1. The effects of several detergents (Brij 58, deoxycholate and Lubrol 12A9) and ether on the initial rate of UDP-glucuronosyltransferase activity towards fixed concentrations of five phenolic acceptor substrates of widely different octanol-buffer (pH 7.4) partition coefficient have been compared with those observed in non-activated and Triton X-100-and n-pentane-activated rat liver microsomes. 2. Enzymic activity was dependent on the lipid-solubility of acceptor substrate. Each activator, except Triton X-100, enhanced enzymic activity towards all substrates by a similar factor, which was independent of the octanol-buffer partition coefficient. For Triton X-100 microsomes, the activation was also partition-dependent. 3. The highest activation factor was seen with ether. Pre-incubation of ether-activated microsomes for 30 min at 37 degrees C before assay resulted in inactivation of the enzyme towards more water-soluble substrates. Tryptic digestion (30 min at 37 degrees C) of the ether-activated microsomes resulted in marked reduction of enzyme activity towards all substrates. 4. Ether, and the two detergents, Brij 58 and Lubrol 12A9, released small amounts of protein (5-12% total present); both detergents also released some (8-12%) phospholipid. 5. The Kappm towards acceptor substrate also depended on the octanol-buffer partition coefficient, and was largely unchanged on activation by n-pentane. Vmax was not dependent on partition coefficient and was significantly increased on activation.

ERRATAEnterohepatic circulation in rat and dog of '~C-O-[3-(4-<2 methoxyphenyl>-J-piperazinyl )-2-hydroxypropyl]-3-methoxybenzaldoxim dihydrochloride and it's demethylated metabolite.

14C-0-[3-(4- less than 2-methoxyphenyl greater than -1-piperazinyl)-2-hydroxypropyl]-3-methoxybenzaldoxim dihydrochloride (HWA 923) was well absorbed (approximately 80%) in rat and dog. In normal animals 37-48% of the radioactivity from a 2 mg/kg of body weight oral or parenteral dose was excreted in the urine, and 48-50% in the faeces. When 14C-HWA 923 was given orally to rats with biliary cannulae, only approximately 10% of the dose was excreted in the urine and approximately 68% appeared in the bile. If bile, collected from animals given 14C-HWA 923, was re-infused intraduodenally into surgically prepared rats, approximately 12% was re-excreted in the urine, and approximately 55% re-excreted in the bile. There were considerably higher levels of radioactivity present in rat blood following intravenous administration of 14C-HWA 923 than after an oral dose, suggesting that radioactivity given via the oral route might be excreted directly into the bile without reaching the systemic circulation. In dog, a significant "first-pass" effect was seen for HWA 923. In a surgically prepared dog, where the bile collection was intermittent, 32% of the dose was excreted in the urine and 46% in the bile. An estimated 73% of the dose would have been present in bile, if continuous collection had taken place. In rat, the major urinary metabolite (up to 40% of the urinary radioactivity) was identified, after specific hydrolysis with beta-glucuronidase, as a demethylated product of HWA 923 by co-chromatography in four solvent systems. This metabolite was present, in rat bile as the conjugates (approximately 40% of the biliary radioactivity), together with significant quantities (approximately 20%) of conjugated HWA 923. The two products were also found on hydrolysis o bile, using gut microflora. Similar results were obtained from dog samples. It is postulated that hydrolysis of the glucuronides of unchanged HWA 923 and its demethylated metabolite by gut micro-flora results in enterohepatic circulation of these two compounds in rat and dog.

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