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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 ml/min 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 progressive reduction in the plasma protein binding of clofibrate at plasma concentrations above 50 microgram/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.

1 The pharmacokinetics and bioavailability of cimetidine were studied after 200 mg oral and intravenous doses in 14 patients with liver cirrhosis, and results were compared to a control group of 12 ulcer patients. 2 In cirrhotic patients, the volume of the central compartment (0.41 +/- 0.06 v 0.19 +/- 0.09 1/kg) and the volume of distribution at steady-state (1.02 +/- 0.17 v 0.80 +/- 0.24 1/kg) were significantly increased. No differences were observed in the area volume of distribution, the total systemic plasma clearance and renal clearance. The non-renal clearance was significantly decreased from 191 +/- 46 to 123 +/- 102 ml/min. 3 The bioavailability of cimetidine (area method) was significantly increased from 60 +/- 23% to 77 /+- 18% in the cirrhotic patients. Also increased was the time during which plasma levels exceeded 0.5 microgram/ml. 4 Urinary excretion of cimetidine was increased in liver cirrhosis by 32% after intravenous and by 36% after oral administration, while the amount of the sulphoxide metabolite decreased accordingly. Creatinine clearance in the cirrhotic patients was highly correlated with the renal clearance of cimetidine as well as its total plasma clearance.

The pharmacokinetics of a single 300-mg oral and intravenous and 14 daily 300-mg oral doses of phenytoin were studied in 6 healthy volunteers. The mean plasma elimination t1/2 was the same following intravenous (16.8 +/- 1.3 hr) and oral (17.1 +/- 1.5 hr) doses of phenytoin; however, following chronic oral administration, the t1/2 increased to 18.9 +/- 1.5 hr (p less than 0.05). The absolute bioavailability of an oral dosage form (Dilantin Kapseals) varied from 57.7 to 85.6% when based on the relationship between the corresponding single dose areas under the curve (AUCs). When based on the comparison of the AUC for multiple oral dosing with the single iv dose area, average bioavailability was 85.9% (71.8 to 106.3). Since the variation in the bioavailability and elimination of phenytoin does not allow accurate prediction of the steady-state plasma concentration, monitoring plasma levels may be of special importance.

The correlation between the beta receptor blocking activity of pindolol and plasma level was studied in 8 subjects after a 10-mg oral dose. Exercise tachycardia was markedly reduced over a period of at least 6 hr. Significant effects were recorded 30 min after the drug. For each individual there was a close correlation between log plasma level and beta blockade. The regression lines were parallel as shown by analysis of covariance; the intercepts, however, were significantly different. It can be concluded that there is a correlation between plasma level and beta adrenergic blockade by pindolol, but the data failed to establish in different individuals the blood levels necessary to achieve effective adrenergic blockade.