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) 1995 The British Pharmacological Society