[Biotransformation and pharmacokinetics of (3,4-dichloroanilino)phenylacetonitrile (H 74)]

On studying the biotransformation of the potential spasmolysant (3,4-dichloroanilino)phenyl-acetonitrile (1; H 74), the authors isolated and identified (TLC, UV, high-resolution MS) from the urine and/or the faeces of male Wistar rats, apart from 1 (greater amounts only in the faeces because of incomplete oral absorption), 7 degradation products. In this connexion, the excretion of greater amounts of 3,4-dichloroaniline (2) and the detection of an accumulation of 2 in the serum in case of long-term treatment are above all disquieting from a toxicological point of view. According to extremely poor water solubility associated with high lipophilicity, the gastrointestinal absorption of 1 extends over a relatively long period of time, is incomplete and not proportional to the dose applied. Using a gas chromatographic technique, the authors found almost dose-proportional serum levels of (3,4-dichlorophenylimino)benzaldehyde (4) after oral application of 1, which is attributable to a first-pass effect (after intravenous application, below the limit of detection). 1 is subject to intensive distribution (marked alpha phase; high Vd) and its elimination is relatively slow (slow back flow from deep compartments; high reabsorption). In contrast to this, the elimination of 4 is considerably more rapid.