INVIVO EVALUATION IN THE LACTATING RABBIT OF A MODEL FOR XENOBIOTIC DISTRIBUTION INTO BREAST-MILK

  • 1 March 1988
    • journal article
    • research article
    • Vol. 244  (3) , 919-924
Abstract
A mathematical diffusional model for drug distribution between milk and plasma has been proposed recently. The purpose of this study was to assess the ability of the model to predict milk to plasma drug concentration ratios (M/P) observed in vivo. The distribution of four model compounds (diazepam, phenobarbital, phenytoin and propranolol) was measured in lactating New Zealand White rabbits. M/P ratios were determined in vivo (M/Pobs) under single dose (diazepam = 6.14, phenytoin = 0.690 and propranolol = 2.16) and during steady-state infusions (phenobarbital = 0.566 and propranolol = 2.69). Predicted M/P values (M/Ppred) were calculated from in vitro measures of the unbound fractions of drug in skim milk and serum, respectively), the skim to whole milk drug concentration ratio, milk and plasma pH and the pKa of the model compound. M/Pobs values were highly correlated with M/Ppred (r2 = 0.976) when the data for all four drugs were pooled. No significant difference was found between M/P values observed after a single dose or constant i.v. infusion of propranolol. These results support the usefulness of the diffusional model for predicting M/P in vivo and indicate that single dose data may be used to obtain M/Pobs values reflecting average steady-state milk and plasma levels. The diffusional model has several important applications in the study of drug transfer into milk.