Drug Binding to Plasma Proteins During Human Pregnancy and in the Perinatal Period

Abstract

Plasma protein binding of one acidic drug, cloxacillin, and one basic drug, alprenolol, was determined by equilibrium dialysis at + 37 °C during pregnancy and the 1st postnatal week in 12 women and their newborn infants and in 7 nonpregnant women (controls). A significant increase in fraction free cloxacillin in maternal plasma occurred during pregnancy already from the 2nd trimester compared to the controls (p <0.01) and was most pronounced at delivery (median values 0.126 and 0.069, respectively). A similarly increased fraction free cloxacillin was found in cord blood (median value 0.108) which further increased during the 1 st postnatal week (range 0.112-0.164). In maternal plasma the binding capacity returned to the values of the controls during the same time period. The binding of cloxacillin was significantly correlated with the concentration of albumin (p < 0.01). High correlation was also found between binding of the basic drug alprenolol and concentration of orosomucoid (p < 0.005). This was most obvious in the newborn infants with low concentrations (range 0.1-0.3 g/1) and in the mothers during the puerperium with high concentrations of orosomucoid (range 0.7-2.5 g/1). On the basis of plasma protein binding data in the mother and her child, a maternal to fetal plasma concentration ratio was calculated. For cloxacillin this ratio was close to unity (1.03), while it was significantly above unity for alprenolol (1.72). At equilibrium, therefore, the total plasma concentration of alprenolol in the mother can be expected to exceed the concentration in her infant.

Protein binding predictions in infants

“…The concentration of HSA is approximately 36 g/L in cord blood compared to 45 g/L in adult plasma [14][15][16][17][18][19][20] . The infant-to-nonpregnantadult concentration ratio for HSA is 0.81 (Table 1).…”

“…The infant-to-nonpregnantadult concentration ratio for HSA is 0.81 (Table 1). In pregnant adults, HSA concentrations are lower throughout the later stages of pregnancy and appear to rebound to nonpregnant adult levels by 1 month postpartum 14,21,22 , resulting in a ratio of 1.16 ( …”

“…Cord AAG concentrations average 0.24 g/L compared to 0.60 g/L for normal adult plasma 14,16,23,24 , which results in an average ratio of 0.38 for AAG (Table 1). In contrast to HSA concentrations, AAG concentrations in the mother at delivery are similar to those of nonpregnant adults (Table 1).…”

Human variability and susceptibility to trichloroethylene.

“…The alveolar surface area increases from 3 m2 at birth to 75 m2 in adulthood; as a result, the air-totissue gas exchange increases more than 20-fold. In addition, although the respiratory volume is the same in adults and children (10 mL/kg body weight/breath), the number of breaths per minute is increased in the infant [40 (108,109). Plasma albumin is also decreased in children (108,109).…”

“…In addition, although the respiratory volume is the same in adults and children (10 mL/kg body weight/breath), the number of breaths per minute is increased in the infant [40 (108,109). Plasma albumin is also decreased in children (108,109). These factors will likely not affect the distribution of TCE in children because TCE does not bind significantly to proteins.…”