Редактирование: CYP3A5

Cytochrome P450 3A5 (EC 1.14.14.1) (CYPIIIA5) (Cytochrome P450-PCN3)

==Publications==

{{medline-entry
|title=Effect of Age and Allele Variants of [[CYP3A5]], [[CYP3A4]], and [[POR]] Genes on the Pharmacokinetics of Cyclosporin A in Pediatric Renal Transplant Recipients From Serbia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29135906
|abstract=The interindividual variability of cyclosporin A (CsA) pharmacokinetics might be explained by heterogeneity in the cytochrome P450 3A (CYP3A) subfamily. Altered CYP3A enzyme activity was associated with variant allele of P450 oxidoreductase gene ([[POR]]*28). The aim of this study was to assess the impact of age, [[CYP3A5]]*3, [[CYP3A4]]*22, and [[POR]]*28 alleles on CsA pharmacokinetics in pediatric renal transplant recipients. Renal transplant patients receiving CsA (n = 47) were genotyped for [[CYP3A5]]*3, [[CYP3A4]]*22, and [[POR]]*28. [[CYP3A5]] nonexpressers had higher overall dose-adjusted predose concentration (C0/dose; ng/mL per mg/kg) compared with expressers (31.48 ± 12.75 versus 22.44 ± 7.12, P = 0.01). [[CYP3A5]] nonexpressers carrying [[POR]]*28 allele had a lower overall dose-adjusted concentration (C2/dose) than those with [[POR]]*1/*1 genotype (165.54 ± 70.40 versus 210.55 ± 79.98, P = 0.02), with age as covariate. Children aged 6 years and younger had a lower overall C0/dose (18.82 ± 4.72 versus 34.19 ± 11.89, P = 0.001) and C2/dose (106.75 ± 26.99 versus 209.20 ± 71.57, P < 0.001) compared with older children. Carriers of [[CYP3A5]]*3 allele aged ≤6 years required higher dose of CsA and achieved lower C0/dose and C2/dose, at most time points, than older carriers of this allele. Carriers of [[POR]]*28 allele aged ≤6 years required higher doses of CsA, whereas they achieved lower C0/dose and C2/dose, at most time points, in comparison to older carriers of this allele. The significant effect of age (P < 0.002) and [[CYP3A5]] variation (P < 0.02) was shown for overall C0/dose, whereas age (P < 0.00001) and [[POR]] variation (P = 0.05) showed significant effect on C2/dose. Regression summary for overall C2/dose in patients aged 6 years younger showed a significant effect of both [[CYP3A5]] and [[POR]] variations (P < 0.016). Younger age, [[POR]]*28 allele, and [[CYP3A5]]*3 allele were associated with higher CsA dosing requirements and lower concentration/dose ratio. Pretransplant screening of relevant polymorphisms in accordance with age should be considered to adjust therapy.
|mesh-terms=* Adolescent
* Aging
* Alleles
* Child
* Cyclosporine
* Cytochrome P-450 CYP3A
* Cytochrome P-450 Enzyme System
* Female
* Gene Expression Regulation
* Genetic Variation
* Humans
* Immunosuppressive Agents
* Kidney Transplantation
* Male
* Serbia
* Transplant Recipients

|full-text-url=https://sci-hub.do/10.1097/FTD.0000000000000442
}}
{{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=Donor [[CYP3A5]] genotype influences tacrolimus disposition on the first day after paediatric liver transplantation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28044353
|abstract=The aim of the present study was to investigate the influence of the cytochrome P450 (CYP) 3A4/5 genotype in paediatric liver transplant recipients and donors, and the contribution of age and gender to tacrolimus disposition on the first day after transplantation. The contribution of the CYP3A4/5 genotype in paediatric liver transplant recipients and donors to the tacrolimus blood trough concentrations (C  ) and the tacrolimus concentration/weight-adjusted dose ratio on day 1 was evaluated in 67 liver-transplanted children: 33 boys and 34 girls, mean age 4.5 years. Donor [[CYP3A5]] genotype appears to be significantly associated with tacrolimus disposition on the first day after liver transplantation (P < 0.0002). Other physiological factors, such as recipient age and donor gender may also play a role and lead to significant differences in tacrolimus C  and tacrolimus concentration/weight-adjusted dose ratio on day 1. However, according to the general linear model, only recipient age appears to be independently associated with tacrolimus disposition on the first day after liver transplantation (P < 0.03). Indeed, there was a faster tacrolimus metabolism in children under 6 years of age (P < 0.02). Donor [[CYP3A5]] genotype, recipient age and, to a lesser extent, donor gender appear to be associated with tacrolimus disposition on day 1 after transplant. This suggests that increasing the starting tacrolimus doses in paediatric patients under 6 years of age who receive a graft from a male extensive metabolizer may enhance the possibility of their tacrolimus levels reaching the therapeutic range sooner.
|mesh-terms=* Adolescent
* Aging
* Body Weight
* Child
* Child, Preschool
* Cytochrome P-450 CYP3A
* Female
* Genetic Variation
* Genotype
* Humans
* Immunosuppressive Agents
* Infant
* Linear Models
* Liver Transplantation
* Male
* Sex Characteristics
* Tacrolimus
* Tissue Donors
|keywords=* CYP3A genotyping
* children
* immunosuppression
* liver transplantation
* tacrolimus
* therapeutic drug monitoring
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427244
}}
{{medline-entry
|title=Relationship between mRNA expression levels of [[CYP3A4]], [[CYP3A5]] and SXR in peripheral mononuclear blood cells and aging in young kidney transplant recipients under tacrolimus treatment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25916520
|abstract=The activity of several key enzymes involved in the metabolism of many drugs is subject to change closely related to the age of patients. This possibility must also be considered in the case of tacrolimus, the most important calcineurins inhibitor, which is widely used in pediatric kidney transplantation. As well as in the liver and intestine, some of the enzymes involved in the metabolism of tacrolimus were also isolated in the peripheral blood mononuclear cells (PBMCs), where also appear to play an important regulatory action. Therefore, the influence of some external factors on the expression of specific mRNA can be determined noninvasively. The correlation between the levels of mRNA specific for key enzymes SXR, CYP3A and [[ABCB1]] involved in the metabolism of tacrolimus was evaluated in PBMCs obtained from a selected population of 29 young kidney transplant recipients. A possible correlation between the expression of these specific mRNAs and tacrolimus pharmacokinetics was also investigated. The patients' age and their blood concentrations of SXR mRNA were directly correlated with the expression of [[CYP3A4]], [[CYP3A5]] mRNAs, but not of [[ABCB1]] mRNA in the PBMCs. tacrolimus-normalized daily dose was strongly correlated with patient's age and multivariable regression indicates the [[CYP3A4]]-specific mRNA as the sole independent variable influencing tacrolimus concentration-to-dose ratio. Aging and SXR mRNA significantly affect the expression of [[CYP3A4]]- and [[CYP3A5]]-specific mRNA as measured by their concentration in PBMC.
|mesh-terms=* ATP Binding Cassette Transporter, Subfamily B
* Adolescent
* Aging
* Cytochrome P-450 CYP3A
* Female
* Humans
* Immunosuppressive Agents
* Kidney Transplantation
* Male
* Monocytes
* Pregnane X Receptor
* RNA, Messenger
* Receptors, Steroid
* Tacrolimus
|keywords=* ABCB1
* CYP3A4
* CYP3A5
* SXR
* mRNA
* pediatric kidney transplant
* peripheral blood mononuclear cells
* tacrolimus
|full-text-url=https://sci-hub.do/10.2217/pgs.15.18
}}
{{medline-entry
|title=Age and [[CYP3A5]] genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21930396
|abstract=Tacrolimus is one of the commonly used immunosuppressive drugs for pediatric heart transplants. Large variation exists in pharmacokinetics during the direct post-transplant period, resulting in an increased risk of adverse events. Limited data are available on the interaction of age, [[CYP3A5]] and [[ABCB1]] genotype, and disease severity on the variation in disposition and outcome in pediatric heart transplant recipients. We studied the relationship between age and [[CYP3A5]] and [[ABCB1]] genotype and the Pediatric Risk of Mortality (PRISM) score on tacrolimus dose (mg/kg), steady-state trough concentrations, and concentration/dose ratio, as well as rejection and renal function for 14 days after heart transplant in children. Tacrolimus was administered to 39 children (median age, 6.0 years) after transplant. A correlation was found between the age at the time of transplant and the tacrolimus dosing requirements (r(s) = -0.447, p = 0.004) and the concentration/dose ratio (r(s) = 0.351, p = 0.029). [[CYP3A5]] expressors required median (interquartile range) higher doses of tacrolimus (0.14 [0.09] vs 0.06 [0.04] mg/kg/12 hours, p = 0.001), and had lower concentration/dose ratios (45.34 [44.54] vs 177.78 [145.38] ng/ml per mg/kg/12 hours, p < 0.0001). This relationship was not seen with the [[ABCB1]] genotype. Age and [[CYP3A5]] genotype predicted the tacrolimus dosing requirements as well as the concentration/dose ratio (R(2) = 0.351, p = 0.001 and R(2) = 0.521, p < 0.001). No relationship was found between any of the [[CYP3A5]] or [[ABCB1]] genotypes and the estimated glomerular filtration rate. Younger age and [[CYP3A5]] expressor genotype were independently associated with higher dosing requirements and lower tacrolimus concentration/dose ratios.
|mesh-terms=* ATP Binding Cassette Transporter, Subfamily B
* ATP Binding Cassette Transporter, Subfamily B, Member 1
* Aging
* Child
* Cytochrome P-450 CYP3A
* Dose-Response Relationship, Drug
* Female
* Genotype
* Glomerular Filtration Rate
* Graft Rejection
* Heart Transplantation
* Humans
* Immunosuppressive Agents
* Kidney
* Male
* Retrospective Studies
* Severity of Illness Index
* Tacrolimus
* Time Factors
* Treatment Outcome

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640375
}}
{{medline-entry
|title=Engraftment syndrome, but not acute GVHD, younger age, [[CYP3A5]] or MDR1 polymorphisms, increases tacrolimus clearance in pediatric hematopoietic [[SCT]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/20383212
|abstract=We investigated clinical factors that affected the clearance of tacrolimus (FK506) administered by continuous drip infusion to children who had received allogeneic hematopoietic [[SCT]]. Blood FK506 levels were measured every day in 27 patients in an attempt to adjust the dose to maintain the target range (10-15 ng/mL). Patients who developed engraftment syndrome (ES) and acute GVHD and patients less than 7 years of age showed a higher FK506 clearance calculated from body weight (BW) for 5 or more consecutive days compared with the control groups. A time-course study showed that the occurrence of ES, but not acute GVHD, was related to increased clearance of FK506. When calculated from body surface area (BSA), a significant increase in FK506 clearance was observed in patients with ES, but not in those less than 7 years of age. FK506 clearance was not influenced by [[CYP3A5]], multidrug resistance 1 or [[ABCG2]] genotypes. None of the clinical parameters affected blood FK506 levels. Determination of the FK506 dose on the basis of frequent monitoring of the blood concentration seems to minimize the serious adverse effects induced by the immunosuppressant. It may be more accurate to dose FK506 according to BSA rather than BW for pediatric patients.
|mesh-terms=* ATP Binding Cassette Transporter, Subfamily B
* ATP Binding Cassette Transporter, Subfamily B, Member 1
* ATP Binding Cassette Transporter, Subfamily G, Member 2
* ATP-Binding Cassette Transporters
* Adolescent
* Aging
* Child
* Child, Preschool
* Cytochrome P-450 CYP3A
* Drug Dosage Calculations
* Erythema
* Female
* Fever
* Graft vs Host Disease
* Hematopoietic Stem Cell Transplantation
* Humans
* Hypoxia
* Immunosuppressive Agents
* Infant
* Male
* Metabolic Clearance Rate
* Neoplasm Proteins
* Polymorphism, Genetic
* Pulmonary Eosinophilia
* Syndrome
* Tacrolimus
* Weight Gain

|full-text-url=https://sci-hub.do/10.1038/bmt.2010.64
}}
{{medline-entry
|title=No impact of age on dose-adjusted pharmacokinetics  of tacrolimus, mycophenolic acid and prednisolone 1 month  after renal transplantation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/19730841
|abstract=The purpose of the study was to assess the impact of age on the pharmacokinetics of immunosuppressive drugs. One hundred and ten renal transplant recipients, including 12 elderly patients over 60 years of age, 57 middle-aged patients between 40 and 59 years and 41 young adult patients 20 to 39 years of age were studied. To evaluate dose-adjusted pharmacokinetics and cytochrome P450 (CYP) 3A5 pharmacogenetics, the concentrations of tacrolimus, mycophenolic acid (MPA), MPA glucuronide (MPAG) and prednisolone were measured at 1 month post-transplantation. There were no differences in dose (D) and body weight (BW)-adjusted pharmacokinetic parameters of tacrolimus among the three groups. D/BW-adjusted C(max), C(0) and AUC(0-12) values of tacrolimus were significantly greater in patients with the [[CYP3A5]]*3/*3 genotype than in those with the [[CYP3A5]]*1 allele in young and middle-aged patients as previously reported, but not in the elderly. There were no significant differences in the D-adjusted pharmacokinetics of prednisolone and MPA among the three groups. The aging process itself may have a small effect on the pharmacokinetics of tacrolimus, MPA, or prednisolone. However, a larger number of subjects need to be studied to confirm the impact of age on the [[CYP3A5]] pharmacogenetics of tacrolimus in the elderly.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aging
* Analysis of Variance
* Area Under Curve
* Body Weight
* Cytochrome P-450 CYP3A
* Dose-Response Relationship, Drug
* Enzyme Inhibitors
* Female
* Genotype
* Humans
* Immunosuppressive Agents
* Kidney Transplantation
* Male
* Middle Aged
* Mycophenolic Acid
* Prednisolone
* Tacrolimus
* Time Factors

|full-text-url=https://sci-hub.do/10.1007/s00228-009-0721-9
}}
{{medline-entry
|title=A drug transporter for all ages? [[ABCB1]] and the developmental pharmacogenetics of cyclosporine.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/18518855
|abstract=Evaluation of: Fanta S, Niemi M, Jönsson S et al.: Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of [[ABCB1]]polymorphisms. Pharmacogenet. Genomics 18(2), 77-90 (2008). The clinical use of the immunosuppressive agent cyclosporine is complicated by its toxicity, narrow therapeutic window and highly variable pharmacokinetics between individuals. In adults, genetic polymorphisms in the genes encoding the cyclosporine-metabolizing enzymes [[CYP3A4]] and [[CYP3A5]], as well as the [[ABCB1]] gene, which encodes the efflux-pump P-glycoprotein, seem to have a limited effect, if any, on cyclosporine pharmacokinetics. However, the authors have now reported for the first time an association between cyclosporine oral bioavailability and the [[ABCB1]] c.1236C>T and c.2677G>T polymorphisms, as well as the related haplotype c.1199G-c.1236C-c.2677G-c.3435C, in children with end-stage renal disease older than 8 years of age. Carriers of the variant alleles had a cyclosporine oral bioavailability that was around 1.5-times higher compared with noncarriers. This association was not observed in children younger than 8 years of age. In addition, no relation between cyclosporine disposition and genetic variation in the [[CYP3A4]], [[CYP3A5]], [[ABCC2]], [[SLCO1B1]] and [[NR1I2]] genes was observed. These data suggest that the effect of [[ABCB1]] polymorphisms on cyclosporine pharmacokinetics is related to age, and thus developmental stage. Although further study is necessary to establish the predictive value of [[ABCB1]] genotyping for individualization of cyclosporine therapy in children older than 8 years, an important step towards further personalized immunosuppressive drug therapy has been made.
|mesh-terms=* ATP Binding Cassette Transporter, Subfamily B
* ATP Binding Cassette Transporter, Subfamily B, Member 1
* Adult
* Aging
* Child
* Cyclosporine
* Humans
* Immunosuppressive Agents
* Inactivation, Metabolic
* Kidney Transplantation
* Pharmacogenetics
* Polymorphism, Single Nucleotide

|full-text-url=https://sci-hub.do/10.2217/14622416.9.6.783
}}
{{medline-entry
|title=A study of genetic ([[CYP2D6]] and [[ABCB1]]) and environmental (drug inhibitors and inducers) variables that may influence plasma risperidone levels.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/17541883
|abstract=Risperidone (R) is metabolized to 9-hydroxyrisperidone (9-OHR) by cytochrome P450 2D6 ([[CYP2D6]]). The main objective of this naturalistic study was to investigate the variables associated with two plasma ratios: the plasma R:9-OHR concentration ratio and the total concentration-to-dose (C:D) ratio. These ratios were studied as continuous measures by linear regression analyses and as three dichotomous variables in logistic regression analyses: R:9-OHR ratio >1 (indicative of lack of [[CYP2D6]] activity), C:D ratio >14 (indicative of diminished R elimination), and C:D ratio <3.5 (indicative of increased R elimination). Plasma R levels; genotypes for [[CYP2D6]], [[CYP3A5]]; and [[ABCB1]] genes, and co-medication, including CYP inhibitors and CYP3A inducers, were studied in 277 patients. Almost all [[CYP2D6]] poor metabolizers (PMs) had an inverted R:9-OHR ratio (>1). Having a [[CYP2D6]] PM phenotype was strongly associated with a C:D ratio >14 (OR=8.2; 95% confidence interval [CI]=2.0-32.7), indicating diminished R elimination. [[CYP2D6]] ultrarapid metabolizers (UMs) did not exhibit an increased R elimination. Some [[ABCB1]] (or MDR1) variants were significantly associated with increased R:9-OHR ratios and decreased C:D ratios, but the results were neither consistent nor robust. Taking CYP inhibitors was significantly associated with a C:D ratio >14 (OR=3.8; CI=1.7-8.7) and with an inverted R:9-OHR ratio. Taking CYP3A inducers was significantly associated with a C:D ratio <3.5 (OR=41.8; CI=12.7-138), indicating increased R elimination. Female gender and old age appeared to be associated with a lower R elimination. Our study indicated that the [[CYP2D6]] PM phenotype may have a major role in personalizing R doses, whereas the [[CYP3A5]] PM phenotype probably has no role. CYP inducers and inhibitors appear to be relevant to R dosing. New studies are needed, particularly to further assess the role of the [[CYP2D6]] UM phenotype and [[ABCB1]] variants in R pharmacokinetics.
|mesh-terms=* ATP Binding Cassette Transporter, Subfamily B
* ATP Binding Cassette Transporter, Subfamily B, Member 1
* Adult
* Aging
* Antipsychotic Agents
* Cytochrome P-450 CYP2D6
* Cytochrome P-450 CYP2D6 Inhibitors
* Cytochrome P-450 CYP3A
* Cytochrome P-450 Enzyme Inhibitors
* Cytochrome P-450 Enzyme System
* Drug Interactions
* Enzyme Induction
* Female
* Humans
* Isoxazoles
* Linear Models
* Male
* Middle Aged
* Organic Anion Transporters
* Paliperidone Palmitate
* Pyrimidines
* Risperidone
* Sex Factors

|full-text-url=https://sci-hub.do/10.1055/s-2007-973836
}}
{{medline-entry
|title=A review of developmental aspects of cytochrome P450.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/9853690
|abstract=This article surveys the development of human hepatic P450 cytochromes (CYPs) involved in xenobiotic metabolism from the fetus through the life span and explores possible clinical consequences of developmental issues. These hepatic P450 CYPs come "on line" at different times during fetal and infant development, and each one is discussed in that temporal sequence. [[CYP3A7]]. the major fetal hepatic cytochrome, is present during organogenesis, and it is involved in steroid metabolism. Variably expressed in some fetuses, [[CYP3A5]] is also present at significant levels in about half of all children. In adults, [[CYP3A4]] is the major functional member of the CYP3A subfamily. [[CYP1A1]] is also present during organogenesis, and it metabolizes exogenous toxins, some of which are procarcinogens. [[CYP2E1]] may be present in some second-trimester fetuses, and it may be involved in prenatal alcohol metabolism. After birth, hepatic [[CYP2D6]] and CYP2C8/9 and CYP2C18/19 become active. Both [[CYP2D6]] and [[CYP2C19]] have genetic polymorphisms that can bring about differing capacities to metabolize exogenous drugs, including psychotropic drugs. [[CYP1A2]] becomes active in the fourth to fifth postfetal months. It provides the best current examples of the importance of developmental changes in xenobiotic-metabolizing P450 CYPs through its metabolism of caffeine and theophylline in premature infants, neonates, and adolescents.
|mesh-terms=* Aging
* Animals
* Cytochrome P-450 Enzyme System
* Female
* Fetus
* Humans
* Liver
* Pregnancy
* Xenobiotics

|full-text-url=https://sci-hub.do/10.1089/cap.1998.8.161
}}