The multiple dose pharmacokinetics of proguanil.
Proguanil, a prophylactic antimalarial agent, is metabolised by the polymorphic isoenzyme CYP2Cmep in man. In this study the multiple dose pharmacokinetics of proguanil were investigated in subjects who were phenotyped previously as extensive (n = 6) or poor (n = 2) metabolisers of the drug. Steady-state plasma concentrations of proguanil were achieved within 48 h in extensive metaboliser subjects and chronic administration of the drug did not appear to alter the disposition of proguanil or that of its active metabolite, cycloguanil. The currently recommended dosage regimen appears to be appropriate for extensive metabolisers of proguanil. Poor metabolisers of proguanil had significantly lower plasma concentrations of the active metabolite cycloguanil compared with extensive metabolisers. Thus, even on multiple dose administration these subjects may not achieve adequate plasma concentrations of cycloguanil. Deficient metabolism of proguanil to cycloguanil leads to an increased appearance of the N-dealkylated metabolite p-chlorphenylbiguanide in the urine of poor metabolisers.
Helsby
N A
NA
Department of Pharmacology and Therapeutics, University of Liverpool.
Edwards
G
G
Breckenridge
A M
AM
Ward
S A
SA
D000328:Adult; D001645:Biguanides / Q000097:blood / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D002727:Proguanil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014227:Triazines / Q000097:blood / Q000652:urine
D001645:Biguanides; D014227:Triazines; C026009:cycloguanil; C025963:4-chlorophenylbiguanide; D003577:Cytochrome P-450 Enzyme System; D002727:Proguanil