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Objective To summarize the therapeutic effects of living related donor liver transplantation for Crigler-Najjar syndrome type Ⅰ (CNS type Ⅰ). Methods A 3-month-old male infant had appeared a progressive xanthochromia of the skin and sclera 4 d after birth without obvious cause. Other causative factors were eliminated after relevant tests were completed, and identified as CNS type Ⅰ by genetic testing. Living related donor liver transplantation was performed with his mother as the donor. An immunosuppression regimen was routinely applied postoperatively and tacrolimus doses were adjusted according to biochemical indicators and cytochrome P450 (CYP) 3A5 genotype of the recipient. Results The liver enzymes of the recipient returned to normal at 7 d postoperatively, and bilirubin decreased daily and fell to the normal range at 22 d postoperatively. Followed up to the submission date, the recipient's xanthochromia of skin and scleral faded with normal bilirubin and stable liver enzymes. The condition of the recipient was generally good with high quality of life. Conclusions Living donor liver transplantation can treat unconjugated hyperbilirubinemia and other diseases caused by CNS type Ⅰ, which greatly improve the quality of life of patients.
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RESUMO Os polimorfismos genéticos do CYP3A5 têm sido apontados enquanto fatores influenciadores na eficácia farmacológica com tacrolimo em pacientes em terapia imunossupressora no pós-transplante hepático. O presente estudo objetiva realizar uma revisão da literatura acerca da influência dos polimorfismos genéticos do citocromo P450 3A5 (CYP3A5) na eficácia terapêutica com tacrolimo em indivíduos pós-transplante hepático. Revisão da literatura. Foi utilizada a combinação dos descritores "tacrolimo", "transplante de fígado", "inibidores do citocromo P-450 CYP3A" e "polimorfismo genético", nas bases de dados: PubMed, The Cochrane Library, Scopus e Scielo, sendo avaliados apenas estudos publicados entre 2009 e 2019 em inglês, português ou espanhol. Ao todo foi feita a sumarização de seis estudos, cada um avaliando uma diferente população. Inicialmente, foram abordados os aspectos farmacológicos do tacrolimo, incluindo detalhes sobre sua farmacodinâmica, farmacocinética e toxicidade. Na seção seguinte, foi realizada a avaliação de estudos que tratam da relação entre os polimorfismos genéticos do CYP3A5 e a eficácia farmacológica com o tacrolimo, incluindo as especificações étnicas e as limitações gerais dos estudos. Os polimorfismos genéticos do CYP3A5 têm apontado para alterações no metabolismo do tacrolimo de acordo com um recorte étnico e populacional, com destaque para os alelos *1 e *3*3, refletindo na necessidade de ajuste de dose ou até mesmo nas taxas de rejeição do órgão.
ABSTRACT Genetic polymorphisms of CYP3A5 have been pointed out as factors that influenciates tacrolimus immunosuppressive efficacy in post liver transplant patients. This study aims to review the literature on the influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphisms of tacrolimus in post-liver transplant patients. This study is a literature review. A combination of the descriptors "tacrolimus", "liver transplant", "cytochrome P-450 CYP3A inhibitors" and "genetic polymorphism" were used in the databases PubMed, Cochrane Library, Scopus and Scielo, being evaluated only studies between 2009 and 2019 in English, Portuguese or Spanish. A total of six studies, each from a different population were summarized. Initially, the pharmacological aspects of tacrolimus were discussed, including details on its pharmacodynamics, pharmacokinetics and toxicity After that, we analyzed the studies that correlates CYP3A5 genetic polymorphisms and tacrolimus efficacy, including the ethnical specifications and the general limittions of the studies. The CYP3A5 polymorphisms have pointed to alterations in the metabolism of tacrolimus according to the ethnic and populational genotype, specially the *1 and *3*3 alleles, reflecting in the need for dose adjustment and also in post liver transplant rejection.
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Humans , Liver Transplantation , Tacrolimus/therapeutic use , Cytochrome P-450 CYP3A/genetics , Polymorphism, Genetic , Polymorphism, Single Nucleotide , Immunosuppressive AgentsABSTRACT
Objective To investigate the relationship between the metabolic rate of tacrolimus (FK506) and BK virus infection early after renal transplantation. Methods Eighty recipients undergoing allogenic renal transplantation in Institute of Organ Transplantation of the 309thHospital of Chinese People's Liberation Army were recruited in this study. The polymorphism of cytochrome P450 (CYP) 3A5 gene was detected in 80 recipients. All patients were divided into fast metabolism group ( CYP3A5*1/*3 and CYP3A5*1/*1 genotypes, n=38) and slow metabolism group ( CYP3A5*3/*3 genotype, n=42) based on the gene detection results. The distribution of CYP3A5 genotypes in 80 recipients was analyzed. The metabolic rate [concentration/dose ratio (C/D value)] of FK506 was statistically compared between two groups. The incidence of BK virus infection events [BK viruria, BK viremia and BK virus nephropathy(BKVN)] within postoperative 6 months were compared between two groups. Results Among 80 recipients, 5 cases (6%) were detected with CYP3A5*1/*1 genotype, 33 (41%) with CYP3A5*1/*3 genotype, and 42 (53%) with CYP3A5*3/*3 genotype. Among the 160 alleles in 80 recipients, 117 CYP3A5*3 allele were identified, suggesting that the mutation rate of CYP3A5*3 allele was 73.1%. In the fast metabolism group, the C/D values at postoperative 1, 3, and 6 months were significantly lower than those in the slow metabolism group (all P<0.01). The incidence rates of BK viruria in the fast and slow metabolism groups were 37% and 29%, 18% and 2% for BK viremia, and 3% and 0 for BKVN, respectively. In the fast metabolism group, the incidence of BK virenia was significantly higher than that in the slow metabolism group (P=0.02). The incidence of BK viruria and BKVN did not significantly differ between two groups (both P>0.05). Conclusions According to the CYP3A5 genotyping outcomes, the recipients with a high metabolic rate of FK506 have a high risk of BK viremia early after renal transplantation.
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Objective To establish an allele-specific PCR method for the detection of cytochrome P-450 CYP3A5 (A6986G) and multiding resistance gene MDR-1 (C3435T) polymorphisms,and investigate the correlations of their polymorphisms with blood tacrolimus (Tac) concentration/dose (C/D) ratio in renal transplant recipients.Methods The allele-specific PCR primers were designed according to the polymorphism sites of CYP3A5 (A6986G) and MDR-1 (C3435T) genes.Then,their polymorphisms in the genomic DNA of peripheral blood samples from 72 renal transplant recipients were analyzed,and the results were validated by DNA sequencing.The blood Tac concentration was determined by the chemiluminescence microparticle immunoassay and the differences of concentration,dose and C/D ratio of blood Tac in renal transplant recipients with different genotypes were compared at 1 month after transplantation.Results The coincidence rate between the established allele-specific PCR and DNA sequencing was 100％.The frequencies of CYP3A5 * 1/* 1,* 1/* 3 and * 3/* 3 genotypes in 72 renal transplant recipients were 18.1％,31.9％ and 50.0％,respectively,and those of MDR-1 C/C,C/T and T/T genotypes were 27.8％,58.3％ and 13.9％,respectively.There were significant differences in blood Tac concentration (P =0.014) and Tac C/D ratio (P =0.019) between different CYP3A5 genotypes of renal transplant recipients.Further analysis found that the Tac C/D ratio of CYP3A5 * 3/* 3 genotype was significantly higher than that of CYP3A5 * 1/* 1 and * 1/* 3 genotypes (P ＜ 0.05).Conclusion The allele-specific PCR method for the detection of CYP3A5 and MDR-1 polymorphisms is successfully established and the polymorphism of CYP3A5 * 3 gene in renal transplant recipients is obviously correlated with the pharmacokinetics of Tac.
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Objective To investigate the predictive and prognostic value of genetic detection of Kirsten rat sarcoma viral oncogene homolog(KRAS),Fc gamma receptors (FCGR),cytochrome P450 3A5 (CYP3A5) and CYP1A1 in patients with metastatic colorectal cancer (mCRC) receiving C225 combined with CapeOx chemotherapy.Methods Twelve KRAS wild-type (WT) mCRC patients were selected receiving C225 (cetuximab) combined with CapeOx (capecitabine/oxaliplatin) chemotherapy.KRAS,FCGR,CYP3A5,CYP1 A1 gene mutation were detected before treatment.The expressions of phosphatase and tensin homolog deleted on chromosome ten (PTEN) were detected in colorectal cancer tissues and the corresponding adjacent tissues expression with immunohistochemical staining (SP method).The relationship between FCGR,CYP3A5,CYP1A1 mutation,and PTEN expression and survival time were analyzed.Results The mutation rates of FCGR,CYP3A5,and CYP1 A1 were 16.7％ (2/12),25％ (3/12) and 16.7％ (2/12) in 12 patients with KRAS WT,respectively.PTEN was expressed mainly in the nucleus in yellowish brown.The rates of expression in the tissue adjacent to the cancer and in the tumor tissue were 100％ (12/12) and 41.7％ (5/12),respectively.PTEN expression in tumor tissue was reduced or absent.The study indicated that the objective response rate [complete response + partial response (CR + PR)] was 80％ in patients whose KRAS,FCGR,CYP3A5,and CYP1A1 were all in wild type,the CR + PR rates in FCGR,CYP3A5,and CYP1A1 gene mutation group were 0,33.6％ and 50％.The objective response rates of patients with PTEN expression or null were 50％ and 37.5％,respectively (P ＜ 0.05).The progression free survival (PFS) with KRAS/FCGR/CYP3A5/CYP1A1 wild type or mutation were 15.56 or 8.12 months (P ＜ 0.05).The overall survival (OS) with wild type or mutation of KRAS/FCGR/CYP3A5/ CYP1A1 were 25.03 or 19.21 months(P ＜0.05).The PFSs of positive or negative expression of PTEN in patients were 9.13 or 7.87 months (P ＜0.05),and the OSs of positive or negative expression of PTEN in patients were 24.25 or 18.74 months (P ＜0.05).Conclusions FCGR,CYP3A5 and CYP1A1 mutations and PTEN expression null both have been associated with resistance to cetuximab in mCRC patients.FCGR,CYP3A5,CYP1A1 and PTEN can be served as the predictive biomarkers for the response to cetuximab.
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Objective To evaluate the effect of CYP3A4*1G genetic polymorphism on the pharmacokinetics of levobupivacaine after epidural administration.Methods One hundred and eleven American Society of Anesthesiologists physical status Ⅰ or Ⅱ patients,aged 30-60 yr,weighing 56-79 kg,scheduled for elective lower extremity surgery under epidural anesthesia,were enrolled in the study.Blood sampies were collected from the central vein before anesthesia for detection of CYP3A4*1G genotypes by polymerase chain reaction-restriction fragment length polymorphism.The patients were divided into 3 groups according to the CYP3A4*1G genotypes:wild hemozygote (CYP3A4*1/*1) group (w/w group),mutation heterozygote (CYP3A4*1/*1G) group (m/w group) and mutation hemozygote (CYP3A4*1G/*1G) group (m/m group).An epidural catheter was placed at the L1,2 interspace,and 0.75％ levobupivacaine 1.8 mg/kg was injected.Thirty-four patients were randomly selected,and blood samples from the central vein were collected at0,10,20,30,45,60,90,120,180,240,360,480,840 and 1 440 min after administration for determination of plasma concentrations of levobupivacaine by high-performance liquid chromatography.The pharmacokinetic parameters were calculated.Results There were 42 cases in group w/w,59 cases in group m/w,and 10 cases in group m/m.The frequency of CYP3A4*1G variant allele was 35.6％ in the 111 patients underwent lower extremity surgery.There were no significant differences between the three groups in the plasma concentrations of levobupivacaine at different time points,elimination halflife,clearance,distribution volume,elimination rate constant,peak plasma concentration,time to peak plasma concentration or area under the concentration-time curve (P＞0.05).Conclusion CYP3A4*1G genetic polymorphism is not one of the genetic factors contributing to the individual variation in the pharmacokinetics of levobupivacaine after epidural administration.
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The incompatibility of traditional Chinese medicine is an important part of traditional Chinese medicine compatibility theory,while early toxicity predetermination of traditional Chinese medi?cine is an important component of drug safety evaluation. Once a simple and reliable method to predict the compatibility of Chinese medicine and Chinese traditional medicine is established,it is possible to obtain the data of toxic reaction of Chinese herbal medicine quickly and early. Pregnane X receptor (PXR)is a ligand dependent transcription factor,acting as a ligand or activator of a large number of clinical drugs and of cytochrome P-450 CYP3A (CYP3A) gene expression induced by PXR. In the course of treatment of diseases,the activation of PXR may increase the risk of drug interactions and adverse reactions,resulting in decreased efficacy and even toxicity. This paper may provide a new method of drug toxicity predetermination depending on the PXR-CYP3A pathway.
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OBJECTlVE To investigate the association between CYP3A5 genotypes and the early efficacy of tacrolimus ( Tac) and cyclosporin A ( CsA) in renal transplantation recipients, and provide a basis for individualized treatment. METHODS Seventy-four kidney transplantation recipients were en-rolled in this study between August 2012 and April 2013. Thirty-one patients were treated with the combi-nation of CsA, MMF and methylprednisolone while the rest were treated with Tac, MMF and methylpred-nisolone. The genotype CYP3A5 was detected by sequence specific primer-polymerase chain reaction ( SSP-PCR) before transplantation. The levels of Tac and CsA were detected by ELlSA and chemilumi-nescence, respectively, to monitor the blood concentration/dose of drugs ( c/D) at 2 weeks, 1 month, 2 months, 3 months and 6 months after transplantation. Simultaneously, the concentrations of blood glu-cose, creatinine, urea nitrogen and uric acid were determined with hexokinase method, creatininase method, urease method and uricolase method, respectively. RESULTS Among the 74 recipients, 9.5%carried CYP3A5?1/?1, 48.6%carried CYP3A5?1/?3 and 41.9%carried CYP3A5?3/?3. According to the phenotype of CYP3A5, the patients were divided into CYP3A5 expression group ( including CYP3A5?1/?1 and CYP3A5?1/?3) and non-expression group ( including CYP3A5?3/?3) , which accounted for 58.1%and 41.9%of the cases, respectively. Among the patients taking Tac, the median value of c/D at 2 weeks, 1 month, 2 months, 3 months and 6 months was 25.49, 49.64, 53.72, 51.9 and 44.5 in CYP3A5 expression group, and 65.48,100.84,99.54,123.01 and 133.21 in non-expression group. The c/D ratio of CYP3A5 non-expressers was higher than among CYP3A5 expressers at each time point ( P<0.05) . The initial dose of Tac 0.1 mg·kg-1 was high for CYP3A5 non-expressers, and the kidney function recovered more slowly than among CYP3A5 expressers and kidney damage occurred. However, there was no association between CYP3A5 genotype and the early efficacy of CsA. The levels of blood glucose, creatinine, urea nitrogen and uric acid were not significantly different between CYP3A5 expression and non-expression groups. CONCLUSlON CYP3A5 non-expression recipients whose starting amount of Tac was 0.1 mg·kg-1 have drug overdoses. CYP3A5 genotype is one of the factors affecting the efficacy of Tac. CYP3A5 genotype has no association with the efficacy of CsA in renal transplantation recipients.
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OBJECTlVE To establish Tg(-6.3CYP3A65∶EGFP) transgenic zebrafish for quick, intuitive detection of heavy metals ( copper, cadmium and zinc) , dioxin-like PCBs ( PCB126) and other environmental pollutants. METHODS Tol2 transposon system was used to generate transgenic zebrafish lines Tg(-6.3CYP3A65∶EGFP) in which CYP3A65 promoter regualated labeled fluorescence. The effect of heavy mentals ( copper, cadmium and zinc ) and PCB126 on the relative amounts of CYP3A65 gene expression was determined by observing the change in fluorescence intensity. RESULTS The relative gene expression of CYP3A65 was significantly increased after 96 h exposure to copper 0.1 and 0.2μmol·L-1 , cadmium 0.35 and 0.7μmol·L-1 , zinc 1.5 and 3μmol·L-1 , and PCB126 2-32μmol·L-1 , respectively ( P<0.01) , but decreased after 96 h exposure to copper 0. 9 μmol·L-1 , cadmium 2. 7 and 5.4 μmol·L-1 , and zinc 24μmol·L-1 , respectively( P<0.01) . CYP3A65 gene expression was significantly increased after 168 h exposure to copper 0.1 and 0.2 μmol·L-1 , cadmium 0.35 and 0.7 μmol·L-1 , zinc 1.5 and 3 μmol·L-1, and PCB126 2-32 μmol·L-1, respectively(P<0.01), but decreased after 168 h exposure to copper 0.9 μmol·L-1, cadmium 2.7 and 5.4 μmol·L-1, and zinc 12 and 24 μmol·L-1( P<0.05) , in a concentration-dependent manner. CONCLUSlON The results suggest that zebrafish CYP3A65 gene expression and the CYP3A65 labeled fluorescence lines can be another candidate biomarker for detecting environmental pollutants.
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Objective To investigate the impact of CYP3A5 and ABCB1 polymorphisms on the initial individualized treatment with tacrolimus (FK506) in renal transplant recipients during switching from cyclosporine (CsA) to FK506. Methods Polymerase chain reaction and restriction fragment length polymorphism method (PCR-RFLP) was employed to investigate CYP3A5 (A6989G) and ABCB1 (exon12 [C1236T], exon21G[A] 2677T and exon26 [C3435T]) genotype data. The initial trough concentration/ dose (Co/D) values were compared among different CYP3A5 genotypes in renal transplant recipients switching from CsA to FK506 using one-way ANOVA. In addition, the initial C0 /D values were also compared among different ABCB1 (exon12[C1236T], exon21G[A]2677T and exon26[C3435T]) genotypes and their haplotypes using one-way ANOVA. Results The FK506 C0 /D values were significantly different between different CYP3A5 genotypes (AA, AG and GG) at the 7th, 14th, 21th and 28th day of conversion from CsA to FK506 in renal transplant recipients CP
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Objective To investigate 4 variants single nucleotide polymorphisms (SNPs) of 5-lipoxygenase-activating protein(ALOX5AP) in lipoxygenase pathway and in cytochrome P450 pathway as susceptibility genes for stroke in a southeastern Chinese population,and evaluate the associations between susceptibility genes and cerebral infarction,to find whether gene-gene interactions increase the risk of cerebral infarction.Methods By case-control study,two hundred and ninety-two patients with cerebral infarction and 259 healthy control subjects were included.Eight variants in 5 candidate genes were examined for stroke risk,including the SG13S32 (rs9551963),SG13S42 (rs4769060),SG13S89 (rs4769874),and SG13Sl14 (rs10507391) variants of the ALOX5AP gene,the G860A (rs751141) variant of the soluble epoxide hydrolase (EPHX2) gene,the A1075C (rs1057910) variant of the CYP2C9 *2 gene,the C430T (rs1799853) variant of the CYP2C9* 3 gene,and the A6986G (rs776746) variant of the CYP3A5 gene.Gene-gene interactions were explored using generalized multifactor dimensionality reduction (GMDR)methods.Results There were no statistically significant differences in the frequencies of the genotypes of the 8 candidate genes.The GMDR analysis showed a significant gene-gene interaction between SG13S114 and A6986G,with scores of 10 for cross-validation consistency and 9 for the sign test (P =0.011).These genegene interactions predicted a significantly higher risk of cerebral infarction (adjusted for age,hypertension,and diabetes mellitus;OR =1.804,95％ CI 1.180-2.759,P =0.006).Conclusions A two-loci gene interaction confers significantly higher risk for cerebral infarction.The combinational analysis used in this study may be helpful in the elucidation of genetic risk factors for common and complex diseases.
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Objective To investigate the effect of CYP3A5 * 3 and MDR1C3435T polymorphisms on the blood trough concentration of sirolimus in the Chinese renal transplantation recipients with stable renal function and the influencing factors for individual differences.Method 112 cases of Chinese renal transplantation recipients with stable renal function were recruited in this study.Related data of the recipients,including gender,age,height and body mass,were recoded.CYP3A5 and MDR1 genotypes were determined by the direct sequencing.Blood trough concentration of sirolimus was measured by using chemiluminescence microparticle immuno assay (CMIA).The influencing factors of individual differences in sirolimus blood trough concentration was analyzed,and the correlation of CYP3A5 * 3 and MDR1C3435T gene polymorphisms with sirolimus blood trough concentration was evaluated.Result Of the 112 cases,there were 10 cases (8.93％) of CYP3A5 * 1/* 1,49 cases (43.75％) of CYP3A5 * 1/* 3,and 53 cases (47.32％) of CYP3A5 * 3/* 3.Allele frequencies of CYP3A5 * 1 and * 3 were 30.81％ and 69.19％,respectively.There were 31 recipients (27.68％) with MDR1 3435CC,60 (53.57％) with MDR1 3435CT,and 21 (18.75％) with MDR1 3435TT.Allele frequencies for C and T at position 3435 of MDR1 were 54.46％ and 45.54％,respectively.In this study,recipients' CYP3A5 * 3 genotype was the main factor (P =0.000) of sirolimus blood trough concentration,but dose,gender,age,height,postoperative time,the level of serum creatinine,hemoglobin levels,combined use of CsA and MDR1C3435T genotype had no effects on sirolimus blood trough concentration (P ＞ 0.05).sirolimus blood trough concentration/(dose weight) in * 1/* 1,* 1/* 3 and * 3/* 3 recipients was (0.0721 ± 0.0202),(0.1055 ± 0.0395),and (0.1395 ± 0.0537) μg·L-1 ·mg-1 ·kg-1,respectively,The sirolimus blood trough concentration/ (dose weight) in * 1/* 3 recipients was 1.46 times higher than that in * 1/* 1 recipients,and that in * 3/* 3 recipients were 1.93 times higher than that in * 1/* 1 recipients.There was significant difference in sirolimus blood trough concentration/(dose weight) between recipients with different CYP3A5 * 3 genotypes (P =0.000).Conclusion The CYP3A5 * 3 gene polymorphism is closely related to the blood trough concentration/dose of sirolimus,and is the main factor of the blood trough concentration of sirolimus between individuals.
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Objective To study the effect of cefetamet hydrochloride injection on the activity of 3 kinds of cytochrome P450 (CYP450) isoforms (CYP1A2, CYP3A4 and CYP2E1) in rat liver microsomes. Methods The SD rats were randomly divided into two groups: control group and cefetamet hydrochloride (CH) group, with each group containing 3 male rats and 3 female rats. The CH group was injected with cefetamet hydrochloride into the tail vein at 50 mg/(kg • d), twice a day for 7 days. A HPLC method was used for simultaneous determination of the production of metabolites and the degradation of the prototype probe substrates of 3 kinds of CYP450 isoforms, so as to evaluate the activity of hepatic CYP450. The analytical column was Diamonsil C18 column (150 mm X 4. 6 mm, 5 Fm), with the flow rate being 1. 0 mL/min. The mobile phase consisted of methanol (0. 1% formic acid) (A)-water (0. 1% formic acid)(B), 0-5 min; 18%A, 5-10 min; 18%-60%A, 10-15 min: 60%A and detected at 247 nm for determination of CYP1A2 activities; methanol (A)-water (0. 02% formic acid)(B), 0-11 min: 40%-60%A and detected at 223 nm for determination of CYP3A4 activities; and methanol (A)-water, 0-10 min: 37%-75%A and detected at 287 nm for determination of CYP2E1 activities. Results Probe substrates and their metabolites showed good linearity within the determining range (r≥0. 999 7). The precision of the method was 0. 05). Conclusion CH injection can significantly induce hepatic microsome CYP3A4 expression in SD rats, but has no induction or inhibition effect on CYP1A2 and CYP2E1, indicating that potential drug-drug interaction might occur when CH injection is coadministered with drugs metabolized by CYP3A4.
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Objective To retrospectively investigate the effects of CYP3A5 * 3,CYP3A4 * 18B and CYP3A5-CYP3A4 phenotype on the C0,D and C0/D of tacrolimus (Tac) in renal transplantation recipients.Methods The CYP3A5 * 3 and CYP3A4 * 18B genotypes of the 61 patients were detected by DNA direct sequencing,and the C0 was detected by ELISA.The differences of C0,D and C0/D on the day 14,and month 1,2 and 3 after transplantation were compared among different genotypes of recipients treated with Tac.Results The frequency of the CYP3A5 * 3 and CYP3A4 * 18B was 74.6％ and 26.2％ respectively.When the D of the recipients with CYP3A5 * 1 ( * 1/* 1 + * 1/* 3)was 1.3-1.6 times to theCYP3A5*3/*3,theC0 of *3/*3 group was 1.1-1.5 times to the * 1group,and the C0/D was 1.8 2.4 times to the CYP3A5 * 1.For CYP3A4,the D of CYP3A4 * 18B group ( * 1/* 18B+ * 18B/* 18B) was 1.2-1.5 times to the CYP3A5 * 1/* 1,but the C0 of 1/* 1was 1.2-1.4 times to the * 18B,the C0/D was 1.5-1.8 times to the * 18B.For the CYP3A5 CYP3A4 phenotype,the D of the recipients with AAAA was 1.3-1.7 times to the GG-GG,the C0 of GG-GG was 1.5-2 times to the AA-AA,the C0/D of the recipients with G@GG was 2.5-3 times to the AA-AA.In the recipients with C0/D above or below the median of C0/D,the distribution of CYP3A5,CYP3A4 and CYP3A5-CYP3A4 phenotypes was different significantly.Conclusion There is a significant correlation between the CYP3A5,CYP3A4 and pharmacokinetics of Tac.It's more powerful evaluating the CYP3A5-CYP3A4 phenotype rather than just one genotype of the recipients.So detecting the CYP3A5 * 3 and CYP3A4 * 18B genotypes prior to transplantation is meaningful for us to determine an appropriate initial and long-time dosage of Tac.
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Imatinib has proved to be effective in the treatment of chronic myeloid leukemia, but plasma levels above 1,000 ng/mL must be achieved to optimize activity. Therapeutic drug monitoring of imatinib is useful for patients that do not present clinical response. There are several analytical methods to measure imatinib in biosamples, which are mainly based on liquid chromatography with mass spectrometric or diode array spectrophotometric detection. The former is preferred due to its lower cost and wider availability. The present manuscript presents a review of the clinical and analytical aspects of the therapeutic drug monitoring of imatinib in the treatment of chronic myeloid leukemia. The review includes references published over the last 10 years. There is evidence that the monitoring of plasmatic levels of imatinib is an useful alternative, especially considering the wide pharmacokinetic variability of this drug.
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Plasma , Pyrimidines/pharmacokinetics , Algorithms , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Chromatography , Drug Monitoring , Drug Therapy , Cytochrome P-450 CYP3A/metabolism , Imatinib Mesylate , /pharmacokinetics , Antineoplastic Agents/therapeutic useABSTRACT
AIM To express recombinant human cytochrome P450 3A4 mutants CYP3A4.3, CYP3A4.4, CYP3A4.5 and CYP3A4.18, and to employ them for in vitro metabolism studies of CYP3A4. METHODS Use Bac-to-Bac baculovirus expression system to recombinant baculovirus carrying cDNA of CYP3A4 mutants CYP3A4.3, CYP3A4.4, CYP3A4.5 and CYP3A4.18. Spodoptera frugiperda 9 (Sf9), cells were co-infected by recombinant viruses of CYP3A4 mutants, human NADPH-P450 oxidoreductase and cytochrome b5 to obtain recombinant proteins CYP3A4.3, CYP3A4.4, CYP3A4.5 and CYP3A4.18 with metabolic activity. RESULTS The mRNA transcription of CYP3A4 mutants in Sf9 cells were validated by RT-PCR. Testosterone and 7-benzyloxy-4-(trifluoromethyl) coumarin were metabolized by the lysates of Sf9 cells infected by the recombinant viruses. CONCLUSION CYP3A4 mutants CYP3A4.3, CYP3A4.4, CYP3A4.5 and CYP3A4.18 with metabolic activity were successfully expressed by baculovirus-insect cell expression system. The results indicated that recombinant CYP3A4. 5 showed lower activity comparing to the wild type protein towards testosterone, while CYP3A4. 18 with higher activity, and for CYP3A4.3 and CYP3A4.4 showing similar activity to the wild type protein.
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Cytochrome P450 3A4 (CYP3A4), is the dominant human liver hemoprotein enzyme localized in the endoplasmic reticulum (ER), and is responsible for the metabolism of more than 50% of clinically relevant drugs. While we were studying CYP3A4 expression and activity in human liver, we found that anti-CYP3A4 antibody cross-reacted with a lower band in liver cytoplasmic fraction. We assessed the activities of CYP3A4 and its truncated form in the microsomal and cytoplasmic fraction, respectively. In the cytoplasmic fraction, truncated CYP3A4 showed catalytic activity when reconstituted with NADPH-cytochrome P-450 reductase and cytochrome b5. In order to determine which site was deleted in the truncated form in vitro, we transfected cells with N-terminal tagged or C-terminal tagged human CYP3A4 cDNA. The truncated CYP3A4 is the N-terminal deleted form and was present in the soluble cytoplasmic fraction. Our result shows, for the first time, that N-terminal truncated, catalytically active CYP3A4 is present principally in the cytoplasm of human liver cells.