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Excerpt
Proguanil (PG) is oxidised to cycloguanil (CG) by human liver cytochrome P450 2C19 (CYP2C19). Three to 5% of Caucasians and 15-25% of Orientals do not express active CYP2C19 and have impaired metabolism of PG and other drugs. These individuals can be identified by administering a standard dose of PG and measuring the PG urinary metabolic ratio (MR, PG/CG). In this study we investigated the relationship between CYP2C19 genotype and PG MR in 39 healthy ethnic Chinese living in Australia. Urine was collected for 8h after taking 100mg PG and the urinary PG and CG concentrations were measured by HPLC. The CYP2C19 wild-type allele (CYP2C19*1) and two mutant alleles (CYP2C19*2,*3) were identified in whole blood using PCR and enzyme digestion. The MRs and recoveries of CG in urine, (expressed as a percent of PG dose, %CG) in subjects with different CYP2C19 genotypes are given in the table as the median (range). The difference in medians between the genotypes was assessed using the Kruskal-Wallis statistical test.
The urinary recovery of PG was not different between the genotypes (P>0.1). However, individuals with the *2/*2, *3 genotype had the lowest CG recoveries and hence the highest PG MRs. The urinary recovery of CG in the *1/*1 individuals was higher than in the *1/*2s indicating that the *1/*1 individuals formed more CG and as a consequence had higher MRs than the *1/*2s. In conclusion, CYP2C19 contributes to the interindividual variation in CG formation in Chinese and a CYP2C19 gene-dose effect for PG oxidation to CG has been observed.
