Using considerably improved analytical methods, the kinetics and effects of clonidine were observed in healthy volunteers over periods of time more than 3 times longer than those previously reported. The high sensitivity and small work load of the newly developed method permitted the performance of low-dose and multipledose trials. 1. The complete bioavailability of clonidine and its elimination half-life (20 to 25.5 h) remained constant after single and multiple doses. 2. Approximately 62% of a given dose was excreted unchanged in the urine, independent of the quantity administered (0.075, 0.15, 0.2, 0.25 or 0.3 mg), the drug formulation (solution, tablet, Perlonget) or of the mode of administration (i.v., p.o.; single or multiple doses). 3. As the pharmacokinetics of the drug were affected by entero-hepatic circulation, it cannot be described by a conventional, open one or two compartment model. 4. The time courses of the plasma clonidine concentration and its drug effects ran asynchronously. 5. On cessation of chronic clonidine administration, blood pressure and plasma catecholamine levels increased to pretreatment levels without exhibiting any "overshoot" reaction.
Single-dose kinetics of mexiletine (MEX) was studied in six healthy subjects after three different formulations. The respective doses were 200 mg (intravenous infusion), 400 mg (two conventional capsules), and 432 mg (sustained-release dosage forms). By a three-compartment open model with lag time the kinetic parameters of the drug were calculated from the experimental plasma level data. The mathematical analysis of the processes of distribution and elimination was restricted to the intravenous data only, and the resulting transfer constants were introduced into the evaluations of the oral experiments. With this procedure one common value for the plasma t 1/2 of elimination was obtained (t 1/2 gamma = 6.34 +/- 1.5 hr). Mean values for the total volume of distribution (Vdtot) and the total body clearance (Cltot) were 5.5 l/kg and 10.3 ml/min/kg. After capsules, peak plasma concentrations (Cmax = 0.77 microgram/ml) were reached after 2.2 hr. and the sustained-release form built up a flat maximum of concentration (Cmax = 0.34 microgram/ml) after 9.2 hr. Mexiletine is highly bioavailable, almost identical for the two oral formulations: 87.3% (capsule) and 78.7% (slow release). Under physiologic urinary pH1 7.5% to 9.2% of the dose was excreted unchanged by the kidneys.
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