Plasma protein binding of disopyramide in pregnant and postpartum women, and in neonates and their mothers.

Abstract

1 The protein binding of disopyramide was measured in plasma obtained from nonpregnant women, pregnant women in the first, second, and third trimesters, matched pairs of mothers and neonates (cord plasma), and 1 month postpartum women (n = 6 or 8 of each). 2 Plasma samples spiked with 0.2-12.0 ug ml-l of the drug were ultrafiltered and the free fractions were measured with a fluorescent polarization immunoassay.3 The mean (± s.d.) percentages of free drug at a total concentration of 3.0 pug ml-' observed in the third trimester (46 ± 9%) and neonate (79 ± 5%) groups were greater (P < 0.05 or 0.01) than that in the non-pregnant group (34 + 7%). In contrast, the corresponding value observed in the postpartum group (23 ± 8%) was less (P < 0.05) than that in the non-pregnant group. In addition, there was a significant (P < 0.01) difference in the mean percentage of free drug at 3.0 ,ug ml-' in plasma from mothers (43 ± 9%) and neonates (79 ± 5%).4 A multiple regression analysis indicated that a,-acid glycoprotein (r = -0.88, P < 0.01), rather than albumin (r = -0.008), dominated the binding of disopyramide within the therapeutic range of drug concentration. An analysis of the binding parameters of disopyramide suggested that alterations in binding were attributable to changes in the capacity rather than the affinity of binding. 5 These data suggest that: 1) the antiarrhythmic effects of disopyramide at a given total (free + bound) therapeutic plasma concentration may be greater in women in the third trimester of pregnancy and in neonates, but may be reduced in postpartum women at 1 month, compared with non-pregnant women; 2) plasma a,-acid glycoprotein concentration may serve as a useful index to predict alterations in disopyramide binding; and 3) the mean foetal/maternal total plasma concentration ratio of disopyramide within the therapeutic total drug concentration of 2.0 to 5.0 jig ml-' in maternal plasma should be about 0.78.Keywords disopyramide protein binding pregnancy neonate postpartum ao-acid glycoprotein

Differential protein binding of indinavir and saquinavir in matched maternal and umbilical cord plasma

“…The present results indicate the AAG concentration differential contributes significantly to the differential binding of indinavir and saquinavir in matched samples. This is in agreement with other basic drugs including pethidine [26], lignocaine [27] and disopyramide [28], which were less bound in umbilical cord than maternal plasma. In the current study, the combined effects of AAG and HSA did not fully explain the variability in the f u of the two PIs.…”

“…In addition, HSA concentrations were higher, while AAG concentrations were substantially lower, in umbilical cord compared with maternal plasma. Similar transplacental concentration gradients for HSA [23][24][25] and AAG [26][27][28] have been shown to contribute to the differential protein binding of drugs in the maternal-fetal unit.…”

Pharmacokinetic and Pharmacodynamic Considerations for Drugs Binding to Alpha-1-Acid Glycoprotein

“…Pregnancy can also impact AAG levels. In human AAG levels are lower in the pregnant female and continue to decline throughout pregnancy until birth when they begin to climb back to pre-pregnancy values (53,56,57). Wood and Wood (51) reported the same values in female non-pregnant healthy volunteers and pregnant women, however the study size was relatively small (n = 10).…”

“…Ontogeny AAG levels range from undetectable in the developing human fetus, to 0.1-0.2 mg/ml in cord blood (47,51,53), up to 0.3 mg/ml at birth (34,51,(54)(55)(56)(57), steadily increasing to 0.4-0.7 mg/ml at 2-3 months (34,50,55), and achieving adult levels (0.6-0.9 mg/ml) by 10-12 months of age (33,34,58) (Table IV). Similarly, AAG is undetectable (<0.04 mg/ml) in the cord blood of dogs, thus significantly lower compared to adult dogs (0.32 mg/ml) (25).…”

Cardiovascular Pharmacotherapeutic Considerations During Pregnancy and Lactation

“…During the third trimester, Echizen and coworkers showed that the protein binding of disopyramide is decreased significantly. 53 As a consequence, there is an increase in the antiarrhythmic activity at the same therapeutic plasma concentration. With a therapeutic disopyramide maternal plasma concentration of 2.0 to 5.0 g/mL, the mean fetal:maternal plasma ratio at term was 0.78.…”