Placental drug transfer: Effects of gestational age and species

Mihaly, G W; Morgan, Denis J.

doi:10.1016/0163-7258(83)90015-3

Cited by 72 publications

(25 citation statements)

References 68 publications

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“…Similar changes have been shown for a number of other drugs in near-term pregnant women (Herngren et al, 1983;Dean et al, 1980). It is well known that reduced maternal drug binding, as well as pregnancy itself, can influence drug clearance in the mother; the effect will vary according to the organ and mechanism of elimination (Mihaly & Morgan, 1984;Routledge, 1986). Since the reduced drug binding to maternal plasma may be associated with a change in maternal clearance, this generally lower drug binding indicates that, for highly bound drugs, the unbound as well as the total plasma concentration may need to be monitored in full term pregnant women.…”

Section: Discussionmentioning

confidence: 61%

“…However, since drug binding was not examined, absolute foetal exposure (i.e. the unbound concentration of drug in foetal plasma (Mihaly & Morgan, 1984) could not be established.…”

Section: Discussionmentioning

confidence: 99%

“…According to Mihaly & Morgan (1984), absolute foetal exposure is largely determined by the unbound drug concentration in maternal plasma. Since quinidine is less highly bound in maternal plasma than quinine, for the same total drug concetitration in the mother, the absolute foetal exposure of the foetus will be greater for quinidine than quinine by a factor of 1.5 to 2.…”

Section: Discussionmentioning

confidence: 99%

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Differences in the binding of quinine and quinidine to plasma proteins.

Mihaly

Ching

Klejn

et al. 1987

Brit J Clinical Pharma

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1 Little is known about the comparative plasma protein binding of the antimalarial agents quinine (QN) and its isomer quinidine (QD). We have examined the in vitro binding of QN and QD to albumin, a,-acid glycoprotein, normal human plasma, and maternal and foetal umbilical cord plasma. 2 QN was more avidly bound than QD, and binding of both drugs was substantially higher to a,-acid glycoprotein than to albumin, indicating that ot,-acid glycoprotein is the more important binding protein.3 Protein and drug concentration dependent binding was evident for both QN and QD. The unbound fraction of both drugs fell with increasing albumin (10 to 60 g 1-1) and a,r-acid glycoprotein (0.5 to 2.0 g 1-1) concentration, and there was a marked increase in unbound fraction of QN (6 to 19%) and QD (13 to 36%) in human plasma when drug concentrations were increased over the antimalarial therapeutic range (0.5 to 10 mg 1-1). 4 In human volunteer plasma, the unbound fractions of QN and QD were 7.5 ± 2.2% and 12.3 ± 2.3% respectively, whilst the unbound fractions for both drugs were significantly higher in maternal plasma (QN = 13.0 ± 5.4%, QD= 18.3 ± 2.5%) and significantly higher still in foetal umbilical cord plasma (QN = 25.7 10%, QD = 35 ± 5.3%).

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Section: Discussionmentioning

confidence: 61%

“…However, since drug binding was not examined, absolute foetal exposure (i.e. the unbound concentration of drug in foetal plasma (Mihaly & Morgan, 1984) could not be established.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Differences in the binding of quinine and quinidine to plasma proteins.

Mihaly

Ching

Klejn

et al. 1987

Brit J Clinical Pharma

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“…at ASPET Journals on May 10, 2018 dmd.aspetjournals.org the fetus is exposed to maternally administered drugs, often in high concentrations (Mihaly and Morgan, 1983). The ability of the fetus to tolerate this exposure is poorly understood.…”

Section: Furnes Et Almentioning

confidence: 99%

Identification of Novel Variants of the Flavin-Containing Monooxygenase Gene Family in African Americans

Furnes¹,

Feng²,

Sommer³

et al. 2003

Drug Metab Dispos

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ABSTRACT:Sequence polymorphisms in enzymes involved in drug metabolism have been widely implicated in the differences observed in the sensitivity to various xenobiotics. The flavin-containing monooxygenase (FMO) gene family in humans catalyzes the monooxygenation of numerous N-, P-and S-containing drugs, pesticides, and environmental toxicants. Six genes (FMO1-6) have been identified so far, but the major alleles of FMO2 and FMO6 encode nonfunctional proteins due to a nonsense mutation and splice-site abnormalities, respectively. Data on structural variants exist for human FMO2 and 3, whereas very little is known about the other FMO genes. FMO1-6 were scanned in 50 individuals of African-American descent using the method, detection of virtually all mutationssingle-strand conformational polymorphism. A total of 49 sequence variants were identified in a total 1.35 megabases of scanned sequence, of which 29 were variants affecting protein structure or expression. Some of these are expected to affect the activity of the protein, including a nonsense mutation in FMO1 (R502X) and missense mutations in FMO1 (I303T), FMO4 (E339Q), and FMO5 (P457L) that occur in highly conserved amino acids. Additional deleterious substitutions in FMO2 (del337G) and FMO6 (Q105X) were also identified. Multiple structural variants in the FMO gene family were observed in this African-American sample. Some of the substitutions identified in this study might be useful markers in future association studies assessing sensitivity to environmental toxicants and common disease.

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“…These types of functional assessments help to predict placental transfer and fetal exposure after maternal dosing. Additional factors that influence the placental transfer of chemicals are uterine/placental blood flow, placental permeability, and placental metabolism (Juchau 1980a(Juchau , 1980bMihaly and Morgan 1983;Miller et al 1976;Mirkin and Singh 1976;Waddell and Marlowe 1981). These factors are not static during pregnancy but may change as gestation progresses.…”

Section: Phase Ii: Data Analysis and Development Of Risk Assessment Amentioning

confidence: 99%

Incorporating children's toxicokinetics into a risk framework.

Ginsberg

Slikker

Bruckner

et al. 2004

Environ Health Perspect

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Children's responses to environmental toxicants will be affected by the way in which their systems absorb, distribute, metabolize, and excrete chemicals. These toxicokinetic factors vary during development, from in utero where maternal and placental processes play a large role, to the neonate in which emerging metabolism and clearance pathways are key determinants. Toxicokinetic differences between neonates and adults lead to the potential for internal dosimetry differences and increased or decreased risk, depending on the mechanisms for toxicity and clearance of a given chemical. This article raises a number of questions that need to be addressed when conducting a toxicokinetic analysis of in utero or childhood exposures. These questions are organized into a proposed framework for conducting the assessment that involves problem formulation (identification of early life stage toxicokinetic factors and chemical-specific factors that may raise questions/concerns for children); data analysis (development of analytic approach, construction of child/adult or child/animal dosimetry comparisons); and risk characterization (evaluation of how children's toxicokinetic analysis can be used to decrease uncertainties in the risk assessment). The proposed approach provides a range of analytical options, from qualitative to quantitative, for assessing children's dosimetry. Further, it provides background information on a variety of toxicokinetic factors that can vary as a function of developmental stage. For example, the ontology of metabolizing systems is described via reference to pediatric studies involving therapeutic drugs and evidence from in vitro enzyme studies. This type of resource information is intended to help the assessor begin to address the issues raised in this paper.

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Placental drug transfer: Effects of gestational age and species

Cited by 72 publications

References 68 publications

Differences in the binding of quinine and quinidine to plasma proteins.

Differences in the binding of quinine and quinidine to plasma proteins.

Identification of Novel Variants of the Flavin-Containing Monooxygenase Gene Family in African Americans

Incorporating children's toxicokinetics into a risk framework.

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