Plasma Protein Binding of Drugs in Pregnancy and in Neonates

Abstract

Plasma protein binding of drugs has important implications for drug disposition and action since it is the first, and controlling, step in drug distribution. Physiological changes in pregnancy include significant changes in plasma composition which affect drug binding and subsequent drug response; the extent of these changes depends on the stage of gestation. Both albumin and alpha 1-acid glycoprotein fractions are reduced, and consequently the binding of both acidic and basic drugs may be affected. This may lead to difficulties in maintaining adequate plasma concentrations of highly protein-bound drugs, since the measurement of total drug concentration in plasma may no longer be a valid indicator for dose adjustment. The newborn infant displays a continually changing plasma profile. The presence of fetal proteins and endogenous substrates known to interfere with drug binding can lead to unexpected complications due to a higher than expected 'free' drug fraction. Furthermore, a decrease in the affinity of albumin for bilirubin during this period may lead to bilirubin displacement by drugs such as diazepam, sulphonamides and salicylate, resulting in clinical jaundice which would not occur beyond the neonatal period. Plasma composition and its effect on drug binding should be taken into account when prescribing highly protein bound drugs with narrow therapeutic: toxic ratios.

Protein binding predictions in infants

“…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 ( …”

Pharmacokinetics of Clindamycin in Pregnant Women in the Peripartum Period

“…High concentrations of alpha 1 -acid glycoprotein result in high levels of protein binding (up to 92% at an alpha 1 -acid glycoprotein concentration of at least 201 mg/dl), whereas due to the nonlinearity in the level of protein binding, an increase in the clindamycin concentration leads to an increase in the level of protein binding (up to 88% at a concentration of 4 mg/liter) (16). In our patients, the percentage of protein binding is unknown, but compared to that found in nonpregnant healthy volunteers, it is likely to be reduced due to the state of pregnancy; but it is possibly increased during labor, stress, or the presence of infection (26). Since only the free unbound fraction of drug is active and the level of plasma protein binding of clindamycin is relatively high, even a minor increase in the level of protein binding might influence its efficacy.…”

“…The concentration of alpha 1 -acid glycoprotein in neonates increases with gestational age (26). As has been shown for alprenolol, the affinity of alpha 1 -acid glycoprotein might be decreased in the first 7 days of life, partly due to displacement by bilirubin (26).…”

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

“…Significant changes in plasma protein composition can occur during pregnancy (31,32). Both albumin and α-1 acid glycoprotein fractions are reduced during pregnancy, and the pharmacokinetics of highly protein-bound acidic and basic drugs are affected.…”