In the preceding paper (Cummings, Martin & Park, 1967) theoretical considerations have been presented relating to a drug which is eliminated by apparent first order processes of urinary excretion and metabolism. These considerations have indicated that when the excretion rate constants of drug metabolites are greater than the elimination rate constant of the drug, plots of log rate of excretion of drug and of drug metabolite eventually become linear and parallel to each other. Experimental verification of this is now attempted with a study of the excretion of paracetamol and its metabolites in man.

Consideration of the therapeutic effect or toxic action of a drug must also include consideration of the potential effect of its metabolites. Therefore regard should be given not only to the qualitative aspects of drug metabolism, but also to the kinetics of metabolite formation and metabolite elimination.The following considerations relate to the application of kinetic equations to the processes of elimination of a drug and its metabolites and their use for the evaluation of rate constants for these processes from urinary excretion data.Drugs are eliminated from the body by excretion and by transformation to metabolites. These processes occur simultaneously but the extent of each varies from one drug to another. The metabolites of the drug are then also eliminated by excretion and further metabolism. The amount of drug in the body at any time depends both on its rate of absorption and its rate of elimination. Similarly the amount of a metabolite in the body will depend on its rate of formation and its rate of elimination and will increase until these rates are equal; this growth in the amount of metabolite has been referred to by Cummings & Martin (1963) as metabolite accrual. It is well recognized that when a drug is rapidly metabolized to a metabolite which is slowly eliminated, the amount of metabolite in the body may eventually exceed the amount of drug. Little consideration has been given, however, to the amount of metabolite in the body when the metabolite is rapidly eliminated, and it has sometimes been incorrectly assumed that the rate of elimination of a metabolite can then be equated to its rate of formation. Drug excretion, drug metabolism and metabolite elimination can be treated as a number of consecutive and parallel processes for which it is frequently possible to obtain overall rate constants and in certain instances specific rate constants. The magnitude and duration of metabolite accrual is governed by the value of these rate constants.Kinetic equations for the elimination of a model drug and its metabolitesThe elimination of a drug by excretion and metabolism and the subsequent elimination of the metabolites, is considered in respect of a model drug. In the first instance this drug is postulated to be instantaneously absorbed and equilibrated in the body water, so that the amount of drug in the body at zero time is equated to the amount administered. The

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Harrow, Middlesex HAl 3UJ1 The nine infants participating in this study were born to mothers who received continuous therapy with a-methyldopa (0.75-2.0 g/day) for several weeks extending to the time of delivery. 2 The concentration of free and total (free plus conjugated) a-methyldopa was determined by gas chromatography-mass spectrometry in amniotic fluid, umbilical cord plasma and maternal plasma at delivery; also in urine collected over timed intervals from neonates during the first days after birth. 3 The results indicate that a-methyldopa administered to the mother is present in the infant at birth at a level comparable to the maternal level and persists for some days. The ratio of conjugated to free drug increases with time after birth. 4 The excretion of free and conjugated a-methyldopa in the urine indicated that the drug is slowly eliminated in the neonate by excretion in the urine and apparently by metabolism, mainly to the sulphate conjugate. 5 The concentration of free and conjugated a-methyldopa in amniotic fluid tended to be higher than in umbilical cord plasma but lower than in neonatal urine, conjugated drug predominated.