Elsevier

Reproductive Toxicology

Volume 16, Issue 1, January–February 2002, Pages 1-7
Reproductive Toxicology

Review
Atenolol: pharmacokinetic/dynamic aspects of comparative developmental toxicity

https://doi.org/10.1016/S0890-6238(01)00193-9Get rights and content

Introduction

Atenolol is a cardioselective β-adrenoreceptor blocking agent, used for treatment of hypertension, including hypertension in pregnancy. Beta-adrenoreceptor antagonists have been implicated in the production of intrauterine growth retardation and a considerable range of neonatal problems including hypoglycemia, bradycardia, respiratory depression and death [1], [2]. The relationship between these complications and drug administration is often difficult to evaluate because of the anecdotal or retrospective nature of observations. In addition, since β-blockers are used in pregnancies having a major complication (e.g. severe hypertension), it can be very difficult to differentiate drug effects on the fetus from those caused by the underlying maternal disease.

This paper reviews pharmacokinetic and pharmacodynamic issues relevant to atenolol prenatal toxicity in humans and in experimental animal species with the aim of better understanding the origin of adverse developmental outcomes that have been associated with atenolol exposures in pregnancy.

Section snippets

General

Chemically, atenolol is a phenylacetamide [(4–2′-hydroxy-3′-isopropyl-aminopropoxy) phenylacetamide]. It is a relatively polar, hydrophilic compound. In adult nonpregnant subjects, the disposition of atenolol has been studied in humans and in several animal species: rats, mice, rabbits, dogs, and rhesus monkeys [3], [4].

The absorption of the drug upon oral administration in humans and most laboratory animal species is rapid but incomplete. Due to incomplete intestinal absorption, the systemic

General

Atenolol is a cardioselective beta1-adrenoreceptor blocking agent without intrinsic sympathomimetic activity. It has a markedly greater effect on cardiac than bronchial or vascular adrenoreceptors [22], [23] and reduces blood pressure mainly by reducing cardiac output, in contrast to the nonselective β-blockers that reduce blood pressure mainly by decreasing the peripheral vascular resistance [24]. Atenolol mainly causes its hypotensive effect by decreasing heart rate and cardiac contractility

Summary and conclusion

The comparability of developmental effects of atenolol in humans and in animal models is affected by animal/human pharmacokinetic/dynamic differences. Because of considerable differences in atenolol gastrointestinal absorption in dogs versus other animal species and humans, data collected in the dog need to be interpreted with consideration of the internal dose for extrapolation to humans if this experimental model is used for predicting human developmental effects. Although atenolol absorption

Acknowledgments

The authors are grateful to Drs. William Slikker, Deborah Hansen, John Young, National Center for Toxicological Research, Jefferson, AR, and Dr Hugh Barton, EPA, Research Triangle Park, NC, who have reviewed an earlier version of this paper.

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      Oral doses of atenolol are approximately 56% absorbed and subsequently eliminated by renal excretion. Most of an orally absorbed dose (85–100%) is eliminated in urine within 24 h. Thus, considering pharmacokinetic data such as renal clearance and distribution volume, atenolol urine concentrations may be from 10 mg L−1 to 40 or 60 mg L−1 [2–4]. Hence, spiked urine samples were diluted 1:100 in order to obtain equally spaced concentrations in the range 0–0.60 mg L−1, according to the previously checked linear concentration range.

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    The views expressed in this paper are those of the authors, and do not necessarily represent the views or policies of the US Environmental Protection Agency or the Food, and Drug Administration.

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