OBJECTIVE: To investigate whether urinary proguanil (chlorguanide) metabolite ratios incorporating its minor metabolite, 4-chlorophenylbiguanide, define individuals as extensive metabolisers (EMs) or poor metabolisers (PMs) of CYP2C19 more reliably than the standard phenotyping ratio [proguanil/cycloguanil (PG/CG)]. METHODS: Thirty-eight ethnic Chinese subjects ingested 100 mg proguanil, collected urine for 8 h and were genotyped for CYP2C19*1, *2 and *3 alleles. Proguanil metabolite ratios (PG/CG; proguanil/4-chlorophenylbiguanide (PG/CPB); proguanil/(cycloguanil+4-chlorophenylbiguanide) [PG/(CG+CPB)] were determined from the urinary recoveries of proguanil, cycloguanil and 4-chlorophenylbiguanide. Proguanil phenotypes were determined from the ratios using frequency distribution histograms, probit and normal test variable plots. RESULTS: Data from 35 subjects were suitable for analysis. Of subjects, 5 were CYP2C19*2/*2, 1 was *2/*3, 21 were *1/*2 and 8 were *1/*1. A rank order of proguanil metabolic ratios was observed, with *1/*1 subjects having the lowest, *1/*2 intermediate and *2/*2, *2/*3 having the highest ratios (P<0.0001). All subjects with PM genotypes were classified as PMs of proguanil by probit analysis of PG/CPB and PG/(CG+CPB) ratios, but not PG/CG. CONCLUSION: A gene-dose effect of CYP2C19 genotype on the conversion of proguanil to cycloguanil and 4-chlorophenylbiguanide has been demonstrated in ethnic Chinese subjects. Complete concordance between PM CYP2C19 genotype and PM phenotype was only achieved with probit analysis of proguanil metabolite ratios that incorporated 4-chlorophenylbiguanide.
OBJECTIVE: To investigate whether urinary proguanil (chlorguanide) metabolite ratios incorporating its minor metabolite, 4-chlorophenylbiguanide, define individuals as extensive metabolisers (EMs) or poor metabolisers (PMs) of CYP2C19 more reliably than the standard phenotyping ratio [proguanil/cycloguanil (PG/CG)]. METHODS: Thirty-eight ethnic Chinese subjects ingested 100 mg proguanil, collected urine for 8 h and were genotyped for CYP2C19*1, *2 and *3 alleles. Proguanil metabolite ratios (PG/CG; proguanil/4-chlorophenylbiguanide (PG/CPB); proguanil/(cycloguanil+4-chlorophenylbiguanide) [PG/(CG+CPB)] were determined from the urinary recoveries of proguanil, cycloguanil and 4-chlorophenylbiguanide. Proguanil phenotypes were determined from the ratios using frequency distribution histograms, probit and normal test variable plots. RESULTS: Data from 35 subjects were suitable for analysis. Of subjects, 5 were CYP2C19*2/*2, 1 was *2/*3, 21 were *1/*2 and 8 were *1/*1. A rank order of proguanil metabolic ratios was observed, with *1/*1 subjects having the lowest, *1/*2 intermediate and *2/*2, *2/*3 having the highest ratios (P<0.0001). All subjects with PM genotypes were classified as PMs of proguanil by probit analysis of PG/CPB and PG/(CG+CPB) ratios, but not PG/CG. CONCLUSION: A gene-dose effect of CYP2C19 genotype on the conversion of proguanil to cycloguanil and 4-chlorophenylbiguanide has been demonstrated in ethnic Chinese subjects. Complete concordance between PM CYP2C19 genotype and PM phenotype was only achieved with probit analysis of proguanil metabolite ratios that incorporated 4-chlorophenylbiguanide.
Authors: S A Ward; W M Watkins; E Mberu; J E Saunders; D K Koech; H M Gilles; R E Howells; A M Breckenridge Journal: Br J Clin Pharmacol Date: 1989-06 Impact factor: 4.335