Clofibrate kinetics after single and multiple doses The kinetics of chlorphenoxyisobutyric acid (CPlB) were studied in 5 healthy subjects after single 500-mg, I,OOO-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 ofCPIB 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 I,OOO-mg doses but increased to 6.8 mllminfor the 2,000-mg dose and was even higher (8.1 mllmin) in steady-state. This change in Ci is a consequence of a progressive reduction in the plasma protein binding of clofibrate at plasma concentrations above 50 p.,g/ml, since Ci rises in association with reduced protein binding at the high plasma concentrations measured after the 2,000-mg single dose and in steady-state. Ci 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.
Roland Gugler, M.D., and Joachim Hartlapp, M.D. Bonn, Germany Department of Medicine. University of Bonn
Clofibrate is the ethyl ester of chlorphenoxyisobutyric acid (CPIB). It is well established that CPIB, the active form of clofibrate, reduces plasma cholesterol and triglyceride levels in man.l, 4. II, 12 Despite the wide clinical use of this drug, little is known of its kinetics in man 2, 10, 13 and no clear relationship between plasma concentration and the hypolipidemic effect has been established. Our study was performed to investigate the disposition of clofibrate after single doses and during steadystate after chronic dosing.
Received for publication March 29. 1978. Accepted for publication June 14, 1978. Reprint requests to: Dr. Roland Gugler. Department of Medicine. University of Bonn, 53 Bonn- Venusberg. FRG.
Normal volunteers. Five healthy volunteers (medical students; 4 men, I woman) participated in the studies. Age range was 23 to 28 yr and body weight was 56 to 82 kg. They received no other medications for at least 4 wk before the study and were judged as healthy after a routine clinical history and physical examination. All had normal values of blood hemoglobin, hematocrit, erythrocyte sedimentation rate, serum electrolytes, transaminases, bilirubin, and creatinine. Drug and collection of specimen. Clofibrate was given to all subjects in single oral doses of 500 mg, 1,000 mg, and 2,000 mg with the use of a crossover design. At least I wk elapsed between the administration of different doses.
0009-9236/78/100432+07$00.70/0 © 1978 The C. V. Mosby Co.
Volume 24 Number 4