Clofibrate kinetics after single and multiple doses

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Abstract
The kinetics of chlorphenoxyisobutyric acid (CPIB) were studied in 5 healthy subjects after single 500‐mg, 1,000‐mg, and 2,000‐mg doses of clofibrate, and in steady‐state after 8 days' treatment with 1,000 mg twice daily. Maximum plasma concentrations of CPIB were observed 4 to 6 hr after dosing. A mean plasma half‐life of 16.7 hr was recorded which was independent of dose and duration of treatment. Total plasma clearance (Cl) calculated from area under the curve with the use of the total plasma concentration was 5.6 mllmin for the 500‐ and the 1,000‐mg doses but increased to 6.8 ml/min for the 2,000‐mg dose and was even higher (8.1 ml/min) in steady‐state. This change in Cl is a consequence of a progressive reduction in the plasma protein binding of clofibrate at plasma concentrations above 50 µg/ml, since Cl rises in association with reduced protein binding at the high plasma concentrations measured after the 2,000‐mg single dose and in steady‐state. Cl and apparent volume of distribution were identical for all doses tested when calculations were based on the nonprotein‐bound CPIB concentrations only. Due to the inconsistant protein binding of CPIB, total steady‐state concentrations could not be predicted from the single dose kinetic data.