Die durch Kondensationsreaktionen ausgehend von (I), (III) bzw. (V), LiAlH4‐Reduktionen von Amiden des Typs (VIII) oder Hydrierungen von ungesättigten Derivaten des Typs (IX) dargestellten Titelverbindungen (II), (IV), (VI) und (VIII)‐(X) werden hinsichtlich ihrer Wirksamkeit als Inhibitoren der Dopamin‐Aufnahme durch sxnagtosomale Corpus‐striatum‐Präparationen untersucht.
Plasma concentrations of orphenadrine were measured by a specific gas chromatographic method in 5 healthy male volunteers after a single oral dose of orphenadrine hydrochloride 100mg. The single dose pharmacokinetic profile of orphenadrine was evaluated from these data. The elimination half-life ranged from 13.2-20.1h after the commercial tablet formulation. Plasma concentrations, determined in volunteers and patients under different conditions of repeated oral administration of the same formulation of orphenadrine hydrochloride exceeded the theoretical values, predicted from the single dose pharmacokinetics, by a factor 2 to 3. The elimination half-lives after discontinuation of treatment showed a 2 to 3-fold increase over the single dose values. This demonstrates a clear discrepancy between the multiple and single dose pharmacokinetics of orphenadrine. Experiments in dogs suggested competition for biotransformation between orphenadrine and its metabolite N-demethylorphenadrine. Product inhibition of this type could explain the observed discrepancy.
In a series of hydrocortisone 17-esters, hydrocortisone 17-butyrate (HC-17B) has almost optimal lipophilicity resulting in a topical effect comparable to that of the fluorinated corticosteroids as measured in the McKenzie test on the human skin. In rats its systemic effects are weak, being in the order of those of hydrocortisone. In man systemic effects have been demonstrated, but no exact comparative data are available. Important factors controlling the intensity of systemic effects are: rate of liberation into plasma from the depot in the horny layer, rate of metabolic degradation, and rate of plasma clearance. In rats the main factor seems to be rapid clearance from plasma (t1/2 = 0.5 h) by selective concentration in the liver and, to a lesser extent, in the kidneys. Rapid hydrolysis by esterases in plasma and liver plays an additional role. In man hydrolysis by esterases appears to be rather slow; the rate of clearance from plasma is still unknown, whereas the absorption from the intact skin into the blood seems to be very slow (t1/2 = 25 h).
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