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Concordance between proguanil phenotype and CYP2C19 genotype in Chinese
Janelle M Hoskins1, Gillian M Shenfield, Annette S Gross
1Department of Clinical Pharmacology, Royal North Shore Hospital, NSW 2065, St. Leonards, Australia. janelle@med.usyd.edu.au
European Journal of Clinical Pharmacology
|September 19, 2003
Summary
New proguanil metabolite ratios accurately identify poor metabolisers (PMs) of CYP2C19. Incorporating 4-chlorophenylbiguanide in proguanil metabolite analysis improves phenotype prediction compared to standard methods.
Area of Science:
- Pharmacogenomics
- Drug Metabolism
- Biomarker Discovery
Background:
- CYP2C19 genetic variations influence drug metabolism.
- Accurate phenotyping is crucial for personalized medicine.
- Proguanil is metabolized by CYP2C19, but standard phenotyping has limitations.
Purpose of the Study:
- To evaluate new urinary proguanil metabolite ratios for CYP2C19 phenotyping.
- To determine if 4-chlorophenylbiguanide improves poor metabolizer classification.
- To assess the gene-dose effect of CYP2C19 genotype on proguanil metabolism.
Main Methods:
- 38 ethnic Chinese subjects ingested proguanil and provided urine samples.
- Genotyping for CYP2C19*1, *2, and *3 alleles was performed.
- Urinary proguanil, cycloguanil, and 4-chlorophenylbiguanide were quantified to calculate metabolite ratios.
Main Results:
- 35 subjects' data were analyzed, revealing a gene-dose effect of CYP2C19 genotype on metabolite ratios.
- Proguanil metabolite ratios (PG/CPB and PG/(CG+CPB)) showed complete concordance with poor metabolizer (PM) genotypes.
- The standard PG/CG ratio did not achieve complete concordance with PM genotypes.
Conclusions:
- Urinary proguanil metabolite ratios incorporating 4-chlorophenylbiguanide accurately identify CYP2C19 poor metabolisers.
- A gene-dose effect of CYP2C19 genotype on proguanil metabolism is evident in ethnic Chinese.
- This enhanced phenotyping method offers improved reliability for clinical applications.