Factors affecting the milk-to-plasma drug concentration ratio in lactating women: physical interactions with protein and fat

J Pharm Sci. 1987 Mar;76(3):189-93. doi: 10.1002/jps.2600760302.


The factors that affect M/P (milk-to-plasma) ratios of several compounds were assessed in vitro using samples collected from four healthy lactating women. Three drugs were studied: diazepam, phenytoin, and propranolol. Serum and skim milk protein binding were determined by equilibrium dialysis at 37 degrees C. Skim-to-whole milk concentration ratios (S/M) were determined after incubation of whole milk at 37 degrees C for 1 h. Free fractions in serum and skim milk, respectively, were 0.013 and 0.334 for diazepam, 0.142 and 0.584 for phenytoin, and 0.107 and 0.699 for propranolol. The S/M values were 0.220, 0.727, and 0.610 for diazepam, phenytoin, and propranolol, respectively. An equation was derived which relates M/P to milk and plasma pH, unbound fractions of drug in skim milk and serum, and S/M. The M/P ratios calculated from in vitro data agreed with published in vivo M/P ratios. The results indicated that milk protein binding and fat partitioning can make a substantial contribution in determining M/P, and predictions of M/P made without considering these factors may be misleading.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dialysis
  • Diazepam / metabolism
  • Fats / metabolism
  • Female
  • Freezing
  • Humans
  • In Vitro Techniques
  • Milk Proteins / metabolism
  • Milk, Human / metabolism*
  • Pharmaceutical Preparations / blood
  • Pharmaceutical Preparations / metabolism*
  • Phenytoin / metabolism
  • Propranolol / metabolism*
  • Protein Binding


  • Fats
  • Milk Proteins
  • Pharmaceutical Preparations
  • Phenytoin
  • Propranolol
  • Diazepam