Редактирование: CYP2C9 (раздел)

==Publications==

{{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=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=Genotype-based dosage of acenocoumarol in highly-sensitive geriatric patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25669612
|abstract=Our aim was to determinate the acenocoumarol dose requirement in highly sensitive geriatric patients, based on a minimum of genotype (VKORC1 and [[CYP2C9]]) data. We used a Gaussian kernel density estimation test to identify patients highly sensitive to the drug and PHARMACHIP®-Cuma test (Progenika Biopharma, SA, Grifols, Spain) to determine the [[CYP2C9]] and VKORC1 genotype. All highly sensitive geriatric patients were taking ≤5.6 mg/week of acenocoumarol (AC), and 86% of these patients presented the following genotypes: [[CYP2C9]]*1/*3 or [[CYP2C9]]*1/*2 plus VKORC1 A/G, [[CYP2C9]]*3/*3, or VKORC1 A/A. VKORC1 A and [[CYP2C9]]*2 and/or *3 allelic variants extremely influence on AC dose requirement of highly sensitive geriatric patients. These patients display acenocoumarol dose requirement of ≤5.6 mg/week.
|mesh-terms=* Acenocoumarol
* Age Factors
* Aged, 80 and over
* Aging
* Anticoagulants
* Cytochrome P-450 CYP2C9
* Drug Dosage Calculations
* Drug Monitoring
* Female
* Gene Frequency
* Genotype
* Humans
* Male
* Oligonucleotide Array Sequence Analysis
* Pharmacogenetics
* Phenotype
* Pilot Projects
* Vitamin K Epoxide Reductases

|full-text-url=https://sci-hub.do/10.5414/CP202206
}}
{{medline-entry
|title=The effect of [[CYP2C9]], [[VKORC1]] genotypes and old age on warfarin pharmacologic sensitivity in korean patients with thromboembolic disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22075505
|abstract=The therapeutic dose of warfarin is dependent upon intrinsic patient characteristics that are highly variable. We assessed the effects of [[CYP2C9]], [[VKORC1]] 1173 C/T polymorphisms, and old age on warfarin dosing and sensitivity by measuring plasma S-/R-warfarin levels in Korean patients. INR and the plasma S-/R-warfarin concentrations were determined in 58 patients who had the [[VKORC1]] 1173C/T [[CYP2C9]] genotypes, were on a long-term anticoagulation regimen with warfarin, and took a daily dose of warfarin. The pharmacokinetic sensitivity of warfarin was significantly higher in the [[CYP2C9]] *1/*3 genotypes than in the [[CYP2C9]] *1/*1 genotypes [ratio of S-warfarin concentration/dose, 0.53 vs. 0.21; p=0.01]. Pharmacodynamic sensitivity in older patients (≥ 75 years) with the [[CYP2C9]] *1/*1 and [[VKORC1]] 1173 TT genotypes was significantly higher as compared to younger patients (<75 years) [Ratio of INR/S-warfarin concentration, 4.88 vs. 3.41; p = 0.026]. The [[CYP2C9]]*3 allele and old age (≥ 75 years) with the [[VKORC1]] 1173 T allele were also associated with increased risk of over-anticoagulation. The increase of over-anticoagulation risk and warfarin sensitivity is related to the [[CYP2C9]]*3 allele and old age with the [[VKORC1]] 1173 T allele in Korean patients with thromboembolic disease. These findings suggest that a lower initial and maintenance dose should be considered for the patients with [[CYP2C9]] *3 allele and advanced age in this patient population. However, due to the limited number of patients in the study population, our finding needs to be confirmed by a larger, well-controlled study.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Anticoagulants
* Aryl Hydrocarbon Hydroxylases
* Asian Continental Ancestry Group
* Blood Coagulation
* Cytochrome P-450 CYP2C9
* Dose-Response Relationship, Drug
* Female
* Humans
* Korea
* Male
* Middle Aged
* Mixed Function Oxygenases
* Thromboembolism
* Treatment Outcome
* Vitamin K Epoxide Reductases
* Warfarin


}}
{{medline-entry
|title=Genetic variation in the CYP2C monooxygenase enzyme subfamily shows no association with longevity in a German population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21798861
|abstract=Cytochrome P450 enzymes, especially the CYP2C subfamily, are involved in the generation of reactive oxygen species and are regarded as susceptibility factors for age-related diseases. Furthermore, the CYP2C-encoding genes are known to be highly polymorphic, with a number of variants leading to changes in enzyme activity. These observations prompted us to investigate whether allelic variation in the CYP2C-encoding genes was associated with human longevity. In a comprehensive haplotype tagging approach, we genotyped 56 single nucleotide polymorphisms located in the CYP2C gene family (CYP2C8, [[CYP2C9]], [[CYP2C18]], and CYP2C19) in our extensive collection of 1,384 long-lived individuals (centenarians and nonagenarians) and 945 younger controls. None of the tested single nucleotide polymorphisms showed a significant association with the longevity phenotype at the allele, genotype, or haplotype level. These results suggest that there is no notable influence of sequence variation in the CYP2C genes on longevity in the examined German population.
|mesh-terms=* Aged, 80 and over
* Aryl Hydrocarbon Hydroxylases
* Cytochrome P-450 CYP2C19
* Cytochrome P-450 CYP2C8
* Cytochrome P-450 CYP2C9
* Cytochrome P-450 Enzyme System
* Female
* Genetic Association Studies
* Genetic Predisposition to Disease
* Genetic Variation
* Germany
* Humans
* Linkage Disequilibrium
* Longevity
* Male
* Polymorphism, Single Nucleotide

|full-text-url=https://sci-hub.do/10.1093/gerona/glr117
}}
{{medline-entry
|title=Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21533175
|abstract=Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include [[ZKSCAN5]] (rs11761528; p = 3.15 × 10(-36)), [[SULT2A1]] (rs2637125; p =  2.61 × 10(-19)), [[ARPC1A]] (rs740160; p =  1.56 × 10(-16)), [[TRIM4]] (rs17277546; p =  4.50 × 10(-11)), [[BMF]] (rs7181230; p = 5.44 × 10(-11)), [[HHEX]] (rs2497306; p =  4.64 × 10(-9)), [[BCL2L11]] (rs6738028; p = 1.72 × 10(-8)), and [[CYP2C9]] (rs2185570; p = 2.29 × 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
|mesh-terms=* Actin-Related Protein 2-3 Complex
* Adaptor Proteins, Signal Transducing
* Adult
* Aged
* Aging
* Apoptosis Regulatory Proteins
* Aryl Hydrocarbon Hydroxylases
* Bcl-2-Like Protein 11
* Cytochrome P-450 CYP2C9
* DNA-Binding Proteins
* Dehydroepiandrosterone Sulfate
* European Continental Ancestry Group
* Female
* Gene Expression
* Genome-Wide Association Study
* Homeodomain Proteins
* Humans
* Kruppel-Like Transcription Factors
* Linkage Disequilibrium
* Liver
* Male
* Membrane Proteins
* Middle Aged
* Polymorphism, Single Nucleotide
* Proto-Oncogene Proteins
* Sulfotransferases
* Transcription Factors
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077384
}}
{{medline-entry
|title=Contribution of age, body weight, and [[CYP2C9]] and [[VKORC1]] genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/17899045
|abstract=The objective of this study was to assess the contribution of the [[VKORC1]] and [[CYP2C9]] genotypes and age, body size, and weight of the patients to the warfarin dose requirement in a Chinese population. Blood samples were collected from 178 Chinese patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range (1.5-3.0). The polymorphisms for the [[VKORC1]] (-1639GA) and [[CYP2C9]]*3 genotypes, venous INR, and plasma concentration and unbound concentration of warfarin were then analyzed. [[VKORC1]] (-1639G>A) genotyping showed that 149 patients were homozygous AA, 28 were heterozygous GA, and one was homozygous for the GG genotype. [[CYP2C9]]*3 genotyping showed that 162 patients were *1/*1, and 16 patients were heterozygous *1/*3. Patients with the [[VKORC1]](-1639 GG GA) (3.32  /- 1.02 mg/day) and [[CYP2C9]]*1/*1 (2.06  /- 0.82 mg/day) genotypes required a significantly higher warfarin dose than those with the -1639 AA (1.76  /- 0.57 mg/day; P < 0.001) or [[CYP2C9]]*1/*3 (1.60  /- 1.29 mg/day; P < 0.001), genotype. The multiple linear regression model for warfarin dose indicated significant contributions from age (r (2) = 0.084; P < 0.001), weight (r (2) = 0.063; P < 0.001), [[VKORC1]] genotype (r (2) = 0.494; P < 0.001), and age, weight, and [[CYP2C9]] and [[VKORC1]] genotype together (r (2) = 0.628; P < 0.001). This study shows that age, weight and the [[VKORC1]] and [[CYP2C9]] polymorphism affect warfarin dose requirements in our sample of Chinese patients receiving long-term therapy and showing stable control of anticoagulation. It is anticipated that the use of dosing regimens modified by taking into account the contribution of age, weight, and the [[CYP2C9]] and [[VKORC1]] genotypes has the potential to improve the safety of warfarin therapy.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* Anticoagulants
* Aryl Hydrocarbon Hydroxylases
* Blood Coagulation
* Body Weight
* China
* Cytochrome P-450 CYP2C9
* Female
* Genotype
* Humans
* International Normalized Ratio
* Male
* Middle Aged
* Mixed Function Oxygenases
* Pharmacogenetics
* Polymorphism, Genetic
* Vitamin K Epoxide Reductases
* Warfarin

|full-text-url=https://sci-hub.do/10.1007/s00228-007-0381-6
}}
{{medline-entry
|title=A PK-PD model for predicting the impact of age, [[CYP2C9]], and [[VKORC1]] genotype on individualization of warfarin therapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/17301738
|abstract=The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose individualization. S- and R-warfarin concentrations, INR, and [[CYP2C9]] and [[VKORC1]] genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory E(MAX) model, with S-warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. [[CYP2C9]] genotype and age were identified as predictors for S-warfarin clearance, and [[VKORC1]] genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady-state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for [[CYP2C9]] and [[VKORC1]] genotypes and age to improve a priori and a posteriori individualization of warfarin therapy.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Algorithms
* Anticoagulants
* Aryl Hydrocarbon Hydroxylases
* Cytochrome P-450 CYP2C9
* DNA
* Databases, Factual
* Female
* Genotype
* Humans
* Male
* Middle Aged
* Mixed Function Oxygenases
* Models, Statistical
* Pharmacokinetics
* Population
* Stereoisomerism
* Vitamin K Epoxide Reductases
* Warfarin

|full-text-url=https://sci-hub.do/10.1038/sj.clpt.6100084
}}
{{medline-entry
|title=Influence of [[CYP2C9]] polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/15824753
|abstract=Warfarin is an anticoagulant drug with narrow therapeutic index and high interindividual variability in dose requirement. S-warfarin is metabolized mainly by polymorphic cytochrome P450 (CYP) 2C9. We systematically quantified the influence of [[CYP2C9]] genotype, demographic factors and concomitant drug treatment on warfarin metabolism and maintenance dose. The mean warfarin doses were lower in carriers of one (2.71 mg/day, 59 patients) and two polymorphic alleles (1.64 mg/day, 11 patients) than in carriers of two wild-type alleles (4.88 mg/day, 118 patients). Multiple regression analysis demonstrated that [[CYP2C9]] genotype, age, concomitant treatment with warfarin metabolism inducers and lean body weight contributed significantly to interindividual variability in warfarin dose requirement (adjusted R(2)=0.37). The same factors, except for age, significantly influenced S-warfarin clearance (adjusted R(2)=0.42). These results can serve as a starting point for designing prospective studies in patients in the initiation phase of genotype-based warfarin therapy.
|mesh-terms=* Aged
* Aging
* Anticoagulants
* Aryl Hydrocarbon Hydroxylases
* Blood Proteins
* Body Weight
* Cytochrome P-450 CYP2C9
* Demography
* Drug Interactions
* Female
* Food-Drug Interactions
* Genotype
* Heart Valve Prosthesis
* Humans
* International Normalized Ratio
* Male
* Polymorphism, Genetic
* Regression Analysis
* Serum Albumin
* Stereoisomerism
* Warfarin

|full-text-url=https://sci-hub.do/10.1038/sj.tpj.6500308
}}
{{medline-entry
|title=The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/15364537
|abstract=We have measured cytochrome P450 (CYP) activity in nearly 150 samples of human liver microsomes and 64 samples of cryopreserved human hepatocytes, and we have performed induction studies in over 90 preparations of cultured human hepatocytes. We have analyzed these data to examine whether the expression of CYP enzyme activity in liver microsomes and isolated hepatocytes or the inducibility of CYP enzymes in cultured hepatocytes is influenced by the gender, age, or ethnicity of the donor (the latter being limited to Caucasians, African Americans, and Hispanics due to a paucity of livers from Asian donors). In human liver microsomes, there were no statistically significant differences (P > 0.05) in CYP activity as a function of age, gender, or ethnicity with one exception. 7-Ethoxyresorufin O-dealkylase ([[CYP1A2]]) activity was greater in males than females, which is consistent with clinical observation. Liver microsomal testosterone 6beta-hydroxylase ([[CYP3A4]]) activity was slightly greater in females than males, but the difference was not significant. However, in cryopreserved human hepatocytes, the gender difference in [[CYP3A4]] activity (females = twice males) did reach statistical significance, which supports the clinical observation that females metabolize certain [[CYP3A4]] substrates faster than do males. Compared with those from Caucasians and African Americans, liver microsomes from Hispanics had about twice the average activity of [[CYP2A6]], [[CYP2B6]], and [[CYP2C8]] and half the activity of [[CYP1A2]], although this apparent ethnic difference may be a consequence of the relatively low number of Hispanic donors. Primary cultures of hepatocytes were treated with beta-naphthoflavone, an inducer of [[CYP1A2]], phenobarbital or rifampin, both of which induce [[CYP2B6]], [[CYP2C9]], [[CYP2C19]], and [[CYP3A4]], albeit it to different extents. Induction of these CYP enzymes in freshly cultured hepatocytes did not appear to be influenced by the gender or age of the donor. Furthermore, [[CYP3A4]] induction in hepatocytes isolated from cirrhotic liver was comparable to that in normal hepatocytes, which supports the "healthy hepatocyte, sick environment" hypothesis of liver cirrhosis. This review summarizes these findings and discusses their implications for the use of human liver microsomes and hepatocytes for in vitro studies of drug metabolism and enzyme induction, which play a key role in drug development.
|mesh-terms=* Aging
* Alcohol Drinking
* Animals
* Cells, Cultured
* Cytochrome P-450 Enzyme System
* Enzyme Induction
* Ethnic Groups
* Female
* Hepatocytes
* Humans
* Isoenzymes
* Liver Cirrhosis
* Male
* Microsomes, Liver
* Sex Characteristics
* Smoking

|full-text-url=https://sci-hub.do/10.1016/j.taap.2004.01.010
}}
{{medline-entry
|title=Contribution of age, body size, and [[CYP2C9]] genotype to anticoagulant response to warfarin.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/15001972
|abstract=Our objective was to assess the contribution of [[CYP2C9]] genotype, age, body size, and vitamin K and lipid status to warfarin dose requirements. Patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range of 2.0 to 3.0 were recruited to the study. On arrival at the clinic in the morning, after an overnight fast, a blood sample was taken from each patient for [[CYP2C9]] genotyping and for determination of venous INR and plasma vitamin K, R- and S-warfarin, and triglyceride concentrations. A total of 121 patients were recruited to the study. [[CYP2C9]] genotyping showed that 74 patients were homozygous wild-type (*1/*1), 30 were heterozygous *1/*2, and 15 were heterozygous *1/*3 genotype. One patient was found to have the genotype *2/*3, and another was found to have the genotype *3/*3. The mean warfarin daily dose requirement in milligrams fell from 4.06  /- 1.72 mg in homozygous wild-type patients to 3.63  /- 1.78 mg for *1/*2-positive patients and 2.70  /- 1.36 mg for *1/*3-positive patients. The multiple linear regression model for warfarin dose indicated significant contributions from age (r = 0.41, P <.001), genotype (r = 0.24, P <.005), and age and genotype together (r = 0.45, P <.005). Although there were significant linear correlations between warfarin dose and body surface area (r = 0.21, P =.02), body weight (r = 0.25, P =.005), and plasma vitamin K concentration (r = 0.18, P <.05), none of these variables made a significant contribution to the regression model for warfarin dose. [[CYP2C9]] genotype had a significant effect on S-warfarin clearance (r = 0.34, P <.0001) but none on R-warfarin clearance. This study showed that age and [[CYP2C9]] polymorphism affect warfarin dose requirements in patients receiving long-term therapy and having stable control of anticoagulation. It is anticipated that using dosing regimens modified to take into account the contribution of age and [[CYP2C9]] genotype has the potential to improve the safety of warfarin therapy.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Anticoagulants
* Aryl Hydrocarbon Hydroxylases
* Body Constitution
* Cytochrome P-450 CYP2C9
* Female
* Genotype
* Humans
* Male
* Metabolic Clearance Rate
* Middle Aged
* Polymorphism, Genetic
* Predictive Value of Tests
* Warfarin

|full-text-url=https://sci-hub.do/10.1016/j.clpt.2003.10.001
}}
{{medline-entry
|title=Influence of age and cytochrome P450 2C9 genotype on the steady-state disposition of diclofenac and celecoxib.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/12603175
|abstract=To analyse the influence of age and cytochrome P450 (CYP) 2C9 genotype on the steady-state disposition of the standard NSAID diclofenac and the new COX-2 selective inhibitor celecoxib, both of which are metabolised by the polymorphically expressed [[CYP2C9]]. Double-blind randomised crossover study under steady-state conditions. 12 young (age 32  /- 5 years, bodyweight 71  /- 12kg; mean  /- SD) and 12 elderly (68  /- 2 years, 82  /- 15kg) healthy, drug-free, nonsmoking Caucasians of both sexes. All subjects received oral celecoxib (200mg twice daily) and diclofenac (75mg twice daily) for 15 days separated by a drug-free interval of at least 3 weeks. Following the last morning dose, multiple blood samples were taken for 25 hours. Concentrations of celecoxib and diclofenac were measured by specific and sensitive high performance liquid chromatography. Identification of [[CYP2C9]] genotype was performed by genomic DNA sequencing. Pharmacokinetic parameters for total and unbound drugs were individually analysed by noncompartmental techniques. For diclofenac, area under the concentration-time curve over the dosage interval (AUC(tau)) was larger in young subjects (3.2  /- 1.0 mg * h/L) than in older individuals (2.4  /- 0.4 mg * h/L; p < 0.05). As the terminal half-life (t((1/2)Z)) was very similar in both groups (3.9  /- 4.4 vs 3.5  /- 3.3 hours), either less complete absorption in the elderly or their higher bodyweight could account for the difference. For celecoxib, AUC(tau) (5.8  /- 1.7 vs 5.6  /- 2.3 mg * h/L) and t((1/2)z) (11.8  /- 8.7 vs 11.2  /- 2.9 hours) were almost identical in young and older subjects. Plasma protein binding of both NSAIDs was unaffected by age, and apparent oral clearances for unbound drugs were not different between the two groups of healthy subjects. When considering the genotype of all individuals ([[CYP2C9]]*1/*1, n = 10; [[CYP2C9]]*1/*2, n = 6; [[CYP2C9]]*2/*2, n = 2; [[CYP2C9]]*1/*3, n = 4; [[CYP2C9]]*3/*3, n = 1), no association with any pharmacokinetic parameter of either drug was apparent. Moreover, there was no significant correlation between the AUC values of celecoxib and diclofenac. Age and [[CYP2C9]] genotype do not significantly affect the steady-state disposition of celecoxib and diclofenac. This would indicate that both drugs need no dosage reduction in the elderly (at least up to 75 years) and that, besides [[CYP2C9]], additional CYP species contribute to the elimination of both agents.
|mesh-terms=* Adult
* Aged
* Aging
* Alleles
* Area Under Curve
* Aryl Hydrocarbon Hydroxylases
* Celecoxib
* Cross-Over Studies
* Cyclooxygenase 2
* Cyclooxygenase 2 Inhibitors
* Cyclooxygenase Inhibitors
* Cytochrome P-450 CYP2C9
* Diclofenac
* Double-Blind Method
* Female
* Genotype
* Half-Life
* Humans
* Isoenzymes
* Male
* Membrane Proteins
* Prostaglandin-Endoperoxide Synthases
* Pyrazoles
* Sulfonamides

|full-text-url=https://sci-hub.do/10.2165/00003088-200342030-00003
}}
{{medline-entry
|title=Treatment of the elderly with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors: focus on drug interactions.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/11584328
|abstract=With the aging of the population, death from coronary heart disease (CHD) and stroke has become more prevalent. Cardiovascular disease (CVD) risk factors, such as hypertension, obesity, and diabetes mellitus increase with age as well. Recent secondary-prevention studies have established the positive effect of statins in decreasing the risk of CHD mortality through the lowering of cholesterol. Statins have an excellent safety record, at least with users under age 65, and provide a cheaper alternative to more costly medical options. The most serious side effect associated with their use is myopathy, which is infrequent. Drug interactions have been found with drugs that compete for the same CYP450 isoenzymes as statins. Several drugs have been shown to significantly inhibit the [[CYP3A4]] pathway; in combination with statins such as lovastatin, simvastatin, atorvastatin, and cerivastatin, they have been shown to elevate serum concentrations of these statins, or may increase the risk of myopathy. Alternatively, other drugs can inhibit the [[CYP2C9]] pathway and may elevate serum concentration of fluvastatin. Due to the number of medications the elderly receive, an understanding of the various metabolic pathways is of vital importance to minimize the potential for drug interactions. The elderly population, while at high risk for CVD, is currently undertreated. Statins can effectively lower low-density lipoprotein cholesterol levels and lessen the risk of CVD for this population.
|mesh-terms=* Aged
* Aging
* Cardiovascular Diseases
* Drug Interactions
* Humans
* Hydroxymethylglutaryl CoA Reductases
* Hydroxymethylglutaryl-CoA Reductase Inhibitors
* Risk Factors

|full-text-url=https://sci-hub.do/10.1177/107424840100600302
}}
{{medline-entry
|title=Interindividual variability in sensitivity to warfarin--Nature or nurture?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/11503010
|abstract=Interindividual variability in responses to warfarin is attributed to dietary vitamin K, drug interactions, age, or genetic polymorphism in the cytochrome P4502C9 enzyme ([[CYP2C9]]) (allelic variants 2C9*2 and 2C9*3 ) linked with impaired metabolism of the potent enantiomere S-warfarin. We quantified the relative effects of age and of simultaneously determined [[CYP2C9]] genotype, plasma warfarin and vitamin K concentrations, and concurrent medications on warfarin maintenance doses in 156 patients at optimized stable anticoagulation. Allele frequencies for [[CYP2C9]]*1, [[CYP2C9]]*2, and [[CYP2C9]]*3 were 0.84, 0.10, and 0.06. Warfarin doses were 6.5  /- 3.2, 5.2  /- 2.4, and 3.3  /- 2.0 mg/d in the 3 genotype groups (P < .0001). Warfarin doses decreased with age as follows: 7.7  /- 3.7 versus 4.9  /- 2.9 mg/d at < 50 years and >66 years (P < .001), mainly as a result of decreased plasma warfarin clearance (2.8  /- 1.4 mL/min versus 1.9  /- 0.8 mL/min; P < .001). Vitamin K (1.6  /- 1.1 ng/mL) did not differ among the age or genotype groups. Patients >or=66 years old with the [[CYP2C9]]*3 allele required only 2.2  /- 1.2 mg/d compared with 7.9  /- 3.7 mg/d in those <or=65 years old bearing the [[CYP2C9]]*1 allele (P < .001). On multiple regression, warfarin maintenance doses were independently associated with plasma warfarin (reflecting its metabolic clearance) (r (2) = 0.26), age (possibly reflecting increased intrinsic sensitivity) (r (2) = 0.12), and genotype (reflecting S-warfarin levels) (r (2) = 0.10) but not with plasma vitamin K. At optimized steady state, individual sensitivity to warfarin is determined by [[CYP2C9]] genotype and age with no effect of vitamin K. Prospective studies will determine the impact of these findings in clinical practice.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Alleles
* Anticoagulants
* Aryl Hydrocarbon Hydroxylases
* Cytochrome P-450 CYP2C9
* Cytochrome P-450 Enzyme System
* Dose-Response Relationship, Drug
* Female
* Genetic Variation
* Genotype
* Humans
* Male
* Middle Aged
* Polymorphism, Genetic
* Stereoisomerism
* Steroid 16-alpha-Hydroxylase
* Steroid Hydroxylases
* Vitamin K
* Warfarin

|full-text-url=https://sci-hub.do/10.1067/mcp.2001.117444
}}
{{medline-entry
|title=The selective serotonin reuptake inhibitor sertraline: its profile and use in psychiatric disorders.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/11420570
|abstract=The naphthylamine derivative sertraline is a potent and selective inhibitor of serotonin reuptake into presynaptic terminals. Sertraline has a linear pharmacokinetic profile and a half-life of about 26 h. Its major metabolite, desmethylsertraline does not appear to inhibit serotonin reuptake. Sertraline mildly inhibits the [[CYP2D6]] isoform of the cytochrome P450 system but has little effect on [[CYP1A2]], CYP3A3/4, [[CYP2C9]], or [[CYP2C19]]. It is, however, highly protein bound and may alter blood levels of other highly protein bound agents. Sertraline is a widely used serotonin reuptake inhibitor that has been shown to have both antidepressant and antianxiety effects. Many clinical trials have demonstrated its efficacy in depression compared with both placebo and other antidepressant drugs. Its efficacy has also been demonstrated in randomized, controlled trials of patients with obsessive-compulsive disorder, panic disorder, social phobia, and premenstrual dysphoric disorder. In short-term, open-label studies it has appeared efficacious and tolerable in children and adolescents and in the elderly, and data are positive for its use in pregnant or lactating women. Typical side effects include gastrointestinal and central nervous system effects as well as treatment-emergent sexual dysfunction; withdrawal reactions may be associated with abrupt discontinuation of the agent. The safety profile of sertraline in overdose is very favorable. Sertraline's efficacy for both mood and anxiety disorders, relatively weak effect on the cytochrome P450 system, and tolerability profile and safety in overdose are factors that contribute to make it a first-line agent for treatment in both primary and tertiary care settings.
|mesh-terms=* Aging
* Animals
* Antidepressive Agents, Second-Generation
* Humans
* Mental Disorders
* Serotonin Uptake Inhibitors
* Sertraline

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741657
}}
{{medline-entry
|title=In vivo age-related changes in hepatic drug-oxidizing capacity in humans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/9867310
|abstract=Very few studies have been carried out looking at how the effects of drugs and their toxicity in humans change during their lifespan (developing and ageing). The purpose of this study is to review the literature on the changes in probe-drug metabolism, classified by cytochrome P450 (P450 or CYP) at five stages in life: neonates < 4 weeks, infants < 12 months, children < 19 years, young/mature adults 20-64 years, and elderly adults > 65 years. The main probe drugs include caffeine and theophylline, whose metabolism is catalysed by [[CYP1A2]], tolbutamide, phenytoin and ibuprofen, catalysed by [[CYP2C9]], amitriptyline and nortriptyline, catalysed by [[CYP2C19]], acetaminophen, catalysed by [[CYP2E1]] and lidocaine, midazolam and terfenadine, catalysed by 3A3/4. From the published in vivo studies two different patterns of drug metabolism can be identified: (i) activity is low immediately after birth, increases, then peaks at the young/mature adult level and, finally, decreases in old age (drugs catalysed by [[CYP1A2]], [[CYP2C9]], [[CYP2C19]], [[CYP2D6]] and CYP3A3/4) and (ii) activity increases rapidly after birth to reach a level equivalent to that in the young/mature adult, then gradually decreases and finally decreasing faster in old age (drugs catalysed by [[CYP2E1]]). Further study of the changes in P450 with age is warranted to help prevent adverse reactions and to guide us in tailoring therapy better for the individual patient.
|mesh-terms=* Aging
* Cytochrome P-450 Enzyme System
* Humans
* Isomerism

|full-text-url=https://sci-hub.do/10.1046/j.1365-2710.1998.00164.x
}}
{{medline-entry
|title=Developmental expression of CYP2C and CYP2C-dependent activities in the human liver: in-vivo/in-vitro correlation and inducibility.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/9429229
|abstract=Experiments were performed in vivo and in vitro to date the onset of hepatic CYP2C isoforms and CYP2C-dependent activities during the perinatal period in humans. Proteins were not detected by immunoblotting in fetal livers and developed in the first few weeks after birth, irrespective of the gestational age at birth. Similarly, the hydroxylation of tolbutamide, a marker for [[CYP2C9]] was undetected in fetal liver microsomes and rose in the first month after birth. In adult liver preparations, the hydroxylation of diazepam correlated well with the CYP3 A content of microsomes (r = 0.858, p < 0.01) and with the 6 beta hydroxylation of testosterone (r = 0.830, p < 0.005), whereas demethylation was related to the bulk of CYP2C proteins (r = 0.865, p < 0.005). In fetal liver microsomes, hydroxylation and demethylation activities accounted for less than 5% of the adult activities and both increased immediately after birth to reach adult activities at 1 year of age. When diazepam was given for sedative purpose in neonates and infants, the in-vivo urinary excretion of desmethyl diazepam, temazepam and oxazepam was extremely low in 1-2 day newborns (less than 5 nmol metabolites excreted in 24 h per kg body weight) and developed in the first week after birth. In newborns, barbiturates and to a lesser extent steroids, acted as inducers of CYP2C isoforms and increased tolbutamide hydroxylation, diazepam demethylation and diazepam hydroxylation by 2 to 10-fold. The surge of CYP2C proteins was caused by an accumulation of RNAs occurring in the first week after birth. The hepatic content in [[CYP2C8]], 2C9 and 2C18 RNA displayed the same profile of evolution, which suggested a coregulation of their synthesis during the neonatal period. Taken together, these biochemical and clinical data enable dating of the onset of CYP2C proteins to the first weeks after birth, which is of considerable clinical importance in pediatric pharmacology.
|mesh-terms=* Adult
* Aging
* Child, Preschool
* Cytochrome P-450 Enzyme System
* Diazepam
* Enzyme Induction
* Female
* Fetus
* Gestational Age
* Humans
* Hydroxylation
* Infant
* Infant, Newborn
* Microsomes, Liver
* RNA
* Tolbutamide

|full-text-url=https://sci-hub.do/10.1097/00008571-199712000-00002
}}