The pharmacokinetics of dexamethasone alcohol is described in six male and six female healthy adult volunteers who each received 8 mg of dexamethasone phosphate by bolus intravenous injection. Quantitation of the alcohol was done using a high-performance liquid chromatographic method with improved specificity. Statistical evaluation of the results generated by nonlinear least-squares regression analysis of the plasma concentration-time data shows that the phosphate ester is very rapidly hydrolyzed to the alcohol and a biexponential equation is the simplest polyexponential equation that is consistent with the data. The terminal phase half-life t1/2 beta was significantly greater (P less than 0.05) in males (mean 201.5 min) than in females (mean 142.3 min). They prolonged t1/2 beta in males did not appear to be caused by an impaired capacity to eliminate dexamethasone since the total plasma clearance did not differ between males (mean 24.5 ml/min) and females (mean 242.9 ml/min). There was, however, a high positive correlation between t1/2 beta and Vdss among the 12 adults (r = 0.92, p less than 0.001). There were also significant correlation between Vdss and body weight (r = 0.67, p less than 0.05) and t1/2 beta and body weight (r = 0.80, p less than 0.01). The difference in body weight between the sexes seems to be the main factor contributing to the difference observed in t1/2 beta. An average of only 2.6% of the dose was found unchanged in a 24-hr urine sample, and hence it appears that dexamethasone is primarily eliminated by extrarenal, probably hepatic, mechanisms.

Verapamil kinetics after intravenous and single and long-term oral dosing were studied in 12 patients with coronary artery spasm and four normal subjects. The decline in plasma concentration after intravenous doses was described by triexponential decay equation, with a terminal half-life (t1/2) of 5 hr. After a single oral dose the bioavailability was only 24%, probably because of the first-pass metabolism. During long-term oral doses of 80 mg every 6 hr, mean peak and trough concentrations were 255 +/- 90 and 105 +/- 38 ng/ml, and mean time at which peak concentration occurred was 1.2 +/- 0.5 hr. Norverapamil, the major active metabolite of verapamil, cumulated during oral dosing and may account for a small proportion of the overall pharmacologic effect. Mean elimination t1/2 during long-term oral dosing was longer than after a single dose (9.6 and 5.7 hr, P less than 0.05). Also, during long-term dosing the area under the curve was more than double that of a single dose, and the apparent oral clearance fell from 4.2 to 1.8 l/min (P less than 0.01). These changes may partly be explained by reduction in presystemic metabolism during long-term therapy. Kinetic predictions based on single doses will not give reliable estimates for long-term oral dosage. Less frequent dose schedule may be possible for prolonged therapy.

The pharmacokinetics of betamethasone and its phosphate ester are described in 8 healthy adults after i.v. bolus injection of 10.6 mg betamethasone phosphate. Both compounds were measured by high-performance liquid chromatography with ultraviolet detection using sample handling methods which prevented hydrolysis of the ester in vitro. Betamethasone phosphate disappeared rapidly from plasma (mean half-life = 4.7 min) as betamethasone levels rose. Betamethasone plasma levels reached a peak 10-36 min after administration of the phosphate before declining in a biexponential manner. The terminal slow disposition phase had a mean half-life of 6.5 h. Only about 5% of the dose was recovered from urine as betamethasone, indicating extensive extrarenal clearance of betamethasone. Protein binding and blood/plasma concentration ratio were also determined. In comparison with its stereoisomer, dexamethasone, betamethasone is also cleared mainly by metabolism but has a lower plasma clearance, is less plasma bound, has a higher blood/plasma concentration ratio, and a higher volume of distribution. Endogenous cortisol levels were measured in the subjects who received betamethasone phosphate and in a matched control group of 4 subjects who did not. Betamethasone abolished the normal episodic secretion of cortisol and rapidly reduced its plasma concentration to a basal level. Cortisol plasma levels were not restored at 24 h but had returned to normal by 48 h after dosing.

The pharmacokinetics of sulphamethizole, paracetamol and phenylbutazone were investigated and compared in young and geriatric subjects. The rate and extent of absorption of the drugs did not appear to be affected by increasing subject age. However, the mean half-lives for sulphamethizole and paracetamol were significantly increased in the geriatric subjects. A number of correlations are presented between the elimination rate constants of the drugs and certain subject parameters and variables. The elimination of phenylbutazone was found not to be influenced significantly by subject age. The apparent volumes of distribution of the three drugs were not age-dependent.