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The multiple dose pharmacokinetics of proguanil
N A Helsby1, G Edwards, A M Breckenridge
1Department of Pharmacology and Therapeutics, University of Liverpool.
British Journal of Clinical Pharmacology
|June 1, 1993
Summary
This study shows that poor metabolizers of proguanil may not achieve adequate levels of the active metabolite cycloguanil, even with multiple doses. The standard dosage appears suitable for extensive metabolizers.
Area of Science:
- Pharmacology
- Clinical Pharmacy
- Drug Metabolism
Background:
- Proguanil is an antimalarial drug metabolized by the polymorphic enzyme CYP2C19.
- Individual differences in CYP2C19 activity affect proguanil metabolism, leading to distinct metabolic phenotypes.
Purpose of the Study:
- To investigate the pharmacokinetics of proguanil during multiple-dose administration.
- To compare proguanil and cycloguanil plasma concentrations in extensive and poor metabolizers.
- To assess the adequacy of the current dosing regimen for different metabolic phenotypes.
Main Methods:
- Pharmacokinetic analysis of proguanil and its active metabolite, cycloguanil.
- Phenotyping of subjects into extensive and poor metabolizers based on CYP2C19 activity.
- Multiple dose administration of proguanil.
Main Results:
- Extensive metabolizers reached steady-state proguanil concentrations within 48 hours.
- Poor metabolizers exhibited significantly lower plasma concentrations of cycloguanil compared to extensive metabolizers.
- Increased urinary excretion of p-chlorphenylbiguanide was observed in poor metabolizers.
Conclusions:
- The current proguanil dosage regimen is likely appropriate for extensive metabolizers.
- Poor metabolizers may require alternative dosing strategies to ensure therapeutic cycloguanil levels.
- Metabolic phenotype significantly influences proguanil's pharmacokinetic profile and efficacy.