Evaluation of cytochrome P4502C9 metabolic activity with tolbutamide in CYP2C9*1 heterozygotes

  title={Evaluation of cytochrome P4502C9 metabolic activity with tolbutamide in CYP2C9*1 heterozygotes},
  author={Craig R. Lee and John A. Pieper and Alan L Hinderliter and Joyce A. Blaisdell and Joyce A. Goldstein},
  journal={Clinical Pharmacology \& Therapeutics},
Multiple single‐nucleotide polymorphisms in the gene encoding cytochrome P450 (CYP) 2C9 have been identified, but the functional significance of the various putative defective genotypes in humans merits further study. 
Relationship of P450 2C9 genetic polymorphisms in Chinese and the pharmacokinetics of tolbutamide
Aim:  To study the relationship between P450 2C9 genetic polymorphisms and the pharmacokinetics of tolbutamide in Chinese subjects.
Identification of a novel variant CYP2C9 allele in Chinese.
A novel CYP2C9 allele involving a T269C transversion in exon 2 that leads to a Leu90Pro substitution in the encoded protein was correlated with reduced plasma clearance of drugs that are substrates for CYP 2C9.
Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers
  • H. Shao, X. Ren, D. Wang
  • Biology, Medicine
    Journal of clinical pharmacy and therapeutics
  • 2010
This study aims to investigate the influence of CYP 2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers.
Clinical relevance of genetic polymorphisms in the human CYP2C9 gene
  • U. Schwarz
  • Biology, Medicine
    European journal of clinical investigation
  • 2003
Subjects who are carriers of one or more variant alleles may be at risk for adverse drug reactions/toxicities when prescribed drugs extensively metabolized by CYP2C9.
The aim of this study was to characterize the variation in CYP2C9 phenotype in relation to genotype, with further analysis of the CYP1C9 gene in metabolic outliers, and it became evident that women on oral contraceptives had slower oxidation of losartan than women without OCs.
The impact of CYP2C9 genetics and oral contraceptives on cytochrome P450 2C9 phenotype.
It became evident that women on oral contraceptives (OCs) had slower oxidation of losartan than women without OCs, and CYP2C9 genotype and oral contraceptives both contribute to a large interindividual variation in CYP1C9 activity.
The CYP2C9 polymorphism: from enzyme kinetics to clinical dose recommendations.
Data appear mature enough for the routine consideration of CYP2C9 genotypes in therapy with acenocoumarol, phenytoin, warfarin, and some other drugs, but it is advisable before the routine clinical use of these genotype data to rigorously test the benefits of genotype-based therapeutic recommendations by randomized controlled clinical trials.
Losartan and E3174 Pharmacokinetics in Cytochrome P450 2C9*1/*1, *1/*2, and *1/*3 Individuals
Study Objective. To determine if differences in the pharmacokinetics of losartan and its pharmacologically active E3174 metabolite exist among individuals expressing the cytochrome P450 (CYP)
Genetic Polymorphisms of Cytochrome P450 Enzymes and the Effect on Interindividual, Pharmacokinetic Variability in Extensive Metabolizers
This review evaluates the potential impact of CYP genetic polymorphisms on interindividual PK variability of drugs within an EM population and concludes that optimally designed clinical trials are needed.


Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin.
The present study reports the first example of a null polymorphism in CYP2C9, which dramatically affects the half-life and clinical toxicity of phenytoin, and demonstrates the severe clinical consequences to patients with a null mutation after treatment with normal doses of phenYtoin.
Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data.
Clinical investigations evaluating the metabolic consequences in individuals expressing the CYP2C9*2, *3, *4, *5, or *6 alleles are required before large-scale clinical genotyping can be recommended.
The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement.
D dosage adjustment based on CYP2C9 genotype, especially at the induction of therapy, would be of value in order to lower the risk of concentration dependent drug intoxications in carriers.
The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism.
The present data suggest that the incidence of the Leu359 allelic variant of CYP2C9 may account for the occurrence of poor metabolizers of tolbutamide.
Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.
Consistent with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates.
Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans.
The results strongly suggest that the disposition and hypoglycemic effect of tolbutamide are affected mainly by CYP2C9 genetic polymorphism, but not by CYp2C19 polymorphism and that, at least in vivo, tol butamide remains a selective probe for measuring CYP 2C9 activity in humans.
Allelic and functional variability of cytochrome P4502C9.
It is likely that functional changes occurring as a result of the Ile359Leu transition are responsible for the tolbutamide poor metabolizer phenotype.
Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers.
Tolbutamide was confirmed as a substrate of the genetically polymorphic enzyme CYP2C9, and the pronounced differences in pharmacokinetics due to the amino acid variants did not significantly affect plasma insulin and glucose concentrations in healthy volunteers.