Peter G. Dayton

Accelerated aminopyrine metabolism in human subjects pretreated with phenylbutazone

Abstract Pretreatment of human subjects for 7 to 11 days with phenylbutazone depresses plasma levels of intravenously administered aminopyrine and elevates those of its metabolite, 4-aminoantipyrine. These results were explained by a stimulatory action of phenybutazone on the metabolism of aminopyrine, an effect which was demonstrated previously in the rat.

A STUDY OF STRUCTURE--ACTIVITY RELATIONSHIPS IN REGARD TO SPECIES DIFFERENCE IN THE PHENYLBUTAZONE SERIES.

Abstract Physicochemical properties of phenylbutazone analogues were correlated with their physiological disposition, in particular with reference to species difference. While in man there exists a direct relationship between pKa and half-life, no such correlation was observed in dogs. Half-life in dog appears to depend on factors such as fat/buffer partition coefficient (Kp), plasma protein binding, tissue distribution and drug-metabolizing enzyme activity. Rate of metabolism of analogues, based on plasma level decline, varied extensively in both species. In man it ranged from 1 to 72 hr; in the dog from 0.5 to 33 hr. There are some striking species differences for certain compounds. For instance, oxyphen-butazone has a half-life of 0.5 hr in the dog whereas in man it is 72 hr. On the other hand, the half-life of G-15140 (p,p′-dichloro analogue of phenylbutazone) is of the same order of magnitude for both species. An anomaly to the pKa hypothesis, G-34208 (tertiary-butyl analogue of oxyphen-butazone, pKa 7-1), has been shown to be excreted as a glucuronide. This conversion provides a ready explanation for the short half-life of G-34208, since glucuronides have pKa values of about 3. Another sterically hindered analogue, G-13838 (isopropyi analogue of phenylbutazone), was found to have a volume of distribution twice that of phenylbutazone both in man and dog. The results are discussed in relation to the importance of these factors in the search for new drugs.

The relationship between binding of thiopental to plasma and its distribution into adipose tissue in man, as measured by a spectrophotofluorometric method

Abstract Binding in vitro of thiopental to human plasma was measured by a spectrophotofluorometric method as well as by radioactive procedures. At relatively high concentrations of thiopental, binding remains fairly constant. However, below 6 mg/1., per cent binding increases inversely with concentration. This phenomenon, occurring also in vivo hours after thiopental administration, alters the distribution of the drug between plasma and adipose tissue; eventually the adipose tissue to plasma concentration ratios become lower with diminishing plasma concentration. Such a decrease may be considered the result of a passive mechanism which reduces the effectiveness of certain drugs. Administration of dextran to human subjects was found to lower the concentration of thiopental in plasma mainly by increasing blood volume. A spectrophotofluorometric method for the assay of thiopental has been developed. Specificity has been proven by a quantitative thin-layer Chromatographie technique.

Metabolism of C14-labeled ascorbic, dehydroascorbic and diketogulonic acids in guinea pigs☆

Abstract Experiments were carried out in guinea pigs with l -ascorbic acid-1-C 14 , l -ascorbic acid-6-C 14 , dehydroascorbic acid-1-C 14 , dehydroascorbic acid-6-C 14 , diketogulonic acid-1-C 14 , and diketogulonic acid-6-C 14 . The results obtained by measuring the incorporation of C 14 in expired CO 2 , urinary oxalate, and liver glycogen are in accord with a pathway of metabolism of the vitamin via dehydroascorbic acid and diketogulonic acid. The labeling pattern observed in liver glycogen after administration of l -ascorbic acid-6-C 14 , dehydroascorbic acid-6-C 14 , and diketogulonic acid-6-C 14 was different from that obtained with l -gulonolactone-6-C 13 . These results, along with those showing no detectable conversion of l -ascorbic acid-1-C 14 to urinary l -gulonic acid, indicate that l -gulonic acid is not a major intermediate in the metabolism of the vitamin in guinea pigs. Possible mechanisms for the conversion of l -ascorbic acid to glycogen through l -xylulose and trioses are considered.

Studies of the prolonged biochemical effects of 3-methylcholanthrene and of its physiological disposition in the rat

Abstract The intraperitoneal or subcutaneous injection of rats with 3-methylcholanthrene resulted in increased ascorbic acid excretion and enhanced activity of zoxazolamine hydroxylase for at least 7 weeks. The long-lasting biochemical effects of the hydrocarbon can be explained by its presence in the animal for a prolonged period of time. In contrast to barbital, both Chloretone and 3-methylcholanthrene caused only a slight increase in free d -glucuronic acid excretion; all three compounds markedly stimulate l -ascorbic acid excretion. It was found that in the initial 24 hr following administration, Chloretone produced a marked increase in ascorbic acid excretion and a moderate rise of zoxazolamine hydroxylase activity. Under similar conditions in the initial 24-hr period, 3-methylcholanthrene caused no appreciable effect on ascorbic acid excretion but led to a marked effect on the enzyme. Although both effects eventually paralleled each other, the fact that their onset was not simultaneous suggests that these two biochemical responses may not be interrelated.

Effect of Steroids on Disposition of Oxyphenbutazone in Man.

Summary The anabolic steroid methan-drostenolone causes an elevation in oxyphen-butazone plasma levels in man. The elevation is not due to a slowed rate of metabolism, but to an altered distribution between plasma and tissues. The glucocorticoids, prednisone and dexamethasone, do not influence the blood levels of oxyphenbutazone.