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1.
Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism 总被引:18,自引:0,他引:18
Lin YS Dowling AL Quigley SD Farin FM Zhang J Lamba J Schuetz EG Thummel KE 《Molecular pharmacology》2002,62(1):162-172
We recently demonstrated that a variant allele of CYP3A5 (CYP3A5*3) confers low CYP3A5 expression as a result of improper mRNA splicing. In this study, we further evaluated the regulation of CYP3A5 in liver and jejunal mucosa from white donors. For all tissues, high levels of CYP3A5 protein were strongly concordant with the presence of a wild-type allele of the CYP3A5 gene (CYP3A5*1). CYP3A5 represented greater than 50% of total CYP3A content in nearly all of the livers and jejuna that carried the CYP3A5*1 wild-type allele. Overall, CYP3A5 protein content accounted for 31% of the variability in hepatic midazolam hydroxylation activity. Improperly spliced mRNA (SV1-CYP3A5) was found only in tissues containing a CYP3A5*3 allele. Properly spliced CYP3A5 mRNA (wt-CYP3A5) was detected in all tissues, but the median wt-CYP3A5 mRNA was 4-fold higher in CYP3A5*1/*3 livers compared with CYP3A5*3/*3 livers. Differences in wt-CYP3A5 and CYP3A4 mRNA content explained 53 and 51% of the interliver variability in CYP3A5 and CYP3A4 content, respectively. Hepatic CYP3A4 and CYP3A5 contents were not correlated when all livers were compared. However, for CYP3A5*1/*3 livers, levels of the two proteins were strongly correlated (r = 0.93) as were wt-CYP3A5 and CYP3A4 mRNA (r = 0.76). These findings suggest that CYP3A4 and CYP3A5 genes share a common regulatory pathway for constitutive expression, possibly involving conserved elements in the 5'-flanking region. 相似文献
2.
In vitro metabolism of cyclosporine A by human kidney CYP3A5 总被引:7,自引:0,他引:7
Dai Y Iwanaga K Lin YS Hebert MF Davis CL Huang W Kharasch ED Thummel KE 《Biochemical pharmacology》2004,68(9):1889-1902
The objectives of this study were to characterize and compare the metabolic profile of cyclosporine A (CsA) catalyzed by CYP3A4, CYP3A5 and human kidney and liver microsomes, and to evaluate the impact of the CYP3A5 polymorphism on product formation from parent drug and its primary metabolites. Three primary CsA metabolites (AM1, AM9 and AM4N) were produced by heterologously expressed CYP3A4. In contrast, only AM9 was formed by CYP3A5. Substrate inhibition was observed for the formation of AM1 and AM9 by CYP3A4, and for the formation of AM9 by CYP3A5. Microsomes isolated from human kidney produced only AM9 and the rate of product formation (2 and 20 microM CsA) was positively associated with the detection of CYP3A5 protein and presence of the CYP3A5*1 allele in 4 of the 20 kidneys tested. A kinetic experiment with the most active CYP3A5*1-positive renal microsomal preparation yielded an apparent Km (15.5 microM) similar to that of CYP3A5 (11.3 microM). Ketoconazole (200 nM) inhibited renal AM9 formation by 22-55% over a CsA concentration range of 2-45 microM. Using liver microsomes paired with similar CYP3A4 content and different CYP3A5 genotypes, the formation of AM9 was two-fold higher in CYP3A5*1/*3 livers, compared to CYP3A5*3/*3 livers. AM19 and AM1c9, two of the major secondary metabolites of CsA, were produced by CsA, AM1 and AM1c when incubated with CYP3A4, CYP3A5, kidney microsomes from CYP3A5*1/*3 donors and all liver microsomes. Also, the formation of AM19 and AM1c9 was higher from incubations with liver and kidney microsomes with a CYP3A5*1/*3 genotype, compared to those with a CYP3A5*3/*3 genotype. Together, the data demonstrate that CYP3A5 may contribute to the formation of primary and secondary metabolites of CsA, particularly in kidneys carrying the wild-type CYP3A5*1 allele. 相似文献
3.
Influence of CYP3A5 genetic polymorphism on cyclosporine A metabolism and elimination in Chinese renal transplant recipients 总被引:2,自引:0,他引:2
AIM: To investigate whether the CYP3A5*3 polymorphism would affect cyclosporine A (CsA) metabolism in Chinese renal transplant patients. METHODS: The CYP3A5*3 genotype was determined in Chinese renal transplant recipients using polymerase chain reaction and amplification of specific alleles (PCR-ASA). The concentrations of CsA and metabolites were separately measured by fluorescence polarization immunoassay and dose-adjusted trough concentrations and metabolic ratio (MR) values were calculated. RESULTS: The trough concentrations adjusted with the dose was significantly higher in the wild allele carriers compared to both the homozygous (*3*3) and heterozygous variants (*1*3). However, no significant difference was found for the dose-adjusted metabolite concentrations. The MR values for the 3 genotype groups were as follows: 0.92+/-0.62 for CYP3A5*3/ *3 (n=14), 0.99+/-0.51 for CYP3A5*1/*3 (n=15), and 1.45+/-0.62 for CYP3A5*1/*1 (n=9), respectively. Post hoc comparisons showed that only the MR values between the CYP3A5*3/*3 group and the CYP3A5*1/*1 group were significantly different. CONCLUSION: The CYP3A5*3 polymorphism exerted little effect on cyclosporine metabolism. The MR may be a more accurate indicator for therapeutic drug monitoring, considering its integrated information on body exposure of both parent drugs and metabolites. 相似文献
4.
Objective Omeprazole is metabolized by the two cytochrome P450 isoforms, CYP3A (sulfoxidation) and CYP2C19 (hydroxydation). The aim
of this study was to determine whether the CYP3A5 genotype is an important determinant of inter-individual variability of
total CYP3A activity in vivo.
Methods Plasma levels of omeprazole and omeprazole sulfone were analyzed by high-performance liquid chromatography in blood samples
drawn 4–5 h after 43 CYP2C19 poor metabolizers (PMs) had ingested a single oral 40 mg dose of omeprazole. The CYP3A5*3 allele was identified using a PCR-restriction fragment length polymorphism assay.
Results Among the 43 CYP2C19 PMs, 24 were CYP3A5*3/*3 carriers and 19 were CYP3A5*1 carriers (CYP3A5*1/*1 in one subject and CYP3A5*1/*3 in 18 subjects). No significant difference was found between the mean log10(metabolic ratio) of the CYP3A5*3/*3 carriers (0.314 ± 0.369) and CYP3A5*1 carriers (0.330 ± 0.313).
Conclusions The CYP3A5 genotype was not an important factor underlying the inter-individual variation in the metabolic ratio of omeprazole
to omeprazole sulfone in our study cohort, although genotype can be considered to be responsible for the inter-individual
variation of many CYP3A substrates in vivo. 相似文献
5.
Yang Dai Mary F Hebert Nina Isoherranen Connie L Davis Christopher Marsh Danny D Shen Kenneth E Thummel 《Drug metabolism and disposition》2006,34(5):836-847
Previous investigations of solid organ transplant patients treated with tacrolimus showed that individuals carrying a CYP3A5*1 allele have lower dose-adjusted trough blood concentrations compared with homozygous CYP3A5*3 individuals. The objective of this investigation was to quantify the contribution of CYP3A5 to the hepatic and renal metabolic clearance of tacrolimus. Four primary tacrolimus metabolites, 13-O-desmethyl tacrolimus (13-DMT) (major), 15-O-desmethyl tacrolimus, 31-O-desmethyl tacrolimus (31-DMT), and 12-hydroxy tacrolimus (12-HT), were generated by human liver microsomes and heterologously expressed CYP3A4 and CYP3A5. The unbound tacrolimus concentration was low (4-15%) under all incubation conditions. For CYP3A4 and CYP3A5, V(max) was 8.0 and 17.0 nmol/min/nmol enzyme and K(m,u) was 0.21 and 0.21 muM, respectively. The intrinsic clearance of CYP3A5 was twice that of CYP3A4. The formation rates of 13-DMT, 31-DMT, and 12-HT were >or=1.7-fold higher, on average, in human liver microsomes with a CYP3A5*1/*3 genotype compared with those with a homozygous CYP3A5*3/*3 genotype. Tacrolimus disappearance clearances were 15.9 +/- 9.8 ml/min/mg protein and 6.1 +/- 3.6 ml/min/mg protein, respectively, for the two genotypes. In vitro to in vivo scaling using both liver microsomes and recombinant enzymes yielded higher predicted in vivo tacrolimus clearances for patients with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. In addition, formation of 13-DMT was 13.5-fold higher in human kidney microsomes with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. These data suggest that CYP3A5 contributes significantly to the metabolic clearance of tacrolimus in the liver and kidney. 相似文献
6.
Jeannine S McCune Linda J Risler Brian R Phillips Kenneth E Thummel David Blough Danny D Shen 《Drug metabolism and disposition》2005,33(7):1074-1081
Ifosfamide nephrotoxicity is attributed to the formation of a toxic metabolite, chloroacetaldehyde, via N-dechloroethylation, a reaction that is purportedly catalyzed by CYP3A and CYP2B6. Because allelic variants of CYP3A5 are associated with polymorphic expression of microsomal CYP3A5 in human liver and kidneys, we hypothesized that ifosfamide N-dechloroethylation depends on CYP3A5 genotype. We compared ifosfamide N-dechloroethylation activity in cDNA-expressed CYP3A4 and CYP3A5. Ifosfamide N-dechloroethylation was also assessed in liver (N = 20) and kidney (N = 21) microsomes from human donors with different CYP3A5 genotypes. Ifosfamide N-dechloroethylation was catalyzed by recombinant CYP3A5 at a rate comparable with recombinant CYP3A4. In human liver microsomes matched for CYP3A4 protein content, N-dechloroethylation was more than 2-fold higher in that from donors carrying CYP3A5*1 allele that express CYP3A5 relative to that from donors homozygous for the mutant CYP3A5*3. Correlation analysis revealed that ifosfamide N-dechloroethylation was significantly associated with CYP3A4 and CYP3A5 protein concentration but not with age, sex, or CYP2B6 protein concentration. In hepatic microsomes not expressing CYP3A5 protein, ifosfamide N-dechloroethylation was inhibited 53 to 61% and 0 to 3% by monoclonal antibodies specific for CYP3A4/5 or CYP2B6, respectively. Ifosfamide N-dechloroethylation was not detected in renal microsomes obtained from CYP3A5*3/*3 donors. In contrast, it was readily measurable in microsomes isolated from four kidneys of CYP3A5*1 carriers, which was almost completely inhibited by the CYP3A inhibitor ketoconazole. CYP2B6 protein could not be detected in this panel of human renal microsomes. In conclusion, CYP3A5*1 genotype is associated with higher rates of ifosfamide N-dechloroethylation in human liver and kidneys. 相似文献
7.
CYP3A5 mRNA degradation by nonsense-mediated mRNA decay 总被引:3,自引:0,他引:3
The total CYP3A5 mRNA level is significantly greater in carriers of the CYP3A5*1 allele than in CYP3A5*3 homozygotes. Most of the CYP3A5*3 mRNA includes an intronic sequence (exon 3B) containing premature termination codons (PTCs) between exons 3 and 4. Two models were used to investigate the degradation of CYP3A5 mRNA: a CYP3A5 minigene consisting of CYP3A5 exons and introns 3 to 6 transfected into MCF7 cells, and the endogenous CYP3A5 gene expressed in HepG2 cells. The 3'-untranslated region g.31611C>T mutation has no effect on CYP3A5 mRNA decay. Splice variants containing exon 3B were more unstable than wild-type (wt) CYP3A5 mRNA. Cycloheximide prevents the recognition of PTCs by ribosomes: in transfected MCF7 and HepG2 cells, cycloheximide slowed down the degradation of exon 3B-containing splice variants, suggesting the participation of nonsense-mediated decay (NMD). When PTCs were removed from pseudoexon 3B or when UPF1 small interfering RNA was used to impair the NMD mechanism, the decay of the splice variant was reduced, confirming the involvement of NMD in the degradation of CYP3A5 splice variants. Induction could represent a source of variability for CYP3A5 expression and could modify the proportion of splice variants. The extent of CYP3A5 induction was investigated after exposure to barbiturates or steroids: CYP3A4 was markedly induced in a pediatric population compared with untreated neonates. However, no effect could be detected in either the total CYP3A5 RNA, the proportion of splice variant RNA, or the protein level. Therefore, in these carriers, induction is unlikely to switch on the phenotypic CYP3A5 expression in carriers of CYP3A5*3/*3. 相似文献
8.
Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects 总被引:2,自引:0,他引:2
Simvastatin, a cholesterol-lowering agent, is mainly metabolized by CYP3A4/5. The objective of this study was to investigate the effect of CYP3A5*3 genotype on the pharmacokinetics of simvastatin in humans. Twenty-two men with CYP3A5*1/*1 (n = 4), CYP3A5*1/*3 (n = 8), or CYP3A5*3/*3 (n = 10) genotypes were enrolled. Each subject ingested a 20-mg dose of simvastatin, and plasma simvastatin concentrations were measured for 12 hours after dosing. The mean (+/-SD) area under the plasma concentration-time curve for simvastatin in the CYP3A5*1/*1 carriers (4.94 +/- 2.25 ng x h/mL) was significantly lower than CYP3A5*3/*3 carriers (16.35 +/- 6.37 ng x h/mL; P = .013, Bonferroni test). The mean (+/-SD) oral clearance was also significantly different between CYP3A5*1/*1 carriers (4.80 +/- 2.35 L/h) and CYP3A5*3/*3 carriers (1.35 +/- 0.61 L/h; P < .05, Dunn's test). However, other pharmacokinetic parameters including peak plasma concentrations and half-life did not show any difference between genotype groups. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of simvastatin and provides a plausible explanation for interindividual variability of simvastatin disposition. 相似文献
9.
Uesugi M Masuda S Katsura T Oike F Takada Y Inui K 《Pharmacogenetics and genomics》2006,16(2):119-127
It has been reported that hepatic and intestinal cytochrome P450 (CYP) 3A4, CYP3A5 and P-glycoprotein affect the pharmacokinetics of tacrolimus, and that these proteins are associated with the large inter-individual variation in the pharmacokinetics of this drug. We previously showed that the concentration/dose ratio of tacrolimus tended to be lower in recipients of living-donor liver transplantation (LDLT) with a CYP3A5*1/*1-carrying graft. However, the effect of intestinal CYP3A5 remains to be elucidated. In the present study, we examined the CYP3A5 genotype in both recipients and donors, and the effect of the recipients' polymorphism on the concentration/dose ratio of tacrolimus in patients after LDLT. The CYP3A5*3 allele frequency was 80% in recipients and 77% in donors. The intestinal CYP3A5 mRNA expression level was significantly associated with genotype. The tacrolimus concentration/dose ratio was lower in recipients with the CYP3A5*1/*1 and *1/*3 genotype (CYP3A5 expressors) compared to the CYP3A5*3/*3 genotype (non-expressors). Amongst the combination of CYP3A5 genotypes between the graft liver and the native intestine, CYP3A5 expressors in both the graft liver and the native intestine had the lowest concentration/dose ratio of tacrolimus during 35 days after LDLT. Patients with the intestinal CYP3A5*1 genotype tended to require a higher dose of tacrolimus compared to the other group with the same hepatic CYP3A5 genotype. These results indicate that intestinal CYP3A5, as well as hepatic CYP3A5, plays an important role in the first-pass effect of orally administered tacrolimus. 相似文献
10.
11.
Izumi Iida Atsunori Miyata Masayuki Arai Mitsuyo Hirota Masayuki Akimoto Shohei Higuchi Kaoru Kobayashi Kan Chiba 《Drug metabolism and disposition》2004,32(1):7-9
The effects of allelic variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) on lornoxicam 5'-hydroxylation were studied using the corresponding variant protein expressed in baculovirus-infected insect cells and human liver microsomes of known genotypes of CYP2C9. The results of the baculovirus expression system showed that CYP2C9.3 gives higher K(m) and lower V(max) values for lornoxicam 5'-hydroxylation than does CYP2C9.1. In contrast, K(m) and V(max) values of CYP2C9.1 and CYP2C9.2 for the reaction were comparable. Lornoxicam 5'-hydroxylation was also determined in liver microsomes of 12 humans genotyped for the CYP2C9 gene (*1/*1, n = 7; *1/*2, n = 2; *1/*3, n = 2; *3/*3, n = 1). A sample genotyped as *3/*3 exhibited 8- to 50-fold lower intrinsic clearance for lornoxicam 5'-hydroxylation than did samples genotyped as *1/*1. However, the values for intrinsic clearance for *1/*3 were within the range of values exhibited by samples of *1/*1. In addition, no appreciable differences were observed in kinetic parameters for lornoxicam 5'-hydroxylation between *1/*1 and *1/*2. In conclusion, this study showed that lornoxicam 5'-hydroxylation via CYP2C9 was markedly decreased by the substitution of Ile359Leu (CYP2C9.3), whereas the effect of the substitution of Arg144Cys (CYP2C9.2) was nonexistent or negligible. Additional in vivo studies are required to confirm that individuals with homologous CYP2C9*3 allele exhibit impaired lornoxicam clearance. 相似文献
12.
Gervasini G Vizcaino S Gasiba C Carrillo JA Benitez J 《Therapeutic drug monitoring》2005,27(6):819-821
The goal of this study was to detect genotypic differences between Spaniards and other related populations regarding CYP3A4*1B, CYP3A5*3, and ABCB1 (MDR1) C3435T polymorphisms. DNA from 177 Spanish patients were analyzed for the presence of these mutations using PCR-restriction fragment length polymorphism or direct sequencing. The observed frequencies for CYP3A4*1B, CYP3A5*3, and C3435T alleles were within normal values in Caucasians (0.04, 0.91, and 0.5, respectively). However, 2.8% of the patients were homozygous for the wild-type CYP3A5*1 allele, an extremely uncommon genotype in other Caucasians. In addition, analysis of CYP3A4-3A5 haplotypes revealed the existence of 2 unusual subgroups: patients who were homozygous wild-type for both polymorphisms, and patients showing a CYP3A4*1A/*1B-CYP3A5*3/*3 genotype combination. The incidence of CYP3A5*1/*1 carriers and the occurrence of subjects combining the 2 above-mentioned unusual genotype combinations were more frequent in Spanish-Caucasians compared with American- or European-Caucasians. ABCB1 C3435T genotype frequencies were equally distributed between both single and combined CYP3A4 and 3A5 genotypes. These findings suggest that dose requirements for drugs metabolized by CYP3A and certain allele-disease association studies in white populations could show discrepancies in Spaniards. 相似文献
13.
CYP3A5~*3和CYP3A4~*18B基因多态性对肾移植患者环孢素药代动力学的影响 总被引:6,自引:4,他引:2
目的回顾性研究肾脏移植后1mon,CYP3A5*3和CYP3A4*18B基因多态性对CsA药代动力学参数的影响。方法采用PCR-RFLP方法分析了63名肾脏移植患者CYP3A5*3和CYP3A4*18B基因型;荧光偏正免疫法用于检测肾移植患者静脉全血中的CsA浓度。结果在63名肾移植患者中,CYP3A5*3和CYP3A4*18B突变等位基因发生频率分别为0.770(95CI:0.767~0.773),0.235(95CI:0.235~0.241),而且这些等位基因表现出完全连锁不平衡。在移植术后1mon内,携带CYP3A4*1/*1野生型纯合子患者的C0以及剂量校正谷血浓度(C0/D)均明显高于携带CYP3A4*1/*18B杂合子或CYP3A4*18B/*18B突变型纯合子患者(P<0.05,Mann-WhitneyUtest);CYP3A5*1/*1基因型组的给药剂量明显高于CYP3A5*1/*3或CYP3A5*3/*3基因型组(P=0.004<0.01,Kruakal-Wallistest);CYP34*18B和CYP3A5*3联合考虑,对于CYP3A5表达组,同样发现C0、C0/D在CYP3A4*1/*1组C0以及C0/D均明显高于CYP3A4*1/*18B或CYP3A4*18B/*18B组(P<0.05,Mann-WhitneyUtest);而其他药动学参数在CYP3A5*3及CYP3A4*18B各组间相比差异则没有统计学意义。结论CYP3A5*3和(或)CYP3A4*18B基因多态性对肾移植后1monCsA药代动力学有一定影响,移植前CYP3A5*3基因型的分析仍需进一步研究。 相似文献
14.
The present study aimed to determine whether a polymorphism in CYP3A5, encoding the major CYP3A enzyme in the human kidney, is associated with blood pressure in Caucasians. A homogenous group of 115 young, white male students with normal or mildly elevated, but untreated blood pressure was included. Blood pressure was recorded by ambulatory 24-h blood pressure-monitoring and compared between individuals with high (*1/*3) and low CYP3A5 expression (*3/*3). Moreover, genotype-dependent differences in parameters associated with the renin-angiotensin-aldosterone system were evaluated. Twenty-four hour diastolic blood pressure values were not significantly different between the two groups. However, individuals with the CYP3A5*3/*3 genotype had significantly higher 24-h ambulatory systolic blood pressure values compared to subjects with the CYP3A5*1/*3 genotype (129+/-10 versus 124+/-9, P < 0.05). There was no association of CYP3A5 genotype with angiotensin II plasma concentrations, renal plasma flow, glomerular filtration rate, urinary sodium excretion and parameters determined by echocardiography, but the *3/*3 group had significantly lower serum aldosterone concentrations compared to the individuals with the *1/*3 genotype (101+/-29 versus 117+/-29 pg/ml, P < 0.05). These data, as generated with a homogenous population of young Caucasians, indicate that the CYP3A5 genotype affects blood pressure in humans possibly by genotype-dependent differences in renal, CYP3A5-mediated metabolism of cortisol and/or aldosterone. We interpret the lower serum aldosterone concentration in the genotype group with the elevated systolic blood pressure as a counter-regulatory mechanism to attenuate the increased blood pressure associated with the CYP3A5*3/*3 genotype. 相似文献
15.
Pharmacokinetics of midazolam and 1'-hydroxymidazolam in Chinese with different CYP3A5 genotypes. 总被引:5,自引:0,他引:5
The CYP3A subfamily represents the most abundant cytochrome p450 in the human liver and gastrointestinal tract and plays very important role in xenobiotic metabolism. CYP3A5 is expressed in a relatively small population of whites and Orientals. We recruited 42 Chinese volunteers to determine the genotypes of CYP3A5 by polymerase chain reaction-restriction fragment length polymorphism. Genotype analyses revealed that CYP3A5*3 allele existed in 39 of 42 volunteers. CYP3A5*4 and CYP3A5*5 alleles were found in one volunteer each; and CYP3A5*2 and CYP3A5*6 alleles were not found. The most frequent CYP3A5*3 allele is known not to express CYP3A5. We excluded other genotypes of CYP3A5 to study the significance of CYP3A5*3 in midazolam pharmacokinetics. In this study, each volunteer was given a midazolam tablet (7.5 mg) orally. Blood samples were collected to analyze the time-dependent concentrations of midazolam and 1'-hydroxymidazolam by high-performance liquid chromatography. The average area under plasma concentration curve (AUC, 0-8 h) of midazolam was 9237 +/- 1050 ng-min/ml (mean +/- S.E.M.) in homozygous CYP3A5*3 (n = 14) subjects and 7934 +/- 768 ng-min/ml in heterozygous CYP3A5*1/*3 (n = 12) subjects, respectively. The average AUC (0-8 h) of 1'-hydroxymidazolam was 3748 +/- 427 ng-min/ml in homozygous CYP3A5*3 subjects and 3920 +/- 402 ng-min/ml in heterozygous CYP3A5*1/*3 subjects. The results indicated that the pharmacokinetics of midazolam and 1'-hydroxymidazolam was independent of CYP3A5 expression. Although the genetic polymorphism of CYP3A5 is well known, the results of this study suggested that the clinical consequence might be insignificant. 相似文献
16.
OBJECTIVE: Cyclosporine is extensively metabolized by cytochrome-P450 3A (CYP3A) enzymes in the liver and intestine including the CYP3A5 isoenzyme. CYP3A5 is also expressed in the kidney and has been implicated in blood pressure regulation. Appreciable expression of CYP3A5 occurs in carriers of the CYP3A5*1 allele, while the CYP3A5*3 allele is associated with low expression. We tested whether the presence of the CYP3A5*1 allele in renal transplant recipients and in donor kidneys influences cyclosporine dose requirements, blood pressure and long-term graft survival in renal transplant patients during chronic treatment with a cyclosporine-based immunosuppressive regimen. METHODS: We studied 399 Caucasian patients from our single-center registry with stable graft function for more than 10 weeks after transplantation. The genotypes for CYP3A5*1/*3 were determined by a TaqMan PCR method. Cyclosporine dose requirements, blood pressure and graft survival were analyzed in relation to the presence or absence of the CYP3A5*1 allele in recipients and donor kidneys. RESULTS: The CYP3A5*1 allele was found in 15.5% of the recipients and in 11.8% of the donor kidneys. The recipient CYP3A5*1 allele had no effect on cyclosporine dose and blood concentrations at trough with and without dose-adjustment. Blood pressure, number of antihypertensive compounds used for treatment and graft survival evaluated by Kaplan-Meier curves and Cox regression analysis were also not affected by the CYP3A5*1 allele either in recipients or donor kidneys. CONCLUSIONS: Cyclosporine dose requirements, blood pressure and long-term renal graft survival are not influenced by the CYP3A5*1 allele in Caucasian patients. 相似文献
17.
目的探讨CYP3A5*3基因多态性对肾移植术后他克莫司(免疫抑制药)剂量校正给药2h后浓度的影响。方法选取61例肾移植术后患者,用聚合酶链式反应-限制性片段长度多态性的方法,分析CYP 3A5*3基因型;用微粒酶联免疫吸附法,测定患者他克莫司浓度。并分析CYP 3A5*3基因多态性与他克莫司给药剂量、给药2h浓度(C2)及剂量校正给药2h后浓度(C2/D)的相关性。结果肾移植术后1周及1、3个月,CYP 3A5*1/*1 CYP 3A5*1/*3组和CYP3A5*3/*3组他克莫司剂量比较均无显著性差异。术后1周和1个月,2组间他克莫司C2比较无显著性差异;术后3个月,CYP 3A5*1/*1 CYP 3A5*1/*3组的C2显著低于CYP 3A5*3/*3组(P<0.05)。术后1周及1、3个月,CYP 3A5*1/*1 CYP 3A5*1/*3组的C2/D均明显低于CYP 3A5*3/*3组(P<0.05)。结论肾移植术后,他克莫司C2/D的个体化差异与患者CYP3A5*3基因型密切相关。 相似文献
18.
Tacrolimus Elimination in Four Patients With a CYP3A5*3/*3 CYP3A4*22/*22 Genotype Combination
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Aileen Scheibner Rory Remmel David Schladt William S. Oetting Weihua Guan Baolin Wu Casey Dorr Ajay Israni Pamala A. Jacobson 《Pharmacotherapy》2018,38(7):e46-e52
Cytochrome P450 3A5 (CYP3A5) and cytochrome P450 3A4 (CYP3A4) are the predominate enzymes responsible for tacrolimus metabolism. The presence of CYP3A4 and CYP3A5 genetic variants significantly affects tacrolimus clearance and dose requirements. CYP3A5*3 is a loss‐of‐function variant resulting in no CYP3A5 enzyme production. CYP3A4*22 is a variant that reduces production of functional CYP3A4 protein. Caucasians commonly carry these variant alleles but are very rarely homozygous for both CYP3A5*3 and CYP3A4*22. This report describes four kidney transplant recipients who carry a rare genotype combination (CYP3A5*3/*3 and CYP3A4*22/*22). These patients were identified from a larger cohort of Caucasian kidney transplant recipients (n=1366). To understand the significance of this genotype combination on tacrolimus troughs and doses, we compared these patients to recipients without this combination. Patients homozygous for both variants are at risk for profound reductions in metabolism of CYP3A substrates. A 342% and a 90.6% increase in the median dose‐normalized trough was observed, when the CYP3A5*3/*3 and CYP3A4*22/*22 genotype combination was compared to the CYP3A5*1/*1 and CYP3A4*1/*1 genotype combination and the CYP3A5*3/*3 and CYP3A4*1/*1 genotype combination, respectively. These four individuals only required on average 2.5 mg/day of tacrolimus. Knowledge of these genotypes would be useful in selecting appropriate tacrolimus doses to avoid overexposure. 相似文献
19.
Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. 总被引:8,自引:0,他引:8
Anna Westlind-Johnsson Sarah Malmebo Anna Johansson Charlotta Otter Tommy B Andersson Inger Johansson Robert J Edwards Alan R Boobis Magnus Ingelman-Sundberg 《Drug metabolism and disposition》2003,31(6):755-761