Anticoagulant activity and pharmacokinetic properties of a sub-cutaneously administered mixed micellar formulation of argatroban in experimental animals.

We have studied the anticoagulant properties of a novel mixed micellar formulation containing 14 mg/ml argatroban administered by the sub-cutaneous (s.c.) route to rats, rabbits, dogs and primates. Blood samples were taken at various times post-treatment for the determination of the thrombin time (TT), Ecarin clotting time (ECT) and the activated partial thromboplastin time (aPTT). Plasma levels of argatroban were determined in the dog and primate. Mixed micelles alone (0.15 M sodium glycocholate and 0.15 M egg lecithin) were without effect on the clotting parameters. The mixed micellar formulation of argatroban dose-dependently increased all three clotting parameters in the rat (1-4 mg/kg), the rabbit (1 and 2 mg/kg), the dog (1 and 2 mg/kg) and the primate (0.25 and 0.5 mg/kg). In each case the TT was the most sensitive parameter, followed by the ECT and the aPTT. The duration of action of argatroban in each species was dose dependent and varied from 3 h in the rat to 6 h in the dog. In the latter, the mixed micelle formulation had a significantly increased plasma half-life and mean residence time without affecting the overall area under the curve. The increases in the clotting time were strongly correlated with the plasma levels of argatroban and were linear across the range of concentrations obtained in the dog and the primate, although the aPTT plasma concentration response curve was very flat. Species differences were noted between the increase in clotting time for a given plasma concentration, with the primate being more sensitive than the dog (e.g. 4.7 times more so in terms of the ECT). Thus, a mixed micellar formulation of argatroban, which markedly enhances its solubility, could be useful as a potential anticoagulant for sub-cutaneous administration.

Influence of the rate of intravenous administration of eliprodil (SL 82.0715), a new anti-ischaemic agent, on its distribution in rat plasma and tissues.

This investigation studied the possible effect of different iv administration rates (bolus and infusions) of eliprodil, a new anti-ischemic agent, on the drug distribution in various body compartments. Following bolus administration of a 15-mg kg-1 dose, plasma concentrations were best fitted by a 3-compartment open model of t1/2 alpha = 14 sec, t1/2 beta = 4 min, and t1/2 gamma = 1.8 hr. Plasma and heart Cmax values were lowered by decreasing the infusion rate (the 15-mg dose was administered in 15 or 60 min) whereas brain Cmax values were not modified. In contrast, AUC values did not depend upon the rate of infusion. The present findings may have important implications in relating tissue concentrations with the desired therapeutic effect as well as with the side effects of the drug at its sites of action within brain and heart. The use of a simplified model built with plasma and tissue kinetic parameters following bolus injection allows one to predict the amount of drug present in the organs according to the mode of administration, but not the evolution of tissue to plasma ratio during the infusions.

The disposition and pharmacokinetics of alpidem, a new anxiolytic, in the rat.

The autoradiographic distribution, disposition, biliary excretion, and pharmacokinetics of alpidem in Sprague-Dawley rats were evaluated after iv or oral administration. Following i.v. administration, autoradiography showed that radioactivity was preferentially localized in lipid-rich tissues including central nervous system structures. After a 3-mg.kg-1 i.v. or oral dose of [14C]alpidem, more than 80% of the radioactivity were excreted in the feces over a 6-day period. Biliary excretion of radioactivity in vigile rats, about 74% of the dose over a 7-hr period after either iv or oral administration, showed that alpidem was well absorbed. The absolute bioavailability (13%) data indicated a high first-pass effect. Plasma pharmacokinetic parameters of alpidem were as follows: Vd = 5 liter.kg-1, Cl = 2.2 liter.h-1.kg-1, and terminal t 1/2 beta = 1.2-1.7 hr. Three metabolites with a pharmacological activity similar to that of alpidem were detected in plasma. They were eliminated from the central compartment with half-lives comparable to that of the parent drug. Alpidem crossed the blood-brain barrier following either i.v. or oral administration, resulting in cerebral levels 2.5 to 4 times greater than the plasma levels. Alpidem was eliminated from the central nervous system according a biphasic process with a t 1/2 alpha comparable in plasma and brain. Alpidem represented 94 and 63% of cerebral radioactivity 5 min after i.v. and oral administration, respectively. Two out of the three active plasma metabolites were detected in the brain.

Pharmacokinetics, brain distribution and pharmaco-electrocorticographic profile of zolpidem, a new hypnotic, in the rat.

Zolpidem [N,N-6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3- acetamide] administered as the hemitartrate salt has proven to be an effective hypnotic agent in animals and humans. This study describes the pharmacokinetic behavior of zolpidem in plasma and brain of rat after i.v. and p.o. administration of 2.63 mg.kg-1 of [14C]zolpidem (dose expressed as the base). Autoradiography was used to examine the regional distribution of the compound and the metabolic profile of zolpidem in the plasma and brain was also investigated. The pharmacokinetic data were related to electrocorticogram power spectral analysis. After i.v. administration, the disappearance of zolpidem from plasma fitted a biexponential model with a rapid phase of 0.2 to 0.3 hr and a slower phase of 1.3 to 1.5 hr. After p.o. dosing, peak plasma concentrations where already attained at 15 min (first sampling time). Independent of the route of administration, the concentrations of zolpidem in the brain at shorter times were 30 to 50% those of the plasma values. Furthermore, up to 1 hr, zolpidem accounted for 80 to 90% of brain radioactivity. The rate of disappearance from brain paralleled that from plasma. Autoradiographic studies confirmed the rapid absorption and elimination of zolpidem as well as the relatively homogenous distribution throughout the brain. Electrocorticogram analysis in immobilized rats after i.v. administration of zolpidem showed a rapid onset and a short-acting sedative effect compatible with the kinetic profile of the parent compound. Metabolites of zolpidem displayed a poor penetration into the brain and no significant hypnotic activity. At the dose of zolpidem used, no alteration of the sleep pattern was observed.