The pharmacokinetics and activation of proguanil in man: consequences of variability in drug metabolism.

1. Based on the ratio of drug to active metabolite excreted in urine approximately 3% of a healthy Caucasian population showed a reduced ability to convert proguanil to cycloguanil. 2. Pharmacokinetic analysis showed that this observation resulted from a reduced oral clearance of proguanil in these individuals (245, 534 and 552 ml min-1) compared with the rest of the population (858 +/- 482 ml min-1). 3. Peak plasma concentrations of active metabolite were significantly lower in these subjects (54.2, 26.8 and 51.7 ng ml-1) compared with the rest of the population (141 +/- 45.2 ng ml-1). 4. The observed variability may result from the polymorphic metabolism of proguanil in man.