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

Abstract

Proguanil (PG) oxidative metabolism to cycloguanil (CG) has been linked to the CYP2C 19-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. 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. The disposition of a 100mg 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 1.1 1 ). Blood samples and all urine were collected for 96 h and assayed for PG and CG by h.p.1.c. 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 1-l h whereas for CG it was from 0.02 to 0.71 mg 1-l h. The partial intrinsic clearance to CG ranged 25-fold from 0.41 to 10.1 1 h-l.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. 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.

Consumption of Charcoal‐Broiled Meat as an Experimental Tool for Discerning CYP1A2‐Mediated Drug Metabolism in vivo

“…No effects of consumption of charcoal‐broiled meat were observed in the different probe reactions used for non‐CYP1A2 enzymes in this study. Neither the proguanil metabolic ratio (CYP2C19 (Somogyi et al 1996; Coller et al 1997)), the quinidine 3‐hydroxylation (CYP3A4 (Damkier et al 1999; Nielsen et al 1999)), or tolbutamide 4‐hydroxylation (CYP2C9 (Miners & Birkett 1998)) was affected. Considering the inexplicable lack of induction of CYP1A2 probe reactions, the conclusion drawn from these observations needs to be cautious.…”

Application of Pharmacogenomics to Malaria: A Holistic Approach for Successful Chemotherapy

“…Proguanil is metabolized to cycloguanil, and in vivo , CYP2C19 is the major isoform responsible for the formation of cycloguanil [69,70]. Apart from dapsone and proguanil, not much is known about the metabolism of other antimalarial DHPS (sulfa drugs) and DHFR enzyme inhibitors.…”

“…Proguanil metabolism is mediated via CYP2C19 [69,70]. By measuring the proguanil: cycloguanil metabolic ratio and/or the ability of CYP2C19 to metabolize a probe drug, ( S )-mephenytoin, the poor metabolism (PM) and extensive metabolism (EM) phenotypes are identified [70].…”

Malaria: Genetic and Evolutionary Aspects

“…In vitro, proguanil activation to cycloguanil is mediated by CYP2C19 (~73%) and CYP3A4 (16%) (Birkett et al, 1994;Lu et al, 2000). In vivo, CYP2C19 is the major isoform responsible for the formation of cycloguanil (Ward et al, 1991;Helsby et al, 1993;Somogyi et al, 1996).…”