The Significance of Plasma Protein Binding on the Fetal/Maternal Distribution of Drugs at Steady-State

Hill, Martin D.; Abramson, Fred P.

doi:10.2165/00003088-198814030-00004

Cited by 89 publications

(66 citation statements)

References 80 publications

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“…Plasma protein binding influences the interpretation of data relating to the transplacental transfer and foetal/maternal distribution of drugs (Hill & Abramson, 1988). Previous studies (Hamar & Levy, 1980;Thomas et al, 1976;Tucker et al, 1970) have shown that only free drugs equilibrate between maternal and cord plasma.…”

Section: Discussionmentioning

confidence: 99%

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

Echizen

Nakura

Saotome

et al. 1990

Brit J Clinical Pharma

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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

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Section: Discussionmentioning

confidence: 99%

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

Echizen

Nakura

Saotome

et al. 1990

Brit J Clinical Pharma

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“…First, maternal and fetal difference in the extent of drug binding to plasma proteins is a key determinant of drug availability, 53 and this is particularly important for SRIs that are highly protein 18,19 Second, the magnitude of drug clearance in the fetus is important, particularly with chronic drug dosing that results in steady-state plasma drug concentrations, as is typical for SRI drug therapy. Further, fetal drug clearance can be divided into placental (that is, fetal-to-maternal drug transfer) and nonplacental clearance, including hepatic drug metabolism and renal drug excretion.…”

Section: Fetal Contributions To Ssri Metabolism and Dispositionmentioning

confidence: 99%

Fetal Serotonin Reuptake Inhibitor Antidepressant Exposure: Maternal and Fetal Factors

2012

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Prenatal serotonin reuptake inhibitor exposure is common and neonatal outcomes vary greatly, often leading to confusion about whether to use or even continue antenatal use of these antidepressants. Importantly, some but not all infants are affected, which raises questions about how maternal drug metabolism contributes to fetal drug exposure. To address this key question, our paper reviews the role of key maternal, fetal, and placental pharmacokinetic, metabolic, and genetic factors that affect the extent of fetal drug exposure. Considering the role of these factors may further our understanding of variables that may assist in optimizing maternal psychopharmacotherapy during pregnancy and neonatal outcomes. W W WL'exposition prénatale à un inhibiteur du recaptage de la sérotonine est fréquente et les impacts néonataux varient grandement, ce qui provoque souvent la confusion lorsqu'il s'agit d'utiliser ou même de continuer l'usage prénatal de ces antidépresseurs. D'abord et avant tout, certains bébés, mais pas tous, sont affectés, ce qui soulève des questions sur la façon dont le métabolisme maternel des médicaments contribue à l'exposition foetale aux médicaments. Pour aborder cette importante question, notre article examine le rôle des principaux facteurs maternels, foetaux, pharmacocinétiques placentaires, métaboliques, et génétiques qui affectent la portée de l'exposition foetale aux médicaments. Examiner le rôle de ces facteurs approfondira notre compréhension des variables qui peuvent aider à optimiser la psychopharmacothérapie maternelle durant la grossesse et les résultats néonataux.consider the impact of physiological factors of the pregnancy itself and SRI-related pharmacological factors that influence maternal drug metabolism and, by extension, fetal exposure. Further, neonatal outcomes following in utero SRI exposure depends largely on the extent of fetal drug exposure, and thus understanding factors that affect fetal drug pharmacology also offers important clues to developmental risks associated with prenatal drug exposure. Our paper will review key maternal, placental, and fetal metabolic and genetic factors that influence SRI pharmacology and fetal drug exposure. Both SSRIs (for example, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) and SNRIs (for example, duloxetine and venlafaxine) are increasingly used to manage antenatal mood disturbances 8 and will be referred to as SRIs (meaning, SRI ADs). This review is offered as a way to further our understanding of variables that may account for the variations in maternal perinatal SRI pharmacology and neonatal outcomes, and thereby contribute to assessing the benefits and risks associated with SRI use in this setting. E ach year in North America, 15% to 20% of women experience mood disorders (for example, depression) during their pregnancy, leading to one-third of these women being treated with an SRI AD; however, up to 50% stop medication within the first 60 days of pregnancy.

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“…For drugs bound mainly to al-acid glycoprotein (AAG), binding in foetal serum is lower than in maternal serum, an observation that has been explained by a lower foetal a,-acid glycoprotein (AAG) concentration [1,2]. Many drugs are used as racemic mixtures, and differences in the serum binding of their enantiomers in adults have been reported [3].…”

Section: Introduction Methodsmentioning

confidence: 99%

“…Therefore we have measured the binding of the isomers of propranolol and verapamil in pairs of maternal and foetal serum samples obtained at delivery; both drugs are bound to AAG and show enantioselective serum binding in adults [4][5][6]. We also determined whether, based on the foetal/maternal AAG concentration ratio, foetal binding of the enantiomers can be predicted from maternal binding data [1]. Protein binding Drug binding in serum was determined by equilibrium dialysis at 370 C as described previously [8].…”

Section: Introduction Methodsmentioning

confidence: 99%

Protein binding of propranolol and verapamil enantiomers in maternal and foetal serum.

F¹,

Trappen²,

Dhont³

et al. 1995

Brit J Clinical Pharma

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The protein binding of the enantiomers of propranolol and verapamil was measured in 19 pairs of maternal and foetal serum obtained at delivery. The binding of the enantiomers of both drugs was lower in foetal than in maternal serum. In maternal serum the mean (± s.d.) unbound percentages were 22.4 ± 6.2 and 20.7 ± 6.6 for Rand S-propranolol, and 16.8 ± 5.5 and 22.5 ± 6.2 for R-and S-verapamil; in foetal serum the values were 38.8 ± 8.6 and 40.4 ± 10.6 for R-and S-propranolol, and 34.7 ± 10.5 and 44.8 ± 10.7 for R-and S-verapamil. For propranolol, in maternal, but not in foetal serum, the difference between the binding of the R-and S-enantiomers was significant; the R/S ratio was significantly (P < 0.01) larger in the mother (1.099 ± 0.072) than in the foetus (0.973 ± 0.068). For verapamil, the difference in binding between the R-and S-enantiomers was significant in both maternal and foetal serum, but the R/S ratio was similar in mother (0.735 ± 0.098) and foetus (0.763 ± 0.070). Serum a1-acid glycoprotein (AAG) concentrations were markedly higher and albumin concentrations slightly lower in maternal than in foetal samples. The binding of the four enantiomers in maternal and foetal serum was correlated (P < 0.001) with the AAG concentration (r propranolol: R 0.749, S 0.746; r verapamil: R 0.753, S 0.782). Our findings show that measurement of concentrations of total, unresolved drug allow a reasonably accurate assessment of transplacental gradients of individual isomers.

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The Significance of Plasma Protein Binding on the Fetal/Maternal Distribution of Drugs at Steady-State

Cited by 89 publications

References 80 publications

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

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

Fetal Serotonin Reuptake Inhibitor Antidepressant Exposure: Maternal and Fetal Factors

Protein binding of propranolol and verapamil enantiomers in maternal and foetal serum.

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