalence of diabetes mellitus needing insuline than patients with the rapid and ultrarapid metabolizers CPY2C19 genotype.

Serum Clomipramine and Desmethylclomipramine Levels in a CYP2C19 and CYP2D6 Intermediate Metabolizer

Pharmacogenetics within psychiatry has the potential to aid in the dose and selection of medications. A substantial number of psychiatric medications are metabolized through either of the highly polymorphic drug-metabolizing enzymes CYP2D6 and CYP2C19. Of these, clomipramine is subject to metabolism by both CYP2C19 and CYP2D6, leaving individuals with deficiencies of these drug-metabolizing enzymes at risk of higher concentrations of the parent molecule. Herein, we present the case of a 29-year-old male with diagnoses of depression and obsessive compulsive disorder who had trialed and failed a dozen psychiatric medications, many of which are subject to metabolism by CYP2D6 and/or CYP2C19, and had most recently been taking clomipramine for approximately 2.5 years. Pharmacogenetic testing revealed this patient to be an intermediate metabolizer for both CYP2C19 (*1/*2) and CYP2D6 (*4/*41), which resulted in considerably elevated serum trough concentrations of clomipramine and its active metabolite desmethylclomipramine. This case provides a retrospective view of how the knowledge of an individual's pharmacogenetic test results can aid in their clinical care.

The effect of milk thistle (Silybum marianum) and its main flavonolignans on CYP2C8 enzyme activity in human liver microsomes

Milk thistle is a widely-consumed botanical used for an array of purported health benefits. The primary extract of milk thistle is termed silymarin, a complex mixture that contains a number of structurally-related flavonolignans, the flavonoid, taxifolin, and a number of other constituents. The major flavonolignans present in most extracts are silybin A, silybin B, isosilybin A and isosilybin B, silydianin, silychristin and isosilychristin. Silymarin itself has been reported to inhibit CYP2C8 activity in vitro, but the effect of the individual flavonolignans on this enzyme has not been studied. To investigate the effects of milk thistle extract and its main flavonolignans (silybin A, silybin B, isosilybin A and isosilybin B) on CYP2C8 activity at relevant concentrations, the effect of milk thistle extract and the flavonolignans on CYP2C8 enzyme activity was studied in vitro using human liver microsomes (HLM) incorporating an enzyme-selective substrate for CYP2C8, amodiaquine. Metabolite formation was analyzed using liquid chromatography-tandem mass spectrometry (LC/MS-MS). The concentration causing 50% inhibition of enzyme activity (IC50) was used to express the degree of inhibition. Isosilibinin, a mixture of the diastereoisomers isosilybin A and isosilybin B, was found to be the most potent inhibitor, followed by isosilybin B with IC50 values (mean ± SE) of 1.64 ± 0.66 μg/mL and 2.67 ± 1.18 μg/mL, respectively. The rank order of observed inhibitory potency after isosilibinin was silibinin > isosilybin A > silybin A > milk thistle extract > and silybin B. These in vitro results suggest a potentially significant inhibitory effect of isosilibinin and isosilybin B on CYP2C8 activity. However, the observed IC50 values are unlikely to be achieved in humans supplemented with orally administered milk thistle extracts due to the poor bioavailability of flavonolignans documented with most commercially available formulations.

Utilizing PBPK Modeling to Evaluate the Potential of a Significant Drug-Drug Interaction Between Clopidogrel and Dasabuvir: A Scientific Perspective.

Dasabuvir, a component of VIEKIRA PAK, is a substrate of CYP2C8 enzymes. Prescribing information for VIEKIRA PAK contraindicates gemfibrozil, a strong CYP2C8 inhibitor, because coadministration significantly increases dasabuvir exposures, which may increase the risk of QT prolongation. Clopidogrel may increase dasabuvir exposures primarily due to CYP2C8 inhibition by clopidogrel-acyl-β-D-glucuronide. This commentary outlines the US Food and Drug Administration (FDA) interdisciplinary review team's scientific perspective to address the potential for a significant drug-drug interaction (DDI) between clopidogrel and VIEKIRA PAK.

CYP450 enzymes genetic polymorphism influence on treatment of affective disorders

IntroductionIndividualized treatment decisions in psychiatry may be important, since substantial part of first choice drugs are ineffective or cause side effects. Polymorphic variants of genes that code CYP450 enzymes cause differences in their activity and therefore in efficacy and safety of drugs that are metabolized by them.Aim of the studyDetermine whether pharmacogenetic testing of CYP2D6, CYP2C19 and CYP2C9 polymorphism would have had influence on selected patients’ treatment courses.MethodsFive patients that were diagnosed for treament-resistant mood disorders in Vilnius university hospital Santariskiu clinics centre of neurology, department of psychiatry were invited to give blood samples for genetic testing retrospectively. Patients’ CYP2C19, CYP2D6 and CYP2C9 enzymes genetic polymorphism results were compared with previous empirical pharmacological treatment courses of these patients.ResultsIn four out of five cases significant polymorphism of CYP2C19 enzyme allele was detected. In all of these cases 1*/2* variant, that conditions intermediate metabolizer phenotype, was identified. Alterations in CYP2D6 and CYP2C19 regions were not found. In three cases the presence of varied genetic variant could have been clinically relevant. In two of these cases Sertraline and valproates, that are both metabolized by CYP2C19 enzyme, were taken by patients and side effects were observed. Unsuccessful treatment was repeated without effect, both in clinical and outpatient environment. Continuous rehospitalization took place until appropriate empirical treatments were established.ConclusionsPharmacogenetic testing could have had influence on treatment choices for three out of five selected patients leading to less side effects and rehospitalizations.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Potential Role of Patients’ CYP3A-Status in Clozapine Pharmacokinetics

Background:The atypical antipsychotic clozapine is effective in treatment-resistant schizophrenia; however, the success or failure of clozapine therapy is substantially affected by the variables that impact the clozapine blood concentration. Thus, elucidating the inter-individual differences in clozapine pharmacokinetics can facilitate the personalized therapy.Methods:Since a potential role in clozapine metabolism is assigned to CYP1A2, CYP2C19, CYP2D6 and CYP3A enzymes, the association between the patients’ CYP status (CYP genotypes, CYP expression) and clozapine clearance was evaluated in 92 psychiatric patients.Results:The patients’ CYP2C19 or CYP2D6 genotypes and CYP1A2 expression seemed to have no effect on clozapine serum concentration, whereas CYP3A4 expression significantly influenced the normalized clozapine concentration (185.53±56.53 in low expressers vs 78.05±29.57 or 66.52±0.25 (ng/mL)/(mg/kg) in normal or high expressers, P<.0001), in particular that the patients expressed CYP1A2 at a relatively low level. The functional CYP3A5*1 allele seemed to influence clozapine concentrations in those patients who expressed CYP3A4 at low levels. The dose requirement for the therapeutic concentration of clozapine was substantially lower in low CYP3A4 expresser patients than in normal/high expressers (2.18±0.64 vs 4.98±1.40 mg/kg, P<.0001). Furthermore, significantly higher plasma concentration ratios of norclozapine/clozapine and clozapine N-oxide/clozapine were observed in the patients displaying normal/high CYP3A4 expression than in the low expressers.Conclusion:Prospective assaying of CYP3A-status (CYP3A4 expression, CYP3A5 genotype) may better identify the patients with higher risk of inefficiency or adverse reactions and may facilitate the improvement of personalized clozapine therapy; however, further clinical studies are required to prove the benefit of CYP3A testing for patients under clozapine therapy.

AM-2201 Inhibits Multiple Cytochrome P450 and Uridine 5'-Diphospho-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes.

AM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP) or uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes. We evaluated the inhibitory effect of AM-2201 on the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six major human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) enzymes in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry to investigate drug interaction potentials of AM-2201. AM-2201 potently inhibited CYP2C9-catalyzed diclofenac 4′-hydroxylation, CYP3A4-catalyzed midazolam 1′-hydroxylation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation, and UGT2B7-catalyzed naloxone 3-glucuronidation with IC50 values of 3.9, 4.0, 4.3, and 10.0 µM, respectively, and showed mechanism-based inhibition of CYP2C8-catalyzed amodiaquine N-deethylation with a Ki value of 2.1 µM. It negligibly inhibited CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, and UGT1A9 activities at 50 μM in human liver microsomes. These in vitro results indicate that AM-2201 needs to be examined for potential pharmacokinetic drug interactions in vivo due to its potent inhibition of CYP2C8, CYP2C9, CYP3A4, UGT1A3, and UGT2B7 enzyme activities.

The role of human CYP2C8 in the metabolizing of montelukast-like compounds: a computational study

Docking studies on the selected montelukast-like molecules with the CYP2C8 enzyme were done to investigate their interactions. The results showed that some of the investigated structures have competition with montelukast to bind to the CYP2C8, based on the similarity of their binding energies. Based on the docking results, different interactions between the investigated structures and CYP2C8 were observable such as hydrogen bonding, σ–π, and cation–π interactions. A cation–π interaction between the Arg241 and chloroquinolin moiety was observable in most of the studied cases. A hydrogen bonding interaction between Ser100, Ser103, and Asn217 amino acids with the carboxylate moiety of the montelukast-like molecules was observable, as well. The CYP3A4, CYP2C8, and CYP2C9 have the role to oxidize montelukast to convert it to the more soluble compounds. This process was done by adding OH functional groups to it. New OH groups can facilitate its excretion from the body via kidneys by making it more hydrophilic. Therefore, the LogD values were considered as a measure of the ease of excretion. Based on the calculated LogD values, six of the studied structures will not obtain enough water solubility to be excreted from body by one oxidation process by the CYP2C8 enzyme and more of the oxidation process is needed. Between the studied structures, three of them showed the carboxylate moiety as the preferred binding site to the heme moiety. In total nine compounds need more of the oxidation process to obtain enough solubility to be excreted from the body .

Influence of age and co-medication on the steady-state pharmacokinetics of valproic acid in Tunisian patients with epilepsy

AimValproic acid (VPA) is a widely prescribed broad-spectrum antiepileptic drug. However, the use of VPA is complicated in clinical practice by its remarkably wide variability of pharmacokinetics. The objective of this study was to investigate the effects of demographic factors and associated therapies on steady-state plasma VPA concentrations in patients with epilepsy. MethodsThis retrospective cohort study was carried out using the routine therapeutic drug monitoring (TDM) database. Stepwise logistic regression analysis was used to compare serum VPA levels in 78 epilepsy patients treated with VPA in association with at least one other drug that could have interacted with CYP2C9, CYP2C19 or UGT enzymes. ResultsThe frequency of subtherapeutic serum VPA levels was significantly increased with younger age (P<0.02), the number of co-medications (P<0.007) and use of enzyme-inducing co-medications (P<0.02). No significant correlations between VPA dose and trough plasma concentrations were found, as the latter did not increase in proportion to the dose. ConclusionRoutine monitoring of VPA serum levels would be extremely useful in epilepsy patients in the pediatric age group and in those who require associated enzyme-inducing medications.

CRT-100.66 Platelet Activity in Clopidogrel Users With and Without Omeprazole: Meta-analysis of Pharmacodynamic Function

Clopidogrel is metabolized by CYP2C19 enzyme to its active metabolite and omeprazole is a strong inhibitor of this enzyme and therefore is speculated to decrease the antiplatelet activity of clopidogrel. We searched PubMed, EBSCO and Google Scholar databases to identify studies assessing platelet

Interaction of quercetin and its metabolites with warfarin: Displacement of warfarin from serum albumin and inhibition of CYP2C9 enzyme.

Flavonoids are ubiquitous molecules in nature with manifold pharmacological effects. Flavonoids interact with several proteins, and thus potentially interfere with the pharmacokinetics of various drugs. Though much is known about the protein binding characteristics of flavonoid aglycones, the behaviour of their metabolites, which are extensively formed in the human body has received little attention. In this study, the interactions of the flavonoid aglycone quercetin and its main metabolites with the albumin binding of the oral anticoagulant warfarin were investigated by fluorescence spectroscopy and ultrafiltration. Furthermore, the inhibitory effects of these flavonoids on CYP2C9 enzyme were tested because the metabolic elimination of warfarin is catalysed principally by this enzyme. Herein, we demonstrate that each tested flavonoid metabolite can bind to human serum albumin (HSA) with high affinity, some with similar or even higher affinity than quercetin itself. Quercetin metabolites are able to strongly displace warfarin from HSA suggesting that high quercetin doses can strongly interfere with warfarin therapy. On the other hand, tested flavonoids showed no or weaker inhibition of CYP2C9 compared to warfarin, making it very unlikely that quercetin or its metabolites can significantly inhibit the CYP2C9-mediated inactivation of warfarin.

Effects of Unprocessed Versus Vinegar-Processed Schisandra chinensis on the Activity of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 Enzymes in Rats

Schisandra chinensis (SC) is a well-known traditional Chinese herbal medicine that has been used in clinical practices for thousands of years. However, the differences between the effects of unprocessed and vinegarprocessed Schisandra chinensis (VSC) on cytochrome P450 (CYP450) activities are poorly understood. To evaluate the differences between processed and unprocessed SC on the metabolism of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 substrates in rats using a cocktail method based on a developed and validated high performance liquid chromatography-mass spectrometry (HPLC-MS) method. Six probe substrates (coumarin (CYP2A6), bupropion (CYP2B6), paclitaxel (CYP2C8), tolbutamide (CY2C9), omeprazole (CYP2C19) and metoprolol (CYP2D6)) were delivered simultaneously into rats treated with single or multiple doses of processed or crude SC extract. The plasma concentrations of the six probes were profiled by HPLC-MS, and their corresponding pharmacokinetic parameters were calculated. Treatment with single or multiple doses of either extract of SC or VSC induced CYP2A6, CYP2B6 and CYP2C9 enzyme activity and inhibited CYP2D6, CYP2C19 and CYP2C8 enzyme activity in rats. Furthermore, the inhibitory or induced effect of multiple doses of SC was more potent after vinegar processing than without vinegar processing. CYP2A6, 2B6 and 2C9 enzyme activity were induced significantly after treatment with multiple doses but not after a single dose. CYP2C19 enzyme activity were inhibited significantly after treatment with multiple doses but not after a single dose. These results provide useful scientific data for the safe clinical application of either extract of SC in combination with other drugs, which should lack the side effects induced by other herb-drug interactions.

Electrochemically Driven Omeprazole Metabolism via Cytochrome P450 Assembled on the Nanocomposites of Ceria Nanoparticles and Graphene

Cytochrome P450 enzymes are iron-heme proteins involve in the metabolism of both endogenous and exogenous compounds. Accurate mimicking of the natural metabolic pathways has attracted significant interest in vitro. Herein, a novel bioelectronic platform for drug metabolism catalyzed by cytochrome P450 was successfully constructed. Due to the excellent oxygen buffering property of ceria, and the excellent electrical conductivity and biocompatibility of graphene, CYP2C19 enzyme assembled on the CS/CeNP/RGO modified GC electrode exhibited excellent electrochemical activity, enzymatic activity, and metabolic efficiency toward omeprazole, in which the apparent Michaelis constant Kmapp was calculated to be 8.22 μM, and the catalytic rate constant kcat and catalytic efficiency kcat/Kmapp were calculated to be 5.72 s−1 and 0.696 μM−1 s−1, respectively. With an electrochemically driven way, the as-prepared CYP2C19/CS/CeNP/RGO/GC electrode could be used as an enzymatic reactor for drug metabolism in vitro, the metabolic yield of omeprazole was 17.2% after electrolysis for 4 h when the GC electrode area was about 7.0 mm2, and as a biosensor for omeprazole with high sensitivity of a LOD of 0.42 μM. Therefore, the as-prepared cytochrome P450 electrochemically-driven system can offer us a promising platform for monitoring substrate metabolism, efficient biosensor for toxicity analysis and bioreactor for chemical synthesis.

Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes.

MAM-2201 is a synthetic cannabinoid that is increasingly found in recreational drug abusers and cases of severe intoxication. Thus, characterization of the metabolic pathways of MAM-2201 is necessary to predict individual pharmacokinetics and toxicity differences, and to avoid toxic drug-drug interactions. Collectively, 19 phase 1 metabolites of MAM-2201 were identified using liquid chromatography-Orbitrap mass spectrometry following human liver microsomal incubations in the presence of NADPH: 7 hydroxy-MAM-2201 (M1-M7), 4 dihydroxy-MAM-2201 (M8-M11), dihydrodiol-MAM-2201 (M12), N-(5-hydroxypentyl)-MAM-2201 (M13), hydroxy-M13 (M14), N-dealkyl-MAM-2201 (M15), 2 hydroxy-M15 (M16, M17), MAM-2201 N-pentanoic acid (M18), and hydroxy-M18 (M19). On the basis of intrinsic clearance values in human liver microsomes, hydroxy-MAM-2201 (M1), N-(5-hydroxypentyl)-MAM-2201 (M13), and hydroxy-M13 (M14) were the major metabolites. Based on an enzyme kinetics study using human cDNA-expressed cytochrome P450 (CYP) enzymes and an immunoinhibition study using selective CYP antibodies in human liver microsomes, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes were responsible for MAM-2201 metabolism. The CYP3A4 enzyme played a prominent role in MAM-2201 metabolism, and CYP1A2, CYP2B6, CYP2C8, and CYP2C9 enzymes played major roles in the formation of some metabolites. MAM-2201 is extensively metabolized by multiple CYP enzymes, indicating that MAM-2201 and its metabolites should be used as markers of MAM-2201 abuse and toxicity. Graphical abstract In vitro metabolic pathways of MAM-2201 were characterized in human liver microsomes and recombinant CYPs using LC-HRMS analysis. Total 19 phase I metabolites were identified with predominant contribution of CYP3A4.

The effect of proton pump inhibitors on the CYP2C19 enzyme activity evaluated by the pantoprazole-13C breath test in GERD patients: clinical relevance for personalized medicine

Patients with gastroesophageal reflux disease (GERD) are routinely prescribed one of the six FDA approved proton pump inhibitors (PPI). All of these PPI are inhibitors of CYP2C19 enzyme to varying degrees. The phenotype pantoprazole-13C breath test (Ptz-BT) was used to identify patients who are poor metabolizers (PM) and the extent of phenoconversion of CYP2C19 enzyme activity caused by four PPI (omeprazole, esomprazole pantoprazole and rabeprazole) in 54 newly diagnosed GERD patients prior to initiating randomly selected PPI therapy and 30 d after PPI therapy. The phenoconversion after 30 d of PPI therapy in GERD patients was statistically significant (p =0.001) with omeprazole/esomeprazole (n = 27) strong CYP2C19 inhibitors, while there was no change in CYP2C19 enzyme activity (p = 0.8) with pantoprazole/ rabeprazole (n = 27), weak CYP2C19 inhibitors. The concommitant use of omeprazole/esomeprazole, therefore, could have critical clinical relevance in individualizing medications metabolized primarily by CYP2C19 such as PPI, clopidogrel, phenytoin, cyclophosphamide, thalidomide, citalopram, clonazepam, diazepam, proguanil, tivantinib etc. The rapid (30 min), in vivo, and non-invasive phenotype Ptz-BT can evaluate CYP2C19 enzyme activity. More importantly, it can identify GERD patients with low CYP2C19 enzyme activity (PM), caused by PPI or other concomitant medications, who would benefit from dose adjustments to maintain efficacy and avoid toxicity. The existing CYP2C19 genotype tests cannot predict the phenotype nor can it detect phenoconversion due to non genetic factors.

Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.

The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3β phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.

CYP2C9 Genotypes Modify Benzodiazepine-Related Fall Risk: Original Results From Three Studies With Meta-Analysis

ObjectiveTo investigate whether the CYP2C9*2 and *3 variants modify benzodiazepine-related fall risk. DesignThree prospective studies; the Rotterdam Study, B-PROOF, and LASA. SettingCommunity-dwelling individuals living in or near five Dutch cities. ParticipantsThere were 11,485 participants aged ≥55 years. MeasurementsFall incidents were recorded prospectively. Benzodiazepine use was determined using pharmacy dispensing records or interviews. Cox proportional hazard models adjusted for age and sex were applied to determine the association between benzodiazepine use and fall risk stratified for CYP2C9 genotype and comparing benzodiazepine users to nonusers. The results of the three studies were combined applying meta-analysis. Within benzodiazepine users, the association between genotypes and fall risk was also assessed. ResultsThree thousand seven hundred five participants (32%) encountered a fall during 91,996 follow-up years, and 4% to 15% (depending on the study population) used benzodiazepines. CYP2C9 variants had frequencies of 13% for the *2 allele and 6% for the *3 allele. Compared to nonusers, current benzodiazepine use was associated with an 18% to 36% increased fall risk across studies with a combined hazard ratio (HR) = 1.26 (95% confidence interval [CI], 1.13; 1.40). CYP2C9*2 or *3 allele variants modified benzodiazepine-related fall risk. Compared to nonusers, those carrying a CYP2C9*2 or *3 allele and using benzodiazepines had a 45% increased fall risk (HR, 1.45 95% CI, 1.21; 1.73), whereas CYP2C9*1 homozygotes using benzodiazepines had no increased fall risk (HR, 1.14; 95% CI, 0.90; 1.45). Within benzodiazepine users, having a CYP2C9*2 or *3 allele was associated with an increased fall risk (HR, 1.35; 95% CI, 1.06; 1.72). Additionally, we observed an allele dose effect; heterozygous allele carriers had a fall risk of (HR = 1.30; 95% CI, 1.05; 1.61), and homozygous allele carriers of (HR = 1.91 95% CI, 1.23; 2.96). ConclusionsCYP2C9*2 and *3 allele variants modify benzodiazepine-related fall risk. Those using benzodiazepines and having reduced CYP2C9 enzyme activity based on their genotype are at increased fall risk. In clinical practice, genotyping might be considered for elderly patients with an indication for benzodiazepine use. However, because the exact role of CYP2C9 in benzodiazepine metabolism is still unclear, additional research is warranted.