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1. Diflunisal (DF) is metabolized in humans and rats primarily to its acyl glucuronide, phenolic glucuronide and sulphate conjugates. 2. After i.v. administration of DF acyl glucuronide to pentobarbitone-anaesthetized rats, DF and its phenolic glucuronide and sulphate conjugates appeared rapidly in plasma, indicating ready systemic hydrolysis of the acyl glucuronide and subsequent biotransformation of liberated DF. 3. Approximately 72% of the acyl glucuronide dose was recovered in bile and urine over 6 h: 52% as acyl glucuronide, 6% as phenolic glucuronide, 5% as sulphate, and 8% as isomers of the acyl glucuronide arising from intramolecular acyl migration. 4. Blockage of excretion routes by ligation of the ureters, bile duct, and both ureters and bile duct, decreased plasma clearance of the acyl glucuronide from 7.8 ml/min per kg to 6.0, 3.2 and 2.2 ml/min per kg respectively, and increased the apparent terminal plasma half-life of DF from 2.1 h to 2.6, 3.4 and 6.3 h, respectively. 5. By contrast, DF phenolic glucuronide was quite stable after i.v. administration at the same dose. 6. This study shows that systemic cycling between DF and its acyl glucuronide exists in the rat in vivo, with portions of each cycle of unstable acyl glucuronide through DF yielding stable phenolic glucuronide and (presumptively stable) sulphate conjugate.

It was previously suggested that acetylcholine (ACh.) was the transmitter somewhere in the central nervous system of impulses releasing antidiuretic hormone (ADH) from the pars nervosa of the pituitary, and later (Pickford, 1947) it was shown that ACh. could, under certain conditions, stimulate the celLs of the supraoptic nuclei. The present observations were part of a series made to find whether ACh. is the normal transmitter of impulses at the supraoptic nuclei.The acute and chronic effects of injecting diisopropylfluorophosphate (DFP) amongst the supraoptic cells were noted. As this substance combines irreversibly with choline esterase (ChE) then, if ACh. is the transmitter, the injected DFP should result in a brief inhibition of the rate of urine flow followed first, by polyuria due to the presence of an excess of ACh. and, later, by recovery to normal levels of water exchange, a chain of events that would be analogous to the muscle reactions seen by Harvey, Lilienthal, Grob, Jones & Talbot (1947) on the injection of DFP into the brachial artery of man. These workers noticed that some degree of paresis persisted for 11 weeks. Grob, Harvey, Langworthy & Lilienthal (1947) observed EEG changes after DFP in man for as long as 42 days, so it seemed probable that the time for recovery of the supraoptic neurones would be long. Assuming from the work of Pickford (1939, 1947) the release of the ADH by ACh., we tried to estimate this recovery time by giving intravenous ACh. to dogs after DFP and noting whether or not an inhibition of the rate of urine flow followed. METHODSThe observations were made on dogs. The method of preparation of the animals, the injection of DFP into the supraoptic nuclei and the histological controls were similar to those previously described (Pickford, 1947). The only exceptions to this were that not all the animals had their PH. CXI.6