Metabolic disposition of proguanil in extensive and poor metabolisers of S-mephenytoin 4'-hydroxylation recruited from an Indonesian population.
1. The metabolism of proguanil (PG) was studied by measuring PG, cycloguanil (CG) and 4-chlorophenylbiguanide (CPB) in plasma and urine samples after an oral 200 mg dose of PG hydrochloride administered to 14 extensive (EMs) and 10 poor hydroxylators (PMs) of S-mephenytoin of Indonesian origin. 2. The mean ( +/- s.d.) values of the elimination half-life (t 1/2) and AUC of PG were significantly (P < 0.01) greater in the PM than in the EM group (20.6 +/- 3.1 vs 14.6 +/- 3.5 (95% confidence intervals of difference 3.1 to 8.9) h; and 5.43 +/- 1.89 vs 3.68 +/- 0.83 (0.58 to 2.91) micrograms ml-1 h). 3. Plasma concentrations of CG, an active metabolite, could not be detected in all PMs, and those of CPB were sufficiently high to determine a time-course in only four PMs. Mean AUC(0,24 h) values of CPB were significantly (P < 0.05) lower in the PM (n = 4) than in the EM group (n = 14) (0.47 +/- 0.13 vs 0.88 +/- 0.50 (-0.14 to 0.96) micrograms ml-1 h). 4. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.05) with the t 1/2 (rs = -0.661) and AUC (rs = -0.652) of PG. 5. PG, CG and CPB were detectable in urine at 12 h in all subjects. Log10 percentage urinary recovery of 4'-hydroxymephenytoin correlated significantly (P < 0.01) with urinary PG/CG (rs = -0.876), PG/CPB (rs = -0.833) and PG/(CG + CPB) (rs = -0.831) metabolic ratios.(ABSTRACT TRUNCATED AT 250 WORDS)
Setiabudy
R
R
Department of Pharmacology, Faculty of Medicine, University of Indonesia, Jakarta.
Kusaka
M
M
Chiba
K
K
Darmansjah
I
I
Ishizaki
T
T
D000328:Adult; D001645:Biguanides / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D005260:Female; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D007214:Indonesia; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D002727:Proguanil / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D012044:Regression Analysis; D014227:Triazines / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine
D001645:Biguanides; D014227:Triazines; C026009:cycloguanil; C025963:4-chlorophenylbiguanide; D008617:Mephenytoin; D002727:Proguanil