Serum Protein Binding of Valproic Acid in Fetus‐Mother Pairs Throughout Pregnancy: Correlation With Oxytocin Administration and Albumin and Free Fatty Acid Concentrations

Nau, Heinz; Krauer, Béatrice

doi:10.1002/j.1552-4604.1986.tb02937.x

Cited by 34 publications

(12 citation statements)

References 15 publications

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“…In later gestation, total valproic acid concentrations were 60 and 120 mg/liter in mother and fetus, respectively. Although data confirming this model have been reported only for late pregnancy, Nau and Krauer (1986) wrote in their discussion, "In a few cases in which fetal blood was available from earlier gestation periods, it was found that the total [valproic acid] VPA concentrations in the fetus were lower than in the mother although the free VPA concentrations were similar (unpublished results from this laboratory)." Nau (1986) reviewed species differences in valproic acid developmental toxicity, noting that effective doses and susceptibility to neural tube defects are variable.…”

Section: Case Studies (See Table 2 For Summary) Valproic Acidmentioning

confidence: 76%

“…The differences in maternal and fetal concentrations are better explained by the extent of protein binding for valproic acid. As gestation advances, fetal albumin concentration increases and free valproic acid decreases (Nau and Krauer, 1986). Near term, an increase in free fatty acid concentration in maternal plasma appears to displace valproic acid from binding sites, resulting in more free drug available for transfer to the fetus (Nau et al, 1984).…”

Section: Case Studies (See Table 2 For Summary) Valproic Acidmentioning

confidence: 96%

“…The importance of protein binding in the distribution of valproic acid across the human placenta was suggested by Nau and Krauer (1986), who offered a model of valproic acid in early (as opposed to later) gestation. They assumed similar free valproic acid concentra- Garrettson et al (1975); Levy et al (1975) tions across the placenta at both gestation times (empirically confirmed at term by Nau et al, 1984) with protein bound valproic acid greater in the mother early in gestation and greater in the fetus in later gestation.…”

Section: Case Studies (See Table 2 For Summary) Valproic Acidmentioning

confidence: 98%

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Mechanisms regulating toxicant disposition to the embryo during early pregnancy: An interspecies comparison

Carney

Scialli²,

Watson

et al. 2004

Birth Defects Research Pt C

102

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The dose of toxicant reaching the embryo is a critical determinant of developmental toxicity, and is likely to be a key factor responsible for interspecies variability in response to many test agents. This review compares the mechanisms regulating disposition of toxicants from the maternal circulation to the embryo during organogenesis in humans and the two species used predominantly in regulatory developmental toxicity testing, rats and rabbits. These three species utilize fundamentally different strategies for maternal-embryonic exchange during early pregnancy. Early postimplantation rat embryos rely on the inverted visceral yolk sac placenta, which is in intimate contact with the uterine epithelium and is equipped with an extensive repertoire of transport mechanisms, such as pinocytosis, endocytosis, and specific transporter proteins. Also, the rat yolk sac completely surrounds the embryo, such that the fluid-filled exocoelom survives through most of the period of organogenesis, and can concentrate compounds such as certain weak acids due to pH differences between maternal blood and exocelomic fluid. The early postimplantation rabbit conceptus differs from the rat in that the yolk sac is not closely apposed to the uterus during early organogenesis and does not completely enclose the embryo until relatively later in development (approximately GD13). This suggests that the early rabbit yolk sac might be a relatively inefficient transporter, a conclusion supported by limited data with ethylene glycol and one of its predominant metabolites, glycolic acid, given to GD9 rabbits. In humans, maternal-embryo exchange is thought to occur via the chorioallantoic placenta, although it has recently been conjectured that a supplemental route of transfer could occur via absorption into the yolk sac. Knowledge of the mechanisms underlying species-specific embryonic disposition, factored together with other pharmacokinetic characteristics of the test compound and knowledge of critical periods of susceptibility, can be used on a case-by-case basis to make more accurate extrapolations of test animal data to the human.

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Section: Case Studies (See Table 2 For Summary) Valproic Acidmentioning

confidence: 76%

Section: Case Studies (See Table 2 For Summary) Valproic Acidmentioning

confidence: 96%

Section: Case Studies (See Table 2 For Summary) Valproic Acidmentioning

confidence: 98%

See 1 more Smart Citation

Mechanisms regulating toxicant disposition to the embryo during early pregnancy: An interspecies comparison

Carney

Scialli²,

Watson

et al. 2004

Birth Defects Research Pt C

102

View full text Add to dashboard Cite

show abstract

“…Plasma protein binding and fetal/maternal dispositionNau et al (1981);Nau et al (1986) a Except where indicated all studies were of term infants. t = 19 weeks; * = 14 weeks; " = 16 weeks.b See section 3 of text for details of selection criteria c First reference refers to F 1M study, second refers to binding study.…”

mentioning

confidence: 98%

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

Hill

Abramson

1988

Clinical Pharmacokinetics

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Maternal and fetal plasma differ in their concentrations of the important drug binding plasma proteins, albumin and alpha 1-acid glycoprotein, with albumin being slightly more concentrated in fetal plasma, and alpha 1-acid glycoprotein being only 37% of the maternal concentration at term. In general, these differences relate linearly to the bound to free concentration ratio of drugs associated with these proteins. Although only the free concentration is generally considered to be the pharmacologically active form, these differences can dramatically affect the total concentration and relative distribution of drugs between maternal and fetal plasma. In order to test our hypothesis that plasma protein binding is the major determinant of fetal/maternal drug distribution at steady-state, we examined whether fetal binding could be predicted from adult binding information. Data from studies of maternal plasma protein binding were used to predict fetal plasma protein binding based solely on the differences in protein concentrations. These predictions were compared with observed fetal binding data. This analysis showed a slope near unity and a high correlation (r2 = 0.900) which implies that there are no significant differences between the binding affinities of these proteins. A similar analysis performed using data on drug binding in non-pregnant adults gave an r2 or 0.971. Having established that fetal plasma proteins bind drugs similarly to their maternal counterparts, fetal/maternal plasma drug concentration ratios (F/M) were predicted for various drugs using information from literature on the drug's adult plasma protein binding, the protein to which it binds, and the fetal and maternal plasma concentrations of that binding protein.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…The bound-to-free ratios for furosemide at var ious concentrations of furosemide is de-able without prescription, produces the greatest displacing effect on furosemide. Such a finding has importance for the early stages of gestation when serum albumin con centration is one tenth that at birth [16]. The cause of such a differential inhibitory effect on binding is unknown, however.…”

Section: Resultsmentioning

confidence: 97%

Binding of Furosemide to Albumin Isolated from Human Fetal and Adult Serum

Viani

Cappiello²,

Silvestri³

et al. 1991

Dev Pharmacol Ther

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Albumin was isolated from pooled fetal serum from 58 placentas obtained at normal delivery at term and from pooled adult plasma from 8 individuals. Albumin isolation was carried out by means of PEG precipitation followed by ion-exchange chromatography on DEAE-Sephadex A 50 and then on SP-Sephadex C 50. The electrophoresis on SDS-polyacrylamide gels showed only one spot that comigrated with commercial human albumin. Binding to albumin was measured by equilibrium dialysis of an aliquot of albumin solution (0.7 ml) against the same volume of 0.13 M sodium orthophosphate buffer (pH 7.4). At a total concentration of 2 μg/ml (therapeutic range), the unbound fraction of furosemide was 2.71 % (fetal albumin) and 2.51 % (adult albumin). Two classes of binding sites for furosemide were observed in fetal and adult albumin. The number of binding sites (moles of furosemide per mole of albumin) was 1.22 (fetal albumin) and 1.58 (adult albumin) for the high-affinity site and 2.97 (fetal albumin) and 3.25 (adult albumin) for the low-affinity site. The association constants (M^-1 ) were 3.1 X 10^4 (fetal albumin) and 2.6 X 10^4 (adult albumin) for the high-affinity set of sites and 0.83 X 10^4 (fetal albumin) and 1.0 X 10^4 (adult albumin) low-affinity site. The displacement of furosemide from albumin was studied with therapeutic concentrations of several drugs. Valproic acid, salicylic acid, azapropazone and tolbutamide had the highest displacing effects which were significantly higher with fetal than with adult albumin.

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Serum Protein Binding of Valproic Acid in Fetus‐Mother Pairs Throughout Pregnancy: Correlation With Oxytocin Administration and Albumin and Free Fatty Acid Concentrations

Cited by 34 publications

References 15 publications

Mechanisms regulating toxicant disposition to the embryo during early pregnancy: An interspecies comparison

Mechanisms regulating toxicant disposition to the embryo during early pregnancy: An interspecies comparison

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

Binding of Furosemide to Albumin Isolated from Human Fetal and Adult Serum

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