Pharmacokinetics of oseltamivir among pregnant and nonpregnant women

Beigi, Richard H.; Han, Kelong; Venkataramanan, Raman; Hankins, Gary D.V.; Clark, Shannon; Hébert, Mary F.; Easterling, Thomas R.; Zajicek, Anne; Ren, Zhaoxia; Mattison, Donald R.; Caritis, Steve N.

doi:10.1016/j.ajog.2011.03.002

Cited by 70 publications

(62 citation statements)

References 25 publications

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“…Thus, the general decreased expression of some of the Ces isoforms during early gestation observed here may increase exposure to chlorpyrifos-oxon. Although the expression of CES has not been assessed in pregnancy, bioactivation of the antiviral drug oseltamivir, a CES1 substrate, is decreased in pregnant women, suggesting reduced CES1 activity (Beigi et al, 2011). We also observed reduced expression of Pon1 at GD14, but this did not quite reach statistical significance.…”

Section: Downloaded Frommentioning

confidence: 51%

Alteration of the Expression of Pesticide-Metabolizing Enzymes in Pregnant Mice: Potential Role in the Increased Vulnerability of the Developing Brain

Fortin

Aleksunes²,

Richardson

2012

Drug Metab Dispos

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Studies on therapeutic drug disposition in humans have shown significant alterations as the result of pregnancy. However, it is not known whether pesticide metabolic capacity changes throughout pregnancy, which could affect exposure of the developing brain. We sought to determine the effect of pregnancy on the expression of hepatic enzymes involved in the metabolism of pesticides. Livers were collected from virgin and pregnant C57BL/6 mice at gestational days (GD)7, GD11, GD14, GD17, and postpartum days (PD)1, PD15, and PD30. Relative mRNA expression of several enzymes involved in the metabolism of pesticides, including hepatic cytochromes (Cyp) P450s, carboxylesterases (Ces), and paraoxonase 1 (Pon1), were assessed in mice during gestation and the postpartum period. Compared with virgin mice, alterations in the expression occurred at multiple time points, with the largest changes observed on GD14. At this time point, the expression of most of the Cyps involved in pesticide metabolism in the liver (Cyp1a2, Cyp2d22, Cyp2c37, Cyp2c50, Cyp2c54, and Cyp3a11) were downregulated by 30% or more. Expression of various Ces isoforms and Pon1 were also decreased along with Pon1 activity. These data demonstrate significant alterations in the expression of key enzymes that detoxify pesticides during pregnancy, which could alter exposure of developing animals to these chemicals. IntroductionPesticides are widely used to protect crops, cattle, gardens, and households from infestations. In 2007, it was estimated that 93 million pounds of active ingredients were used in the United States, with organophosphate (OP), carbamate, and pyrethroid (PYR) insecticides the most commonly used (US EPA 2011). Although pesticides are an important tool for ensuring an adequate food supply and protecting public health, there is a risk of untoward effects in nontarget species, including humans, because target and nontarget species often possess a common molecular target of the pesticide. Of particular concern with insecticides, such as OPs and PYRs, is their targeting of the nervous system and the potential increased vulnerability of the developing brain to their neurotoxic effects (Shafer et al., 2005;Jurewicz and Hanke, 2008).Several animal studies have consistently demonstrated that very young animals are more sensitive to the acute toxic effects of OPs and PYRs and that this increased sensitivity is likely the result of immature (Eskenazi et al., 2007), and more than 80% had detectable levels of the OP metabolite dimethylthiophosphate (Woodruff et al., 2011). Similarly, data from the 1999-2002 National Health and Nutrition Examination Survey found that 67% of pregnant women had detectable levels of the PYR metabolite 3-phenoxybenzoic acid (Castorina et al., 2010). Thus, there is widespread exposure of pregnant women to OP and PYR pesticides.Human pregnancy is known to cause a number of physiologic changes that may alter the metabolism of drugs and toxicants, including changes that increase absorption and decrease plasma protein leve...

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Section: Downloaded Frommentioning

confidence: 51%

Alteration of the Expression of Pesticide-Metabolizing Enzymes in Pregnant Mice: Potential Role in the Increased Vulnerability of the Developing Brain

Fortin

Aleksunes²,

Richardson

2012

Drug Metab Dispos

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“…Probably, early identification and treatment were the most important factors in the evolution of illness in both the groups of patients. Most authors recommend oseltamivir as the preferred treatment for pregnant women (11,(21)(22)(23), and this was the antiviral of choice for most cases in our study.…”

Section: Discussionmentioning

confidence: 91%

“…During the pandemic (20), experts debated the most appropriate treatments for use in pregnancy; however, limited data were available at that time (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

Pandemic Influenza A (H1N1) Infection in Pregnant and Nonpregnant Women in Spain (2009–2010)

Suárez-Varela

Gónzález-Candelas

Astray³

et al. 2014

Jpn J Infect Dis

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SUMMARY:The present study aimed to compare the main features of infection with pandemic influenza A virus in pregnant and nonpregnant women admitted to hospitals in Spain during the first waves of the 2009-2010 influenza pandemic. This was a prospective (November 2009 to June 2010), multicenter observational study. All cases were women of reproductive age who had not been vaccinated against seasonal or pandemic influenza A. Influenza infection was confirmed by reverse transcriptionpolymerase chain reaction (RT-PCR). The sociodemographic and clinical data of all cases were reviewed. A total of 219 inpatients, including 49 pregnant women and 170 nonpregnant women, were enrolled in the study upon admission to participating hospitals. The most substantially different symptoms between the groups were respiratory distress and unilobar consolidation, both of which were more frequent among nonpregnant women. Antibiotics and systemic corticosteroids were more frequently used in nonpregnant women; however, there were no differences in the rates of treatment with antivirals. Our findings indicated that the compared with nonpregnant women, pregnant women in this study did not have significantly different symptoms and were not at increased risk of complications from pandemic influenza virus infection.

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“…These recommendations were reasonable, as oseltamivir and active oseltamivir metabolite -carboxylate -are excreted from the body through the kidneys, whereas the glomerular filtration rate increases during pregnancy, which is why circulating blood should feature low metabolite concentration. Two recently published works on oseltamivir PK analysis in pregnant women illustrate common difficulties of conducting such studies [25,26]. Interpretation of the obtained data is complicated by narrowness of our understanding of a drug's PD and the correlation of oseltamivir carboxylate concentration with the clinical effect [24].…”

Section: Approaches To Risk Evaluation Of Pregnant Women Involvement mentioning

confidence: 99%

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 of oseltamivir among pregnant and nonpregnant women

Cited by 70 publications

References 25 publications

Alteration of the Expression of Pesticide-Metabolizing Enzymes in Pregnant Mice: Potential Role in the Increased Vulnerability of the Developing Brain

Alteration of the Expression of Pesticide-Metabolizing Enzymes in Pregnant Mice: Potential Role in the Increased Vulnerability of the Developing Brain

Pandemic Influenza A (H1N1) Infection in Pregnant and Nonpregnant Women in Spain (2009–2010)

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

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Pharmacokinetics of oseltamivir among pregnant and nonpregnant women

Cited by 70 publications

References 25 publications

Alteration of the Expression of Pesticide-Metabolizing Enzymes in Pregnant Mice: Potential Role in the Increased Vulnerability of the Developing Brain

Alteration of the Expression of Pesticide-Metabolizing Enzymes in Pregnant Mice: Potential Role in the Increased Vulnerability of the Developing Brain

Pandemic Influenza A (H1N1) Infection in Pregnant and Nonpregnant Women in Spain (2009&ndash;2010)

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

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Pandemic Influenza A (H1N1) Infection in Pregnant and Nonpregnant Women in Spain (2009–2010)