Possible effect of lactational period on the milk-to-plasma drug concentration ratio in lactating women: results of an in vitro evaluation.
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 fat 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Fleishaker
J C
JC
Department of Pharmaceutics and Pharmaceutical Analysis, College of Pharmacy, University of Kentucky, Lexington 40536.
Desai
N
N
McNamara
P J
PJ
D017255:Acitretin; D000328:Adult; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003975:Diazepam / Q000032:analysis / Q000097:blood; D005260:Female; D006801:Humans; D007774:Lactation; D008895:Milk, Human / Q000032:analysis*; D008962:Models, Theoretical; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000097:blood; D011247:Pregnancy; D011433:Propranolol / Q000032:analysis / Q000097:blood; D014212:Tretinoin / Q000031:analogs & derivatives / Q000032:analysis / Q000097:blood
D004364:Pharmaceutical Preparations; D014212:Tretinoin; D011433:Propranolol; D017255:Acitretin; D003975:Diazepam