DRUG MILK TO SERUM RATIO PREDICTION AND ONTOGENY OF CYP3A CLEARANCE PATHWAY AS A MODEL OF DRUG EXPOSURE IN THE DEVELOPING RAT

Abstract

Transfer of drugs into milk and the clearance of drugs in neonates are critical determinants of the exposure of infants to drugs in breast milk. Models predicting both parameters have been proposed. The objective of this dissertation is to test two models predicting milk to serum ratio and an ontogeny clearance model predicting clearance in the neonate. Predicted milk to serum ratio (M/S) values were generated according to the Atkinson and Begg model. The model did not adequately predict M/S when comparing the predicted values to observed values in the literature. The Fleishaker model was also tested. The model was able to predict whether the drugs appeared in milk by passive diffusion only or whether active transport processes were involved. This model, together with appropriate animal models, is useful in understanding the mechanism of drug transfer into milk. An ontogeny model that predicts clearance was proposed earlier by our laboratory. In order to test the model prediction and assumptions of constant microsomal protein and constant Km for an enzyme-substrate system with age, the male rat was use