Drugs Which Inhibit Prostaglandin Biosynthesis

Three classes of compounds inhibit prostaglandin synthetase. The first group consists of the substrate analogues. The specificity of these analogues is unknown but many possess good inhibitory potency which makes them useful tools to demonstrate the involvement of the synthetase enzyme. However, although they are active in some organised tissue preparations, their use in vivo has not been widespread. The absorption, excretion and distribution of these fatty acids is not yet fully understood and this tends to detract from their usefulness in whole animal work. Apart from the substrate analogues a number of other fatty acids also inhibit the synthetase but probably in a non-specific manner and only in high concentrations.The second class of inhibitors consists of the aspirin-like drugs. Although these may not be as specific as the substrate analogues, they have several advantages; they are readily available, easily administered and in many species abolish prostaglandin synthesis almost completely in therapeutic doses. In addition, a considerable amount is known concerning their absorption, distribution and excretion. The final group of inhibitors which inhibit the synthetase includes such diverse agents as metal ions, anti-oxidants and nucleotides. The concentrations necessary to achieve inhibition are often high and no degree of specificity can be claimed. Thus, these agents are not likely to be of value for in vivo work, although in vitro studies with different cofactors and ions may contribute to our understanding of how the synthetase system is regulated.Concerning the inhibition of the dehydrogenase, the situation is far less clear. Certain substrate analogues appear to be good inhibitors of the purified enzyme, although they have not been tested in vivo. Some of the aspirin-like drugs are also active in this respect, but the concentrations are again rather high. Polyphloretin phosphate inhibits PGDH and on this basis it may be worth investigating other prostaglandin blocking agents or agonists as inhibitors of PGDH.In conclusion, the participation of prostaglandins in complex biological events may be investigated with the aid of substrate analogues or with pharmacological agents which block prostaglandin biosynthesis both in vitro and in vivo. At the time of writing no convenient technique for producing the complementary effect, by inhibition of metabolism, is available.I am grateful to my colleagues, especially Dr. Y. S. Bakhle, for many helpful suggestions and criticism, and also to those workers who allowed me to reproduce their published, and in some cases, unpublished, data.