A model of the first pass passage of drugs from i.v. injection site to the heart-parameter estimates for lignocaine in the sheep

Abstract

A general model, based on indicator dilution principles, of the initial distribution and effects of drugs in a target organ after i.v. bolus administration is presented. The model was validated from previous studies of myocardial pharmacokinetics and pharmacodynamics of lignocaine in sheep. It is proposed that i.v. drug injection produces a concentration "peak" of drug in venous blood, which is attenuated by vascular mixing, and lung and heart kinetics, as the drug is transported from the injection site to the heart where it exerts its effects. The model predicted that the first passage of this peak through the heart was the principal component of myocardial concentrations of lignocaine for 10 min after injection before recirculation became important. Injection rate, cardiac output and myocardial blood flow were important determinants of the magnitude of the first pass peak. The model provides a physiological framework for analysing the initial distribution of drugs.