Pharmacokinetics and Pharmacodynamics of Atenolol During Pregnancy and Postpartum

Hébert, Mary F.; Carr, Darcy B.; Anderson, Gail D.; Blough, David K.; Green, Grace E.; Brateng, Debra; Kantor, Eric D.; Benedetti, Thomas J.; Easterling, Thomas R.

doi:10.1177/0091270004269704

Cited by 61 publications

(50 citation statements)

References 15 publications

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“…In our subjects who were studied postpartum, the mean net tubular secretion clearance of metformin (313 ml/min) was approximately two-thirds of the mean effective renal plasma flow reported previously in nonpregnant women (482 ml/min, based on four studies in a total of 62 women) (Davison and Dunlop, 1980); i.e., metformin tubular secretion is a relatively high extraction process. Given the high body weight of our postpartum subjects and possibly higher effective renal plasma flow, we may be overestimating the extraction ratio of metformin in our subjects (Hebert et al, 2005). Because the estimated tubular extraction ratio for metformin is moderately high, the gestational changes in the net secretory clearance of the drug can potentially be explained by enhanced renal plasma flow.…”

Section: Parametermentioning

confidence: 92%

Pharmacokinetics of Metformin during Pregnancy

Eyal¹,

Easterling²,

Carr³

et al. 2010

Drug Metab Dispos

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177

154

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ABSTRACT:Our objective was to evaluate the pharmacokinetics of metformin during pregnancy. Serial blood and urine samples were collected over one steady-state dosing interval in women treated with metformin during early to late pregnancy (n ‫؍‬ 35) and postpartum (n ‫؍‬ 16). Maternal and umbilical cord blood samples were obtained at delivery from 12 women. Metformin concentrations were also determined in breast milk samples obtained over one dosing interval in 6 women. Metformin renal clearance increased significantly in mid (723 ؎ 243 ml/min, P < 0.01) and late pregnancy (625 ؎ 130 ml/min, P < 0.01) compared with postpartum (477 ؎ 132 ml/min). These changes reflected significant increases in creatinine clearance (240 ؎ 70 ml/min, P < 0.01 and 207 ؎ 56 ml/min, P < 0.05 versus 165 ؎ 44 ml/min) and in metformin net secretion clearance (480 ؎ 190 ml/min, P < 0.01 and 419 ؎ 78 ml/min, P < 0.01 versus 313 ؎ 98 ml/min) in mid and late pregnancy versus postpartum, respectively. Metformin concentrations at the time of delivery in umbilical cord plasma ranged between nondetectable (<5 ng/ml) and 1263 ng/ml. The daily infant intake of metformin through breast milk was 0.13 to 0.28 mg, and the relative infant dose was <0.5% of the mother's weight-adjusted dose. Our results indicate that metformin pharmacokinetics are affected by pregnancy-related changes in renal filtration and net tubular transport and can be roughly estimated by the use of creatinine clearance. At the time of delivery, the fetus is exposed to metformin concentrations from negligible to as high as maternal concentrations. In contrast, infant exposure to metformin through the breast milk is low.

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Section: Parametermentioning

confidence: 92%

Pharmacokinetics of Metformin during Pregnancy

Eyal¹,

Easterling²,

Carr³

et al. 2010

Drug Metab Dispos

Self Cite

177

154

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“…Clinically, the urinary clearance of drugs, such as ceftazidime, atenolol, and amoxicillin, is often elevated during pregnancy (Hebert et al, 2005;Nathorst-Boos et al, 1995;Andrew et al, 2007). The renal secretion and urinary clearance of the cardiac glycoside digoxin has also been shown to increase in a study of 13 pregnant patients .…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation of Brush Border Efflux Transporter Expression in the Kidneys of Pregnant Mice

2012

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Pregnancy increases the urinary excretion of chemicals in women and rodents. It is unknown whether the enhanced clearance of drugs during pregnancy involves changes in the expression of transporters that mediate chemical secretion and reabsorption. The purpose of this study was to quantify the mRNA and protein expression of efflux transporters in kidneys from virgin and pregnant mice on gestational days 7, 11, 14, and 17 and postnatal days 1, 15, and 30 with use of quantitative polymerase chain reaction, Western blot, and immunofluorescence. Multidrug resistance protein (Mdr) 1b mRNA, multidrug resistance-associated protein (Mrp) 4 mRNA, and protein levels decreased significantly by 25-75% throughout pregnancy and lactation. Similarly, Mrp2 and multidrug and toxin extrusion transporter (Mate) 1 mRNA expression were down-regulated 20-40% during mid to late gestation but returned to control levels by postnatal day 15. In contrast, Mrp3 mRNA and protein increased 225% and 31%, respectively, at gestational day 14. Coordinated down-regulation of brush border transporters Mate1, Mrp2, and Mrp4 and up-regulation of the basolateral Mrp3 transporter would reduce chemical secretion into urine. IntroductionPregnancy-induced hormonal and hemodynamic changes significantly alter renal function. In humans and rodents, increases in cardiac output and renal vasodilation enlarge the size of the kidneys, elevate renal plasma flow by 50-85%, and increase the rate of glomerular filtration by 40-65% (Chapman et al., 1998;Conrad, 2004;Maynard and Thadhani, 2009;Cornelis et al., 2011). Clinically, pregnant women exhibit proteinuria, glucosuria, and aminoaciduria, which have been attributed to alterations in renal function (Davison and Dunlop, 1980;Cornelis et al., 2011). Together, hyperfiltration and increased blood flow to the kidneys alter maternal pharmacokinetics by elevating the renal clearance of chemicals during pregnancy.Renal transporters are membrane-spanning proteins that play a critical role in facilitating the movement of toxins and drugs into the urine via secretion and into the blood via reabsorption. To enable these processes, transporters are prominently localized on both the apical (brush border) and basolateral membranes of proximal tubule epithelial cells. Transporters expressed within the kidneys are members of one of the two superfamilies: the solute carrier (SLC) and ATP-binding cassette (ABC) families. Efflux transporters that extrude chemicals from cells are members of both the ABC and the SLC families and include the multidrug resistance-associated proteins (Mrps), multidrug resistance proteins (Mdrs), breast cancer resistance protein (Bcrp), and multidrug and toxin extrusion proteins (Mates) (reviewed in Klaassen and Aleksunes, 2010).Recent studies have begun to explore transporter regulation in the kidneys during pregnancy and the subsequent postpartum period. In one study, expression of renal Mdr1b mRNA in mice decreased between mid and late gestation, with little to no change at the protein level (...

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“…Results of these studies illustrate the absence of any fixed state of PK-and PD-effects during pregnancy: they may vary considerably. The study of atenolol's PK and PD during pregnancy supports these observations, as it demonstrates increase in the drug's renal clearance; however, pharmacodynamic is yet to be defined [35]. As for social risks of drug exposure during pregnancy, they are closely associated with characterological peculiarities of the mother.…”

Section: Approaches To Risk Evaluation Of Pregnant Women Involvement mentioning

confidence: 75%

Modern Paradigm of the Pregnant-Involving Pharmacological Study: Risk Assessment, Ethical Principles and Regulatory Aspect

Александрович¹,

Reshetko²,

Луцевич³

2014

Pediatr. farmakol.

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Clinical practice indicates that the lack of evidence database on the effect of drugs and biological products on the course of pregnancy presents women and doctors in charge with a difficult dilemma, when prescription of the drugs, which have not undergone clinical studies, renders correct dosage and account of potential fetus-associated effects impossible. On the other hand, refusal to use drugs during pregnancy may result in harm to health not only of mothers, but also of their unborn r newborn children caused by the disease-associated pathological alterations [1,2]. Risk/benefit balance of drug therapy is not always clear both for a mother and her fetus; it is circumstantial and specific in every woman [3]. In order to minimize embryofetal risk, it is necessary to identify and avoid using nonessential drugs, regulate dose, frequency and way of administration of the drug and duration of the essential treatment. It ought to be mentioned, though, that development of new drugs for treating pregnancy-associated pathological conditions present scientists with the challenges that only rarely occur in other populations. Any drug interventions awake in women fear of pregnancy-and labor-associated complications. This fact complicates clinical studies of drugs, because any risk assumption renders such clinical studies unacceptable for pregnant women. On the other hand, there is an obvious need in validating drug efficacy and safety data obtained in the clinical studies involving different populations of patients with respect to pregnant women, as their bodies undergo a range of functional changes during gestation [4]. Additional studies aimed at identifying the factors determining pregnancy-associated changes of pharmacokinetics (PK) and pharmacodynamics (PD) of drugs are required for women not to be barred from achievements of the modern pharmacotherapy. There is also an ethical dilemma of involving this particularly sensitive category of patients in randomized controlled studies of safe and efficacy of drugs [5]. At the same time, new discipline -obstetric-fetal pharmacology -may form the basis of extensive study of gestational use of drugs [6]. In order to enable pharmacological studies involving pregnant women, a model, which

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Pharmacokinetics and Pharmacodynamics of Atenolol During Pregnancy and Postpartum

Cited by 61 publications

References 15 publications

Pharmacokinetics of Metformin during Pregnancy

Pharmacokinetics of Metformin during Pregnancy

Down-Regulation of Brush Border Efflux Transporter Expression in the Kidneys of Pregnant Mice

Modern Paradigm of the Pregnant-Involving Pharmacological Study: Risk Assessment, Ethical Principles and Regulatory Aspect

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