Pharmacokinetic evaluation of proguanil: a probe phenotyping drug for the mephenytoin hydroxylase polymorphism.

1. Proguanil (PG) oxidative metabolism to cycloguanil (CG) has been linked to the CYP2C19-mediated genetic polymorphism in S-mephenytoin oxidative metabolism. In many countries, rac-mephenytoin can no longer be administered to humans and hence proguanil may be a more suitable probe for phenotyping purposes. 2. There are limited data on the pharmacokinetics of PG and CG and in particular, whether there is a relationship between the urinary metabolic ratio of PG and its partial intrinsic clearance to CG. 3. The disposition of a 100 mg oral dose of PG was investigated in 10 subjects with widely varying metabolic ratios (pre-study urinary metabolic ratio CG to PG = 0.068 to 1.11). Blood samples and all 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 for CG from 2.8 to 32% of the dose. The overall urinary recovery of PG plus 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 10.1 l h-1. 5. There was a highly significant (r2 = 0.96, P < 0.001) relationship between the urinary metabolic ratio for PG (as CG/PG) and its partial intrinsic clearance to CG. 6. These data have provided evidence for the justification of the use of the urinary metabolic ratio of proguanil for population phenotyping purposes, provided systematic variation in renal drug clearance between populations is considered.