PHARMACOKINETIC EVALUATION OF PROGUANIL - A PROBE PHENOTYPING DRUG FOR THE MEPHENYTOIN HYDROXYLASE POLYMORPHISM

1 Proguanil (PG) oxidative metabolism to cycloguanil (CG) has been lin ked to the CYP2C19-mediated genetic polymorphism in S-mephenytoin oxid ative metabolism. In many countries, rac-mephenytoin can no longer be administered to humans and hence proguanil may be a more suitable prob e for phenotyping purposes. 2 There are limited data on the pharmacoki netics of PG and CG and in particular, whether there is a relationship between the urinary metabolic ratio of PG and its partial intrinsic c learance to CG. 3 The disposition of a 100 mg oral dose of PG was inve stigated in 10 subjects with widely varying metabolic ratios (pre-stud y urinary metabolic ratio CG to PG=0.068 to 1.11). Blood samples and a ll urine were collected for 96 h and assayed for PG and CG by h.p.l.c. 4 The urinary recovery of PG ranged from 30 to 69% of the dose and fo r CG from 2.8 to 32% of the dose. The overall urinary recovery of PG p lus CG ranged from 54 to 77% of the dose. The AUC for PG ranged from 3 .2 to 9.5 mg l(-1) h whereas for CG it was from 0.02 to 0.71 mg l(-1) h. The partial intrinsic clearance to CG ranged 25-fold from 0.41 to 1 0.11 h(-1). 5 There was a highly significant (r(2)=0.96, P<0.001) rela tionship between the urinary metabolic ratio for PG (as CG/PG) and its partial intrinsic clearance to CG. 6 These data have provided evidenc e for the justification of the use of the urinary metabolic ratio of p roguanil for population phenotyping purposes, provided systematic vari ation in renal drug clearance between populations is considered.