The pharmacokinetic parameters and the toxicity pattern of elomotecan suggest that this novel homocamptothecin analog should be further explored in the clinical setting using a dose of 60 mg administered as a 30-min intravenous infusion, once every 3 weeks.
A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (EC1.2.1.3) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in healthy male volunteers following intravenous and oral administration. Cyanamide plasma levels were determined by a sensitive HPLC assay, specific for cyanamide. After intravenous administration cyanamide displayed a disposition profile according to a two-compartmental open model. Elimination half-life and total plasma clearance values ranged from 42.2 to 61.3 min and from 0.0123 to 0.0190 L.kg-1.min-1, respectively. After oral administration of 0.3, 1.0, and 1.5 mg/kg x +/- SEM values of Cmax, tmax (median) and AUC were 0.18 +/- 0.03, 0.91 +/- 0.11, and 1.65 +/- 0.27 micrograms.ml-1; 13.5, 13.5, and 12 min; and 8.59 +/- 1.32, 45.39 +/- 1.62, and 77.86 +/- 17.49 micrograms.ml-1.min, respectively. Absorption was not complete and the oral bioavailability, 45.55 +/- 9.22, 70.12 +/- 4.73, and 80.78 +/- 8.19% for the 0.3, 1.0, and 1.5 mg/kg doses, respectively, increased with the dose administered. The models that consider a first-order absorption process alone (whether with a fixed or variable bioavailability value as a function of dose) or with loss of drug due to presystemic metabolism (with zero-order or Michaelis-Menten kinetics) were simultaneously fitted to plasma level data obtained following 1 mg/kg i.v. and 0.3, 1.0, and 1.5 mg/kg oral administrations. The model that best fit the data was that with a first-order absorption process plus a loss by presystemic metabolism with Michaelis-Menten kinetics, suggesting the presence of a saturable first-pass effect.
The relationship between concentration and inhibitory effect of the alpha 2-adrenoceptor antagonist idazoxan on clonidine-induced mydriasis has been studied in the rat using pharmacokinetic-pharmacodynamic simultaneous modelling. Fifteen minutes after the anaesthesia of rats with sodium pentobarbitone (55 mg kg-1, i.p.), and 5 min after the administration of clonidine (0.3 mg kg-1, i.v.) to rats pretreated with idazoxan (3 mg kg-1, i.v., and 3 and 10 mg kg-1, orally) at different time intervals, pupil diameters were assessed. The pharmacokinetics of idazoxan were adequately described by a monoexponential equation. Using a pharmacokinetic-pharmaco-dynamic linking model, the concentration-effect relationships of idazoxan were derived, and were quantified by the inhibitory simple Emax model. At the effect compartment, the estimated apparent IC50 was 153.6 ng mL-1. Values of clearance, volume of distribution and elimination half-life were 71.2 mL kg-1 min-1, 3134 mL kg-1 and 30.5 min, respectively. These results could contribute to better characterization of the pharmacodynamic and toxicological profiles of idazoxan in experimental models in which a different pharmacokinetic behaviour of the drug is presumed.
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