Studies of the mechanism of drug clearance: with special reference to the clearance of humoral agents

Abstract

1. Continuous infusion of adrenaline in the cat produces over a wide range of doses a plateau response both in the nictitating membrane and blood pressure.2. This indicates that enzyme saturation does not occur even with large doses (correction of conclusion of Clark and Raventos, 19394).3. The relation between the continuous and equivalent quick dosage shored that the amount cleared per minute varied as (concentration present)²/³.4. Such a form of clearance was also found by dosage- duration relation as it showed a linear relation between (dose)¹/³ and the duration of action.5. The mathematical calculations of the course of cumulation and clearance of adrenaline made by means of the formulae derived from the above relation approximate with the observed results.6. Mathematical methods calculating the clearance of adrenaline from its pharmacological effects on the blood pressure and nictitating membrane of cat have been used to study the effects of drugs which inhibit its destruction.7. The rate of clearance of adrenaline calculated was diminished to about 40 per cent. by pyrogallol and to 55 per cent. by cocaine, but was not affected by ascorbic acid.8. Large doses of cocaine inhibited the effect of large doses of adrenaline on the nictitating membrane.9. None of the enzyme inhibitors tested altered the relation found, i.e. continuous dose of adrenaline varies as (quick dose)¹/³.10. The failure of ascorbic acid to prolong the action of adrenaline was not due to its destruction, since its presence in the tissues in adequate concentration (0.15 per cent.) was demonstrated chemically.