Frequency of cytochrome P 450 3A4 variant genotype in transplant population and lack of association with cyclosporin clearance

Rivory, Laurent P.; Han, Qinghua; Clarke, Stephen; Eris, Josette; Duggin, Geoffrey G.; Ray, Emily; Trent, Ronald J.; Bishop, James F.

doi:10.1007/s002280000166

Cited by 52 publications

(27 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The CYP3A4*1B promoter SNP has been extensively studied because of its role in transcriptional regulation in vitro. However, no significant change associated with CYP3A4*1B was observed in midazolam (MDZ) clearance (Wandel et al, 2000;Garcia-Martin et al, 2002;Eap et al, 2004;He et al, 2005) and in cyclosporine clearance (Rivory et al, 2000), supporting the idea that this SNP may not have a significant role in the CYP3A4 expression (Westlind et al, 1999). Genetic polymorphisms in CYP3A4 gene seem to be the reason for interindividual variation in the enzyme activity; however, no key variant alleles of CYP3A4 have been found to support these variations (Lamba et al, 2002a).…”

Section: Introductionmentioning

confidence: 98%

TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

Lee¹,

Lee²,

Jeong³

et al. 2007

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The objective of this study was to identify CYP3A4 variants in Koreans and to characterize their functional consequences in vitro and in vivo. Four single nucleotide polymorphisms were identified in 50 Koreans by direct DNA sequencing. In an additional genotyping using 248 subjects, CYP3A4*18 was confirmed as the most frequent coding variant in Koreans at 1.7%, and its frequency was similar to that of Asians, suggesting that CYP3A4*18 would be the highest coding variant in Asians. The recombinant CYP3A4.18 protein prepared in baculovirus expression system showed 67.4% lower V max and 1.8-fold higher K m for midazolam 1-hydroxylation compared with the wild type. The mean values of C max and area under the concentration curve (AUC) in the CYP3A4*1/*18 and CYP3A5*1/*3 subjects (n ‫؍‬ 8) were 63% and 32% higher than in CYP3A4*1/*1 and CYP3A5*1/*3 carriers (n ‫؍‬ 8), respectively. Although the in vitro assay exhibited a significant reduction of the enzyme activity for midazolam, the in vivo differences associated with the CYP3A4*1/*18 tend to be low (P < 0.07 in C max and P < 0.09 in AUC). In summary, the heterozygous CYP3A4*1/*18 does not appear to cause a significant change of midazolam disposition in vivo; however, the clinical relevance of CYP3A4*18/*18 remains to be evaluated.CYP3A is the most abundantly expressed subfamily of cytochrome P450 (P450) enzymes in the human liver (Shimada et al., 1994). The CYP3A enzymes are responsible for the metabolism of more than 50% of clinically used drugs (Komori et al., 1990;Guengerich, 1999;Lamba et al., 2002a). Four human CYP3A enzymes, CYP3A4, CYP3A5, CYP3A7, and CYP3A43, have been identified. CYP3A4 is regarded as the most dominant CYP3A enzyme in the liver and small intestine of humans. It has been reported that CYP3A4 expression shows large interindividual variation (Guengerich, 1999;Ozdemir et al., 2000;Lin et al., 2002). These variations can lead to different responses to human drugs that are substrates for CYP3A4. Because approximately 85% of this variability is attributed to genetic factors (Ozdemir et al., 2000), genetic analysis is needed to understand interindividual variability. To date, more than 39 allelic variants have been described (http://www.cypalleles.ki.se/cyp3a4.htm) (Dai et al., 2001;Eiselt et al., 2001;Kuehl et al., 2001;Lamba et al., 2002a;Fukushima-Uesaka et al., 2004). Among the CYP3A4 variants, alleles with nonsynonymous single nucleotide polymorphisms (SNPs), i.e., CYP3A4*2, *4, *5, *6, *17, and *18, have been shown to alter enzyme activity, compared with the wild type (Lee and Goldstein, 2005). Although some CYP3A SNPs exhibited an altered intrinsic clearance of CYP3A substrates in vitro, there have been few data explaining their meaningful influences on its substrate clearance in humans. The CYP3A4*1B promoter SNP has been extensively studied because of its role in transcriptional regulation in vitro. However, no significant change associated with CYP3A4*1B was observed in midazolam (MDZ) clearance (Wandel et al., 2000;Garcia-Martin...

show abstract

Section: Introductionmentioning

confidence: 98%

TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

Lee¹,

Lee²,

Jeong³

et al. 2007

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…Thus, the impact of mutations on enzymes involved in CsA or tacrolimus metabolism during the early post-transplant phase is still unknown. The CsA pseudoclearance (a surrogate for CsA clearance estimated from the ratio between CsA dose and the corresponding trough concentration) of the five subjects carrying the altered alleles, although not statistically significant, was in a lower range of dose-and body weight-normalized trough levels, when compared with the wild types, suggesting a potential influence (75). As further support, when a full pharmacokinetic profile is used (77), the dose-normalized CsA AUC was 83% higher in homozygous for the G/G variant compared with wild-type healthy volunteers.…”

Section: Calcineurin Inhibitorsmentioning

confidence: 80%

From Pharmacokinetics to Pharmacogenomics: A New Approach to Tailor Immunosuppressive Therapy

Cattaneo¹,

Perico

Remuzzi

2004

American Journal of Transplantation

View full text Add to dashboard Cite

One of the main tasks in the management of organ transplantation is the optimization of immunosuppressive therapy, in order to provide therapeutic efficacy limiting drug-related toxicity. In the past years major efforts have been carried out to define therapeutic windows based on blood/plasma levels of each immunosuppressant relating those concentrations to drug dosing and clinical events. Although this traditional approach is able to identify environmental and nongenetic factors that can influence drug exposure during the course of treatment, it presents limitations. Therefore, complementary strategies are advocated. The advent of the genomic era gives birth to pharmacogenomics, a science that studies how the genome as a whole, including single genes as well as geneto-gene interactions, may affect the action of a drug. This science is of particular importance for drugs characterized by a narrow therapeutic index, such as the immunosuppressants. Preliminary studies focused on polymorphisms of genes encoding for enzymes actively involved in drug metabolism, drug transport and pharmacological target. Pharmacogenomics holds promise for improvement in the ability to individualize immunosuppressive therapy based on the patient's genetic profile, and can be viewed as a support to traditional therapeutic drug monitoring. However, the clinical applicability of this approach is still to be proven.

show abstract

“…The CYP3A4*1B allele has been linked to significantly higher CsA clearance compared with wild-type homozygotes (Hesselink et al, 2004;Min & Ellingrod, 2003). However, this association was not confirmed in other studies (Rivory et al, 2000;von Ahsen et al, 2001). In whites, the 3A4*1B occurs at a low frequency (Coto & Tavira, 2009), and recruitment of the minimum number of carriers to reach statistical significance is difficult.…”

Section: Cyclosporinementioning

confidence: 87%

Pharmacogenetics and Renal Transplantation

Cheung¹

2011

Kidney Transplantation - New Perspectives

View full text Add to dashboard Cite

Frequency of cytochrome P 450 3A4 variant genotype in transplant population and lack of association with cyclosporin clearance

Abstract: Genotyping for the CYP3A4-G polymorphism is unlikely to assist cyclosporin dose selection in transplant patients.

Cited by 52 publications

References 0 publications

TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

From Pharmacokinetics to Pharmacogenomics: A New Approach to Tailor Immunosuppressive Therapy

Pharmacogenetics and Renal Transplantation

Contact Info

Product

Resources

About

Frequency of cytochrome P 450 3A4 variant genotype in transplant population and lack of association with cyclosporin clearance

Abstract: Genotyping for the CYP3A4-G polymorphism is unlikely to assist cyclosporin dose selection in transplant patients.

Cited by 52 publications

References 0 publications

TheCYP3A4*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

TheCYP3A4*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

From Pharmacokinetics to Pharmacogenomics: A New Approach to Tailor Immunosuppressive Therapy

Pharmacogenetics and Renal Transplantation

Contact Info

Product

Resources

About

TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals

TheCYP3A4^*18Allele, the Most Frequent Coding Variant in Asian Populations, Does Not Significantly Affect the Midazolam Disposition in Heterozygous Individuals