'MacDope': a simulation of drug disposition in the human body: applications in clinical pharmacokinetics.
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abstract
1 We have described a novel approach to absorption, distribution, metabolism and elimination of drugs in which the patient is described using 23 Patient Factors and drugs by up to 50 Drug Factors. Kinetic behavior of a drug results from the interaction of patient and drug factors according to equations describing an eight compartment model. In this model non‐linear processes (protein binding, hepatic drug metabolism and renal tubular transport) are handled by derivations of the law of mass action which have been generalised to permit the consequences of multiple drugs interacting at single macromolecular sites to be correctly calculated. 2 The mathematical description of this model is provided in a companion paper and solution of the equations is only possible using a digital computer. The computer programme is provided with an interactional format which makes operation independent of mathematical skills. Patients are defined by age, sex, height and weight with, or without, organ dysfunction; the programme then generates appropriate factors. Drug enters the system when a prescription is type on the keyboard and required Drug Factors are then retrieved from the disc flies. Drug concentrations in plasma or body fluids are given as simple graphs as a function of time, or in tabular form. 3 Any of the Patient or Drug Factors may be altered before, or during a run and up to three drugs may be simulated at one time thus permitting certain kinetic interactions to be examined. The scope of the simulator is illustrated using aspirin: pH dependent gastric absorption, first‐order conversion of aspirin to salicylate, partly first order and partly saturable hepatic metabolism of salicylate, and the complex renal handling of this drug are all represented. Interaction of phenytoin with salicylate has been examined quantitatively to suggest limited clinical relevance for the observed displacement of phenytoin from serum albumin. The use of the simulator in a short course of pharmacokinetics is briefly described.
