Редактирование: CYP2C19

Cytochrome P450 2C19 (EC 1.14.14.1) ((R)-limonene 6-monooxygenase) (EC 1.14.14.53) ((S)-limonene 6-monooxygenase) (EC 1.14.14.51) ((S)-limonene 7-monooxygenase) (EC 1.14.14.52) (CYPIIC17) (CYPIIC19) (Cytochrome P450-11A) (Cytochrome P450-254C) (Fenbendazole monooxygenase (4'-hydroxylating)) (EC 1.14.14.75) (Mephenytoin 4-hydroxylase)

==Publications==

{{medline-entry
|title=Physiologically Based Pharmacokinetic Approach Can Successfully Predict Pharmacokinetics of Citalopram in Different Patient Populations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31750550
|abstract=A physiologically based pharmacokinetic model (PBPK) was built for citalopram using Simcyp-based absorption, distribution, metabolism, and excretion simulator. Various physicochemical properties of citalopram were obtained from the published literature. The in vitro-in vivo extrapolation method was used to predict clearance in humans from recombinant enzyme data. Tissue distribution was predicted using parameter estimation function to fit the developed model to the observed concentration-versus-time data using nonlinear mixed-effects modeling approach. The model was verified by comparing the PBPK-based predictions with the observed pharmacokinetic (PK) profiles of citalopram in 26 clinical studies across a dose range of 10 to 60 mg. The predicted PK parameters of citalopram after intravenous dosing were within the -10% to 22% of the corresponding PK parameters obtained from the studies with quantified data sets. Most of the predicted PK parameters of citalopram after single-dose oral administration were within the 70%-130% range of the corresponding PK parameters obtained from observed data from 8 studies. After multidose oral administration, percentage error of C  and AUC was between -21% and 25% and -31% and 21%, respectively. Most of the observed data were within the 5th and 95th percentile interval of the variability around the predicted plasma concentrations. With the established model, the PK profiles in geriatric populations, populations with cytochrome P450 (CYP) 2C19 and/or 2D6 extensive metabolizers or poor metabolizers were predicted, and the predictions were in good agreement with the observed data. The model developed is robust to represent the absorption and disposition of citalopram and can predict the impact of patient covariates, such as age and genetic polymorphism of [[CYP2C19]] and [[CYP2D6]], on exposure of citalopram.

|keywords=* citalopram
* genetic polymorphism
* geriatrics
* physiologically based pharmacokinetic modeling
|full-text-url=https://sci-hub.do/10.1002/jcph.1541
}}
{{medline-entry
|title=Longitudinal exposure of English primary care patients to pharmacogenomic drugs: An analysis to inform design of pre-emptive pharmacogenomic testing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31454087
|abstract=To investigate the longitudinal exposure of English primary care patients to pharmacogenomic drugs to inform design of pre-emptive testing. Sixty-three drugs were identified with dosing guidelines based on variants of 19 pharmacogenes in the Pharmacogenomics Knowledgebase on 01 September 2018. Prescribing of these pharmacogenomic drugs between 1993 and 2017 was summarised for a sample of 648 141 English patients aged 50-99 years on 01 January 2013, registered with Clinical Practice Research Datalink practices during 2011-12. Exposure of patients to pharmacogenomic drugs retrospectively (2, 10, 20 y) and prospectively (5 y) was described. During 2011-12, 58% of patients were prescribed at least 1 pharmacogenomic drug, increasing to 80% over the previous 20 years. Multiple exposure was common, with 47% patients prescribed ≥2 pharmacogenomic drugs and 7% prescribed ≥5 pharmacogenomic drugs over the next 5 years. The likelihood of exposure to pharmacogenomic drugs increased with age, with 89% patients ≥70 years prescribed at least 1 pharmacogenomic drug over the previous 20 years. Even among those aged 50-59 years, 71% were prescribed at least 1 pharmacogenomic drug over the previous 20 years. The pharmacogenomic drugs prescribed to the most patients were for pain relief, gastroprotection, psychiatric and cardiovascular conditions. Three pharmacogenes (CYP2D6, [[CYP2C19]] and SLCO1B1) accounted for >95% pharmacogenomic drugs prescribed. In primary care patients, exposure to pharmacogenomic drugs is extremely common, multiplicitous and has commenced by relatively early adulthood. A small number of pharmacogenes account for the majority of drugs prescribed. These findings could inform design of pre-emptive pharmacogenomic testing for implementation in primary care.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Cytochrome P-450 CYP2C19
* Cytochrome P-450 CYP2D6
* Drug Prescriptions
* Female
* Humans
* Liver-Specific Organic Anion Transporter 1
* Longitudinal Studies
* Male
* Middle Aged
* Pharmaceutical Preparations
* Pharmacogenomic Testing
* Precision Medicine
* Primary Health Care
* United Kingdom
|keywords=* clinical pharmacology
* general practice
* pharmacogenomics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955399
}}
{{medline-entry
|title=The safety, tolerability and pharmacokinetics of BI 409306, a novel and potent PDE9 inhibitor: Overview of three Phase I randomised trials in healthy volunteers.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29567399
|abstract=Safety, tolerability and pharmacokinetics of BI 409306, a potent and selective phosphodiesterase 9A inhibitor, were assessed in healthy subjects in three Phase I, within-dose group, double-blind trials. Trial 1 randomised young and elderly subjects to receive BI 409306 25, 50, 100 mg, placebo once daily (OD) or BI 409306 50 mg twice daily (young) for 14 days. Trial 2 randomised young poor metabolisers (PM) of cytochrome P450 isoform 2C19 ([[CYP2C19]]) and elderly subjects to receive BI 409306 25, 50 mg or placebo OD for 14 days. Trial 3 randomised Chinese and Japanese extensive metabolisers of [[CYP2C19]] to receive single doses (SD) of BI 409306 25, 50, 100 mg or placebo and Chinese (PM) to SD of BI 409306 100 mg or placebo (Part 1). Japanese PM received SD of BI 409306 100 mg or placebo (Day 1) followed by BI 409306 100 mg or placebo OD for 7 days after a 48-hour washout period (Part 2). Reported adverse events (AE) were mild-to-moderate intensity and increased with BI 409306 dose. Eye disorders were most commonly reported (Trial 1: 40.0-41.7%, Trial 2: 29.2-37.5%, Trial 3: 18.2-66.7%) and increased with dose and systemic exposure. PM reported more AEs than other treatment groups, corresponding to higher systemic exposure to BI 409306. Systemic exposure to BI 409306 produced dose-dependent increases and was slightly greater in elderly versus young subgroups (Trial 1). Steady state was achieved by Day 2-3. Overall, BI 409306 demonstrated good safety, tolerability and minor accumulation after multiple dosing.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Alleles
* Asian Continental Ancestry Group
* Cytochrome P-450 CYP2C19
* Dose-Response Relationship, Drug
* Double-Blind Method
* Drug Administration Schedule
* European Continental Ancestry Group
* Female
* Genotype
* Healthy Volunteers
* Humans
* Male
* Middle Aged
* Phosphodiesterase Inhibitors
* Pyrazoles
* Pyrimidines
* Young Adult
|keywords=* Healthy volunteers
* Pharmacokinetics
* Phase I
* Phosphodiesterase inhibitors
* Safety
|full-text-url=https://sci-hub.do/10.1016/j.euroneuro.2018.01.003
}}
{{medline-entry
|title=Pediatric Cytochrome P450 Activity Alterations in Nonalcoholic Steatohepatitis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28986475
|abstract=Variable drug responses depend on individual variation in the activity of drug-metabolizing enzymes, including cytochrome P450 enzymes (CYP). As the most common chronic liver disease in children and adults, nonalcoholic steatohepatitis (NASH) has been identified as a source of significant interindividual variation in hepatic drug metabolism. Compared with adults, children present age-related differences in pharmacokinetics and pharmacodynamics. The purpose of this study was to determine the impact of fatty liver disease severity on the activity of a variety of CYP enzymes in children and adolescents. Healthy and nonalcoholic fatty liver disease pediatric subjects aged 12-21 years inclusive received an oral cocktail of four probe drugs: caffeine ([[CYP1A2]], 100 mg), omeprazole ([[CYP2C19]], 20 mg), losartan ([[CYP2C9]], 25 mg), and midazolam (CYP3A4, 2 mg). Venous blood and urine were collected before administration and 1, 2, 4, and 6 hours after administration. Concentrations of the parent drugs and CYP-specific metabolites were quantified in plasma and urine using liquid chromatography with tandem mass spectrometry. In plasma, the decreased metabolic area under the curve (AUC) ratio, defined as the metabolite AUC to parent AUC, of omeprazole indicated significant decreases of [[CYP2C19]] ([i]P[/i] = 0.002) enzymatic activities in NASH adolescents, while the urine analyses did not show significant differences and were highly variable. A comparison between the present in vivo pediatric studies and a previous ex vivo study in adults indicates distinct differences in the activities of [[CYP1A2]] and [[CYP2C9]]. These data demonstrate that pediatric NASH presents an altered pattern of CYP activity and NASH should be considered as a confounder of drug metabolism for certain CYP enzymes. These differences could lead to future investigations that may reveal unexpected variable drug responses that should be considered in pediatric dosage recommendations.
|mesh-terms=* Adolescent
* Adult
* Aging
* Area Under Curve
* Child
* Chromatography, High Pressure Liquid
* Cytochrome P-450 CYP1A2
* Cytochrome P-450 CYP2C9
* Cytochrome P-450 Enzyme System
* Female
* Genotype
* Humans
* Male
* Non-alcoholic Fatty Liver Disease
* Pharmaceutical Preparations
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697442
}}
{{medline-entry
|title=Analysis of the variability of the pharmacokinetics of multiple drugs in young adult and elderly subjects and its implications for acceptable daily exposures and cleaning validation limits.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28396010
|abstract=The elderly constitute a significant, potentially sensitive, subpopulation within the general population, which must be taken into account when performing risk assessments including determining an acceptable daily exposure (ADE) for the purpose of a cleaning validation. Known differences in the pharmacokinetics of drugs between young adults (who are typically the subjects recruited into clinical trials) and the elderly are potential contributors affecting the interindividual uncertainty factor (UF ) component of the ADE calculation. The UF  values were calculated for 206 drugs for young adult and elderly groups separately and combined (with the elderly assumed to be a sensitive subpopulation) from published studies where the pharmacokinetics of the young adult and elderly groups were directly compared. Based on the analysis presented here, it is recommended to use a default UF  value of 10 for worker populations (which are assumed to be approximately equivalent to the young adult groups) where no supporting pharmacokinetic data exist, while it is recommended to use a default UF  value of 15 for the general population, to take the elderly into consideration when calculating ADE values. The underlying reasons for the large differences between the exposures in the young adult and elderly subjects for the 10 compounds which show the greatest separation are different in almost every case, involving the OCT2 transporter, glucuronidation, hydrolysis, [[CYP1A2]], [[CYP2A6]], [[CYP2C19]], [[CYP2D6]], [[CYP3A4]] or [[CYP3A5]]. Therefore, there is no consistent underlying mechanism which appears responsible for the largest differences in pharmacokinetic parameters between young adult and elderly subjects.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Cytochrome P-450 Enzyme System
* Female
* Humans
* Male
* Middle Aged
* Organic Cation Transporter 2
* Pharmacokinetics
* Risk Assessment
* Uncertainty
* Young Adult
|keywords=* Acceptable daily exposure
* Cleaning validation
* Elderly
* Pharmacokinetics
|full-text-url=https://sci-hub.do/10.1016/j.ijheh.2017.03.007
}}
{{medline-entry
|title=Determination of Human Hepatic [[CYP2C8]] and [[CYP1A2]] Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28228413
|abstract=Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s and carboxylesterase enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme are needed to support in vitro to in vivo extrapolation (IVIVE). This study was designed to determine age-dependent human hepatic [[CYP2C8]] expression, for which only limited ontogeny data are available, and to further define [[CYP1A2]] ontogeny. [[CYP2C8]] and 1A2 protein levels were measured by quantitative Western blotting using liver microsomal samples prepared from 222 subjects with ages ranging from 8 weeks gestation to 18 years after birth. The median [[CYP2C8]] expression was significantly greater among samples from subjects older than 35 postnatal days ([i]n =[/i] 122) compared with fetal samples and those from very young infants (fetal to 35 days postnatal, [i]n =[/i] 100) (0.00 vs. 13.38 pmol/mg microsomal protein; [i]p[/i] < 0.0001). In contrast, the median [[CYP1A2]] expression was significantly greater after 15 months postnatal age ([i]n =[/i] 55) than in fetal and younger postnatal samples (fetal to 15 months postnatal, [i]n =[/i] 167) (0.0167 vs. 2.354 pmol/mg microsomal protein; [i]p[/i] < 0.0001). [[CYP2C8]], but not [[CYP1A2]], protein levels significantly correlated with those of [[CYP2C9]], [[CYP2C19]], and [[CYP3A4]] ([i]p[/i] < 0.001), consistent with [[CYP2C8]] and [[CYP1A2]] ontogeny probably being controlled by different mechanisms. This study provides key data for the physiologically based pharmacokinetic model-based prediction of age-dependent pyrethroid metabolism, which will be used for IVIVE to support pyrethroid risk assessment for early life stages.
|mesh-terms=* Adolescent
* Adult
* Aging
* Child
* Child, Preschool
* Cytochrome P-450 CYP1A2
* Cytochrome P-450 CYP2C8
* Female
* Fetal Development
* Gene Expression
* Gene Ontology
* Gestational Age
* Humans
* In Vitro Techniques
* Infant
* Infant, Newborn
* Liver
* Male
* Microsomes, Liver
* Risk Assessment
* Xenobiotics
* Young Adult

|full-text-url=https://sci-hub.do/10.1124/dmd.116.074583
}}
{{medline-entry
|title=Identifying clinically relevant sources of variability: The clopidogrel challenge.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27557470
|abstract=High interindividual variability in clinical outcomes following clopidogrel's standard dosing regimen continues to be a challenge even two decades after its approval. [[CYP2C19]] polymorphisms, obesity, older age, diabetes, and drug-drug interactions have been identified as risk factors for adverse events and treatment failure. We conducted a mechanism-based pharmacokinetic/pharmacodynamic analysis, where we integrated knowledge on in vitro enzyme kinetic, physiological, genetic, and demographic information to characterize changes in platelet reactivity from baseline following clopidogrel antiplatelet therapy. When considering the combined impact of these covariates, our analysis results indicate that higher maintenance doses are required for [[CYP2C19]] intermediate metabolizers and poor metabolizers compared to extensive metabolizers and that respective maintenance doses have to be further increased for obese subjects for each of these [[CYP2C19]] phenotypes. In addition, interindividual differences in the fraction absorbed and the [[CES1]] activity were identified as sources of interindividual differences in clopidogrel's active metabolite concentrations and, thus, platelet reactivity.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Body Mass Index
* Clopidogrel
* Computer Simulation
* Cytochrome P-450 CYP2C19
* Cytochrome P-450 Enzyme System
* Diabetes Mellitus
* Dose-Response Relationship, Drug
* Drug Interactions
* Female
* Gastrointestinal Absorption
* Half-Life
* Humans
* Liver
* Male
* Metabolic Clearance Rate
* Middle Aged
* Models, Biological
* Obesity
* Platelet Aggregation
* Platelet Aggregation Inhibitors
* Polymorphism, Genetic
* Socioeconomic Factors
* Ticlopidine

|full-text-url=https://sci-hub.do/10.1002/cpt.459
}}
{{medline-entry
|title=Impact of age on serum concentrations of venlafaxine and escitalopram in different [[CYP2D6]] and [[CYP2C19]] genotype subgroups.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24858822
|abstract=The aim of the present study was to investigate the effect of age on venlafaxine and escitalopram serum concentrations in various cytochrome P450 (CYP) 2D6 and [[CYP2C19]] genotype subgroups. Serum concentration measurements from CYP-genotyped patients treated with venlafaxine (n = 255) or escitalopram (n = 541) were collected retrospectively from a therapeutic drug monitoring database. Patients were divided into three [[CYP2D6]] (venlafaxine) or [[CYP2C19]] (escitalopram) phenotype subgroups according to inherited genotype, i.e., poor metabolizers (PMs), heterozygous extensive metabolizers (HEMs), and extensive metabolizers (EMs), and subsequently distributed into three age groups, i.e., <40 (control), 40-65, and >65 years. The effect of age on dose-adjusted serum concentrations (i.e., nmol/L/mg/day) of venlafaxine and escitalopram in each of the phenotype subgroups was evaluated by separate multivariate mixed model analyses. In [[CYP2D6]] PMs, the mean dose-adjusted serum concentration of venlafaxine was 8-fold higher in patients >65 years compared with those <40 years (p < 0.001). In comparison, the respective age-related differences in mean dose-adjusted serum concentrations of venlafaxine were much less pronounced in [[CYP2D6]] HEMs and EMs (<2-fold differences between age groups). A similar genotype-related effect of age was not observed for escitalopram (<1.5-fold age differences in all [[CYP2C19]] subgroups). This study suggests that the effect of age on serum concentration of venlafaxine is dependent on CYP genotype, in contrast to escitalopram. Thus, to prevent potential side effects, it might be particularly relevant to consider [[CYP2D6]] genotyping prior to initiation of venlafaxine treatment in older patients.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Antidepressive Agents, Second-Generation
* Citalopram
* Cyclohexanols
* Cytochrome P-450 CYP2C19
* Cytochrome P-450 CYP2D6
* Female
* Genotype
* Humans
* Male
* Middle Aged
* Serotonin Uptake Inhibitors
* Venlafaxine Hydrochloride
* Young Adult

|full-text-url=https://sci-hub.do/10.1007/s00228-014-1696-8
}}