Possible Effect of Lactational Period on the Milk-to-Plasma Drug Concentration Ratio in Lactating Women: Results of an In Vitro Evaluation

• Published in: Journal of pharmaceutical sciences 1989-02, Vol.78 (2), p.137-141
• Main Authors: Fleishaker, Joseph C., Desai, Nirmala, McNamara, Patrick J.
• Format: Article
• Language: English
• Subjects: Acitretin; Adult; Biological and medical sciences; Chemical Phenomena; Chemistry, Physical; Diazepam - analysis; Diazepam - blood; Female; General pharmacology; Humans; Lactation; Medical sciences; Milk, Human - analysis; Models, Theoretical; Pharmaceutical Preparations - analysis; Pharmaceutical Preparations - blood; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pregnancy; Propranolol - analysis; Propranolol - blood; Tretinoin - analogs & derivatives; Tretinoin - analysis; Tretinoin - blood
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600780213

The fat and protein composition of human milk changes dramatically in the first several weeks postpartum. In order to investigate the possible effect of this compositional change on the milk-to-plasma drug concentration ratio (M/P), the following experiment was performed. Milk samples were collected from five healthy lactating women on days 3, 5, 7, and 14 postpartum; blood samples were obtained on these days, as well as on day 1. Serum and skim milk unbound fractions (fp and fm, respectively) and the skim milk-to-whole milk drug concentration ratio (S/M) were determined in vitro in the above samples for diazepam, propranolol, and etretin, an aromatic retinoid. In addition, the composition of these milk and serum samples was also assessed. Using a previously proposed mathematical model for the distribution of drugs between milk and plasma, M/P was calculated from values for fm, fp, S/M, milk pH, and literature values for the pKa values of the compounds. The M/P was calculated for each subject on each day of sample collection. Total serum protein and alpha-1-acid glycoprotein (AAG) levels increased in the first two weeks postpartum. Mean diazepam fp values fell from 0.020 to 0.014 during this period, while propranolol fp values changed inversely with serum AAG levels. Milk whey and total proteins decreased as lactation progressed, but changes in fsat levels were not statistically significant. Calculated propranolol M/P increased during the study period, predominately due to changes in milk pH and propranolol S/M. The results of this study indicate that the plasma protein binding of drugs may be altered in the early postpartum period; this may bear consideration in the maintenance of optimal maternal drug therapy during this period. Drug distribution between milk and plasma may also be affected by lactation stage; however, the effects on M/P appear to be small and subject to a large degree of variability.