Reproductive Toxicology 15 (2001) 467– 478
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Review
Enalapril: pharmacokinetic/dynamic inferences for comparative developmental toxicity夞 A review Sonia A. Tabacovaa,*, Carole A. Kimmelb a
National Center for Toxicological Research, US Food and Drug Administration, 5600 Fishers Lane, Room 16-53, HFT-10, Rockville, MD 20857, USA b National Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, Washington, DC, USA
Abstract Enalapril is an antihypertensive drug of the class of angiotensin-converting enzyme inhibitors (ACEI) used in pregnancy for treatment of pre-existing or pregnancy-induced hypertension. The use of ACE inhibitors (drugs that act directly on the renin-angiotensin system) during the second and third trimester of pregnancy in humans is associated with specific fetal and neonatal injury. The syndrome, termed “ACEI fetopathy” in humans, does not appear to have a similar counterpart in experimental animals. The present paper reviews pharmacokinetic and pharmacodynamic aspects of enalapril that are physiologically important during pregnancy and intrauterine development in humans and in experimental animal species with the aim of better understanding the comparability of the manifestations of enalapril developmental toxicity in animals and humans. The human fetus is at a disadvantage with regard to in utero enalapril exposure in comparison to some of the animal species for which gestational pharmacokinetic data are available. Important reasons for the higher vulnerability of the human fetus are its accessibility by enalapril and the earlier (relative to animal species) intrauterine development of organ systems that are specific targets of ACEI pharmacologic effect (the kidney and the renin-angiotensin system). In humans, these systems develop prior to calcarial ossification at the end of first trimester of pregnancy. The specific pharmacodynamic action of enalapril on these systems during fetal life is the chief determinant of the etiology and pathogenesis of ACEI fetopathy in humans. In contrast, in most of the studied animal species, these target systems are not developed until close to term when the fetus is relatively more mature (and therefore less vulnerable), so that the window of vulnerability is narrower in comparison to the human. Among animal species, the best concordance in fetal pharmacodynamics to the human is seen in the rhesus monkey, but further studies are necessary to determine if similar developmental pathology is induced in this animal model upon repeated administration of the drug during the relevant period of intrauterine development. Animal-human concordance of developmental toxicity is least likely in the rat because of greater disparities in enalapril availability to the fetus and the relative development of the kidney and skeletal ossification compared to that in humans. © 2001 Elsevier Science Inc. All rights reserved. Keywords: ACE inhibitor; Enalapril; Pharmacokinetics; Pharmacodynamics; Developmental toxicity; Animal-human comparisons
1. Introduction The pharmacokinetic and pharmacodynamic properties of drugs and chemicals are important determinants of their developmental toxicity and are critical for extrapolating more accurately experimental animal data to humans in the process of risk assessment. The present paper reviews phar夞 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. * Corresponding author. Tel.: ⫹1-301-827-6697; fax: ⫹1-301-4433019. E-mail address:
[email protected] (S.A. Tabacova).
macokinetic and pharmacodynamic aspects of enalapril that are physiologically important during pregnancy and intrauterine development in humans and in experimental animal species. This review was undertaken with the aim of better understanding the comparability of the manifestations of enalapril developmental toxicity in animals and humans. Enalapril is an antihypertensive drug of the class of angiotensin-converting enzyme inhibitors (ACEI) used in pregnancy for treatment of pre-existing or pregnancy-induced hypertension. The use of ACE inhibitors (drugs that act directly on the renin-angiotensin system) during the second and third trimester of pregnancy in humans is associated with fetal and neonatal injury including hypotension, anuria, renal failure,
0890-6238/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S 0 8 9 0 - 6 2 3 8 ( 0 1 ) 0 0 1 6 1 - 7
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Fig. 1.
and death [1]. Oligohydramnios, presumably resulting from decreased fetal renal function, has been reported in association with fetal limb contractures, skull calvarial hypoplasia, craniofacial deformation, and hypoplastic lung development. The syndrome, termed “ACEI fetopathy” in humans [2], does not appear to have a similar counterpart in experimental animals. Most data on the developmental toxicity of ACE inhibitors in experimental animals and humans pertain to captopril. Less information with regard to animal and, particularly, human developmental toxicity is available for enalapril. Enalapril, (S)-1-[N-[1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-L-proline, belongs to the series of substituted N-carboxymethyl dipeptides. Enalapril is a prodrug, and is an ethyl ester of enalaprilat ((S)-1-[N-[1-carboxy3-phenylpropyl]-L-alanyl]-L-proline), the active angiotensin-converting enzyme inhibitor. Enalapril differs from captopril ((S)-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline) in that it lacks a sulfhydryl group (and mercapto function) that is thought to be responsible for the most common side effects of captopril [3,4]. The structural formulae for enalapril (as enalapril maleate, the salt used in clinical practice) and enalaprilat are shown in Fig. 1.
2. Pharmacokinetic aspects The active form of enalapril (enalaprilat) has potent and prompt activity when given i.v., but it is poorly absorbed from the gastrointestinal tract. To increase gastrointestinal absorption, enalaprilat was modified into the monoethyl ester form (enalapril), which is rapidly absorbed when given orally to humans and animals. In humans, the rate of gas-
trointestinal absorption is 60 to 70% for enalapril compared to less than 10% for enalaprilat [5]. These rates are very similar to those found in experimental animals: 5 to 12% for enalaprilat [6] and 39 to 64% for enalapril in rats and dogs [7,8]. Enalapril absorption is rapid. The Tmax (the time to maximal plasma concentration) for enalapril is 1 h (0.5 to 1.5 h), while the Tmax for enalaprilat is 2 to 8 h with a mean of 4 h [8]. Once absorbed, enalapril is rapidly metabolized by deesterification to the active form, enalaprilat [4]. This postabsorptive hydrolysis takes place in the liver, the most likely site for this conversion in animals (rat, dog) and humans [6]. Hydrolysis by plasma esterases has been demonstrated in the rat, however humans appear to lack this plasma esterase activity [6]. The first detectable concentrations in human serum after oral administration of enalapril are in the form of enalapril rather than enalaprilat [8], indicating that the drug is absorbed intact [4]. However, intact enalapril is almost undetectable in human serum 4 h after oral administration of the drug, while its major metabolite (enalaprilat) is detectable up to 96 h after oral enalapril exposure [8]. Unlike captopril, which has many metabolic products, it appears that the only major metabolite of enalapril is enalaprilat, as shown by studies reporting a 94% total accountability of the administered enalapril dose in the form of enalapril and enalaprilat [8]. Enalaprilat is also the endproduct of enalapril metabolism in humans and most animals, with the exception of the rhesus monkey, which is capable of metabolism beyond enalaprilat [4]. In this species, another active metabolite with a long half-life has been identified as a proline (a desprolyl compound) that represented approximately 16% of the radioactivity in urine [9]. The excretion of enalapril is primarily renal. In the human, 61% of the total oral enalapril dose is recovered in urine and 33% in the feces; 43% and 27%, respectively, are excreted as enalaprilat and the remaining 18% and 6%, respectively, are excreted as enalapril [8]. Most of the intact enalapril is excreted in the first 6 h, while enalaprilat is more slowly excreted over at least 96 h after administration. The fecal recovery of enalapril and enalaprilat represents the small quantity of unabsorbed drug and biliary excretion [4]. The latter has also been observed in rats and dogs [6]. In rats, an average of 26% of an oral enalapril dose of 1 mg/kg is excreted in the urine and 72% in the feces within 72 h after administration; in dogs, at the same oral exposure level, 40% and 36% of the dose are excreted in 72 h in the urine and feces, respectively. Within the same time period, monkeys excrete 25% and 37%, respectively, of a similar oral dose of [proline (UL) 14C]-enalapril [9]. Slight to negligible amounts of enalapril and its active metabolite are excreted in human breast milk. After a single oral enalapril dose of 20 mg (approximately 0.4 mg/kg for a body mass of 50 kg), the mean maximal milk concentrations for enalapril and enalaprilat were 1.74 and 1.72 ng/ mL, respectively [10]. The milk/serum ratio was 0 to 0.04 for enalapril, and 0.02 to 0.03 for enalaprilat. The peak
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levels for enalapril and enalaprilat in breast milk were attained 4 and 8 h, respectively, after an oral enalapril dose of 10 mg [10,11]. Excretion of the drug in milk was also shown in the rat. In lactating rats given a 10 mg/kg oral dose of 14C– enalapril, the drug concentration in milk averaged 0.09 and 0.36 g equivalents/mL at 1 and 4 h after dosing. The respective plasma enalapril concentrations in the rat were 3.64 and 0.59 g equivalents/mL, or a milk/plasma ratio of 0.02 to 0.6 [9]. This ratio is higher in comparison to those for other ACE inhibitors (e.g. captopril and imidapril) in the same species [12]. In general, enalapril pharmacokinetic parameters in adult animals and humans are similar with respect to absorption, metabolic transformation, and excretion. This similarity is also valid for human subjects with clinical indications for enalapril treatment, as the pharmacokinetics in patients with hypertension and congestive heart failure have been shown to be similar to those in healthy subjects [4]. Placental transfer of enalapril has been demonstrated in the human [13], nonhuman primate [14], sheep [15], and hamster [9]. Data on placental passage have not been reported in the rat for enalapril [16], and little passage through rat placenta (below 0.5% and 0.07% of the maternal plasma levels) has been found for other similarly structured ACE inhibitors, imidapril and quinapril, respectively [12,17]. In sheep, at maternal enalapril doses corresponding to the human therapeutic range and administered in late gestation (gestational day 128, term approximately 147 days), enalaprilat is undetectable in fetal plasma and enalapril is found in trace amounts, with unchanged fetal blood pressure and ACE activity [15]. In humans, a transfer rate of about 3% for the active metabolite (enalaprilat) has been reported in an ex vivo placental perfusion model immediately after delivery [13]. In that study, the first to quantify the placental transfer of ACE inhibitors in humans, the placenta was perfused with a medium containing enalaprilat at a level of 800 ng/mL (corresponding to the plasma concentrations observed at doses effective in the treatment of moderate hypertension). Enalaprilat was analyzed on the maternal and fetal sides at 1 to 3-min intervals during a period of 30 min; the area under the curve, maximum concentration, and the time to reach the maximum concentration were calculated in the maternal and fetal perfusion solutions. The data suggested that only small amounts of enalaprilat (2.9% of the maternal level) crossed to the fetal compartment, which was attributed to the highly hydrophylic properties of the compound [13]. Other authors however, have found higher rates of transfer of enalaprilat across the dually perfused human placental lobule. Enalaprilat levels in the fetal perfusate were approximately one-third the levels in the maternal perfusate after up to 6 h of perfusion (unpublished data of R. Miller and J. Manson, as cited in ref. 14). Higher rates of placental transfer in humans have also been implied by case studies reporting enalaprilat levels in neonatal plasma corresponding to the expected enalaprilat concentration in the maternal plasma after maternal oral enalapril treatment at a
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dose of 10 mg/day before delivery [18]. Such higher rates of enalaprilat placental transfer have also been found in nonhuman primates. After a single i.v. administration of enalaprilat to pregnant rhesus macaques between gestational days 122 and 126 (term 167 days), at doses of 0.05 to 0.2 mg/kg, the area under the curve values for fetal plasma enalaprilat were 50% to 65% of maternal values across dose groups [14]. The peak plasma level (136 ng/mL), achieved in maternal primate plasma at a dose of 0.05 mg/kg enalaprilat, was higher than the maximum serum concentration of enalaprilat in humans (30 to 40 ng/mL) after a single oral enalapril dose of 10 mg to hypertensive patients [19]. However, it was similar to the maximum enalaprilat concentration found in human serum (150 ng/mL) after a therapeutic dose of oral enalapril at 40 mg/day [14]. Even if the placental transfer rate in humans is in the lower range of reported values, human fetal concentrations at maternal therapeutic doses would be above the therapeutic dose for newborns, which is 10 to 100 times lower than the adult dose, on a mg/kg basis [13]. Therefore, in the human, enalaprilat crosses the placenta in amounts pharmacologically significant for the fetus that are above the range needed to correct severe hypertension in children [13]. This is important because it shows that, within the maternal therapeutic dose range, the active metabolite could reach the fetus at concentrations sufficient to induce fetal hypotension. In addition, as shown in nonhuman primates [14], the retention of enalapril in fetal plasma is approximately 3 to 4 times longer than in the maternal plasma (mean residence time 2.2 to 2.4 h versus 0.6 to 0.8 h, respectively). This is due to slower urinary excretion because of physiologically low renal perfusion in the fetus [14]. Furthermore, after renal excretion into the amniotic fluid, the agent is swallowed and recirculated in the fetus [20]. The direct availability of enalaprilat to the fetus in pharmacologically active concentrations and for sufficient time periods would obviously be important in the pathogenesis of fetal developmental disorders. The fact that the agent is available through transplacental passage to the fetus in humans and in nonhuman primates (rhesus monkey) favors the predictive value of the rhesus monkey to the human in developmental toxicity studies. The sheep model may not be specifically informative about enalapril developmental effects in the human because of the lower transfer of the drug into the fetal compartment in sheep compared to humans [18]. The lack of data on placental transfer in the rat does not allow assessment of the appropriateness of this experimental model. Although nonhuman primates show otherwise good pharmacokinetic correspondence to the human, the rhesus monkey is capable of metabolizing enalapril beyond enalaprilat, while the human is not. Thus, the human fetus seems to be at a disadvantage with regard to direct in utero exposure in comparison to animal species with uncertain (rat) or minimal (sheep) placental transfer of enalapril. The generally low transplacental pas-
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Fig. 2. The renin-angiotensin-bradykinin system. ECF ⫽ extracellular fluid (Reprinted by permission of Teratology, from Barr M, Jr: Teratogen update: Angiotensin-converting enzyme inhibitors. 50:399 – 409, 1994)
sage of enalapril in comparison to other ACE inhibitors (e.g. captopril) is explained by its poor lipid solubility [15].
3. Pharmacodynamic aspects 3.1. Mechanism of action and pharmacologic effect Enalapril has antihypertensive properties because its active metabolite (enalaprilat) inhibits angiotensin-converting enzyme (ACE) that generates the powerful vasoconstrictor substance angiotensin II (A II) from the inactive precursor angiotensin I (A I), and also inactivates the vasodilating substance bradykinin [3]. By inhibiting ACE, the drug disrupts the renin-angiotensin system (RAS) cascade, a major physiologic regulator of vascular tone and mineral metabolism (Fig. 2). The first step of the RAS cascade [21,22] is the formation of decapeptide A I from its precursor, angiotensinogen (an ␣-2 globulin of hepatic origin), which is catalyzed by renin, a proteolytic enzyme of renal (juxtaglomerular cell) origin. A I has minimal vasoactive properties and no known biologic action in humans, but is rapidly converted to the biologically active octapeptide, A II. This conversion is catalyzed by ACE, a dipeptidyl carboxylpeptidase-converting enzyme that is a zinc metalloprotease. Plasma and cellular ACE levels are genetically determined. ACE exists as two isozymes—somatic (endothelial) and a shorter, testicular—that are transcribed from a single gene by differential utilization of two different promoters [23–25]. While testicular ACE is found only in the germinal epithelium of the testis and its function is not clear [26], somatic ACE—an ectoenzyme present in vascular endothelial cells and most other tissues—plays a central role in the RAS by activating the conversion of A I to A II and inactivating bradykinin [27]. The principal substrates for ACE are A I and the nonapeptide bradykinin (a vasodilating substance). A II is a potent vasoconstrictor (arterial and venous) and stimulates aldosterone secretion from the adrenal cortex. Aldosterone
acts on the distal renal tubules to increase sodium retention and potassium excretion. This suppresses renin release, thus providing a negative feedback. A parallel system involves the formation of bradykinin and its inactivation by ACE (Fig. 2). Bradykinin is involved in prostaglandin formation. A II raises blood pressure, while bradykinin and prostaglandins lower blood pressure. The renin-angiotensin system is an important physiologic mechanism in the homeostatic regulation of blood pressure and the electrolyte composition of body fluids. The potent hypotensive effect of enalaprilat is due to both systemic vasodilatation and a decrease of aldosteronemediated sodium reabsorption in distal renal tubules (through reduction of A II-stimulated aldosterone secretion from adrenal cortex) [4]. The mechanism of action and pharmacologic effect in adults are similar in humans and laboratory animals. Among the latter, the rabbit is more sensitive to the drug than the rat and dog. The ED50 for blockage of the pressor response to exogenous A I by enalaprilat in adult rabbit, rat, and dog are 2.0, 5.1, and 6.4 mg/kg, respectively [18]. For comparison, in humans, oral enalapril doses of 10 and 20 mg/day (approximately 0.1 to 0.3 mg/kg for a 70-kg person) are sufficient to completely block ACE and physiologic responses to exogenous A I, including the pressor response [28]. Given the less than 100% absorption and metabolic conversion of absorbed enalapril into enalaprilat, the approximate dose of enalaprilat sufficient to block the pressor response in the human would be lower than 0.1 mg/kg. The pharmacologic effect of enalapril is characterized by: Y Delayed onset and duration of the hemodynamic effect in comparison to captopril because enalapril is a prodrug that has a much later peak effect and a longer duration of action [4]; Y Good dose-effect dependence: within the range from 1 to 10 mg/day, there is a linear correlation between concentration of the active metabolite (enalaprilat) in human plasma, percentage inhibition of plasma ACE activity, and physiologic responses (blood pressure, pressor response to exogenous angiotensin I, plasma aldosterone, and renin activity) [28 –30]; Y Plateau effect at human doses higher than 10 mg/day: No significant differences between physiologic responses to enalapril at oral doses of 10 and 20 mg/day have been found in humans, suggesting that drug concentrations are attained that are sufficient to completely block angiotensin-converting enzyme. Larger doses of enalapril do not further decrease the blood pressure level but prolong the duration of the hypotensive effect [28 –30]. The existence of a plateau in the pharmacologic action of enalapril with increasing dose should be taken into account in interpreting its developmental effects. Because the adverse fetal effects of enalapril are a consequence of the
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pharmacologic action of its active metabolite [16,31] (see part 3.3), the plateau effect might be misinterpreted as a lack of dose-effect relationship at dose levels above the therapeutic dose range. Such dose levels are often employed in animal experiments. 3.2. Physiologic role of the renin-angiotensin system in pregnancy and fetal life Since the key event in the pharmacodynamics of enalaprilat is disruption of the renin-angiotensin system in the human as well as in animal species, understanding the function and physiologic role of this system in pregnancy and prenatal development is of importance for understanding the pathogenesis of enalaprilat-induced developmental disorders as a prerequisite for comparison of animal and human effects. In the adult animal and human, the renin-angiotensinaldosterone system is known to play an important role in the maintenance of blood pressure, blood volume, and sodium homeostasis [32,33], and to participate in the control of renal hemodynamics and glomerular filtration [34]. Pregnancy is unlike the nonpregnant state where the concentration of plasma renin and angiotensin II are regulated by extracellular volume or sodium balance. In human pregnancy, persistent unsuppressed secretion of renin, and consequently, of angiotensin II and aldosterone occurs in spite of the expansion of extracellular volume and increased sodium delivery to the distal renal tubules [35]. During pregnancy, there is a physiologic increase of renin, angiotensin II, and prostaglandin E2 (PGE2) in the plasma and uterus of women and pregnant animals (rabbit, dog) [36 – 40]. Angiotensin II is known for its regulatory effect on placental prostaglandin synthesis. It preferentially stimulates the release of PGE2 over PGE1. In addition, angiotensin II-vasoconstrictor effects are mediated in part by placental prostaglandins [41]. The physiologic role of elevated A II and PGE2 synthesis during pregnancy is of importance in the maintenance of arterial pressure and also in regulating the uteroplacental blood flow essential for embryo/fetal survival and development [35]. Angiotensin II increases uterine blood flow in pregnant rabbit, dog, and monkey [36,42,43]. This effect may be mediated by uterine prostaglandins since A II increases PGE2 synthesis in the uterus. The dependence of uterine PGE2 synthesis on A II and the importance of uterine A II and PGE2 for maintenance of uteroplacental blood flow and fetal survival have been demonstrated in the rabbit and primates [44]. When A II synthesis is blocked, there is a fall in uterine PGE2 synthesis, a decline in uterine blood flow, and a rise in fetal mortality [35]. Although the angiotensin II level is elevated physiologically during pregnancy, the normal pregnant woman develops vascular refractoriness to its pressor effects [20,45], which is thought to be a consequence of decreased vascular
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smooth muscle responsiveness [46] and increased synthesis of vasodilating prostaglandins [35]. Women who develop pregnancy-induced hypertension (and therefore are likely candidates for enalapril therapy) begin losing their A II refractoriness several weeks before hypertension develops [47]. The enhanced A II sensitivity is due to an increase in A II receptor number [48] that could be explained by the reduced A II and PGE2 synthesis found in hypertensive pregnancy complications, such as toxemia, in association with uterine hypoperfusion and higher fetal mortality [35]. Thus, the most likely users of antihypertensive drugs, including ACE inhibitors, during gestation would be women with hypertensive pregnancy complications who already have low background levels of angiotensin II (due to the pregnancy complication per se) and an elevated background risk of associated adverse fetal effects. ACE inhibitors would add a further decrease in the already lower A II, which is physiologically necessary for normal fetal development. While there have been no animal studies on enalapril embryofetal effects using models of maternal hypertension, most of the human case reports come from enalapril-treated cases of pregnancy hypertension. This fact should be taken into account in the animal-human comparison of enalapril (as well as other ACE inhibitor)-induced fetopathies. Since animal experiments for developmental toxicity assessment are carried out in healthy animals, it could be expected that at equal exposure levels, the adverse effect would be lesser in experimental animals than in the human. A misinterpretation of this as a manifestation of higher sensitivity to the drug in the human in comparison to animals may result. Such a conclusion would be confounded by the underlying maternal disease which, in the case of pregnancy-induced hypertension or pre-eclampsia, might produce background pathophysiologic changes in the fetal compartment concordant with the specific pharmacodynamic action of enalapril. During fetal life the renin-angiotensin system is active and can be stimulated in a manner similar to that in the adult [49,50]. The ACE gene is developmentally regulated. Autoradiographic studies have shown a high transient expression of angiotensin II receptors in mouse, rat, and primate fetuses [51–53]. There are two known types of angiotensin II receptor, type 1 (AT1) and type 2 (AT2) [54]. The AT1 receptor type mediates all known effects of angiotensin II on water and salt homeostasis and blood pressure. A physiologic function for the AT2 receptor is unknown, but its abundance in the fetus has suggested a role in fetal growth and differentiation [55]. AT1 receptor mRNAs have been detected in target organs of the renin-angiotensin system (e.g. kidney, adrenal gland, heart, arteries, and pituitary gland) in the 19-day-old rat fetus [56]. The widespread distribution of AT1 receptors in tissues and organs involved in hydro-mineral equilibrium and blood pressure regulation has been interpreted as an indication that, during fetal development, A II may already act as a regulator of RAS and
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hemodynamics [56]. In the fetal and neonatal period, the activity of the RAS is elevated in comparison to adult levels. Such evidence has been provided by human studies [41], as well as by studies in the rat [57] and lamb [21,58]. However, ontogeny studies have demonstrated that while renal renin synthesis is highly activated at birth and during early postnatal development in several species [59,60], angiotensinogen gene expression in the rat is low at birth [61] and increases with age, the time of weaning (days 20 to 21), being temporally associated with the activation of the ACE gene in this species [62]. What is the physiologic significance of the high activity of the RAS during fetal maturation? There are a number of important factors: Y The RAS plays an essential role in maintaining glomerular filtration and urine production under the conditions of low renal perfusion pressure typical for fetal life [20]. After the onset of fetal renal function at about 10 weeks gestation in the human, fetal urine is the main constituent of amniotic fluid [63]. RAS regulates fetal renal hemodynamics and renal function through angiotensin II, which stimulates aldosterone secretion during fetal development and modulates fetal glomerular filtration rate by controlling renal arteriolar tone [64]. Angiotensin II levels, in turn, are regulated by ACE activity, known to be present in fetal vascular endothelium of humans and different animal species, e.g.: rat [65], rabbit [66], guinea pig [67], and sheep [68]; Y The RAS is important in the control of umbilicalplacental circulation, fetal blood pressure, and cardiovascular function in human and animal species (rabbit, sheep) [21]; Y Angiotensin II acts as a growth factor toward its target tissues (e.g. adrenals) and promotes angiogenesis [20]. Angiogenesis promotion could be of critical importance for the fetus and placenta due to the significant vascularization during gestation; Y Angiotensin II is known for its regulatory effect on prostaglandin synthesis, and prostaglandins (PGE2) play an important role in maintaining the patency of the ductus arteriosus during fetal life [69]; Y The ACE gene plays a role in the regulation of fetal renal growth and function [62]. In summary, the RAS plays an important physiologic role in fetal development. This role appears to be similar in humans and in animal species commonly used for laboratory assessments, and thus provides a reliable basis for animal-to-human comparisons of the developmental consequences of fetal RAS disruption. However, the ACE gene that regulates development of an important RAS component (ACE activity), exhibits polymorphism in human populations, and the prevalence of gene types for high or low ACE activity varies in different populations [70]. In humans, ACE inter-individual variability in plasma or cellular levels
is quite high [71,72], which is associated with an insertion/ deletion (ID) polymorphism of a 287 bp fragment in intron 16 of the ACE gene [73]. Subjects homozygous for the deletion (DD) display the highest values and those homozygous for the insertion (II) display the lowest, with heterozygotes displaying intermediate ACE levels [74]. It has been estimated that the ID polymorphism accounts for about 28% of the variance in ACE activity in a normal Caucasian population [75]. The insertion allele variant (II) might account for 44% of the circulating ACE activity among Caucasians; among Chinese, the prevalence of the insertion allele is much higher than that among Caucasians [70]. Thus, the amount of circulating ACE appears to be determined, at least in part, by the ID genetic polymorphism. The impact of this polymorphism on the sensitivity to ACEIinduced fetopathy has not been studied, but it could be a source of a greater variability in fetal response to ACE inhibition in the human in comparison to laboratory animals. 3.3. Pathogenesis of adverse fetal/neonatal outcomes of prenatal ACE inhibition Enalaprilat, as an ACE inhibitor, competitively blocks the conversion of angiotensin I to angiotensin II, and thus decreases the production of angiotensin II and aldosterone. When administered during pregnancy, the drugs of this class induce fetal hypotension and decrease uterine blood flow and glomerular filtration pressure (GFP) [76] as a consequence of ACE inhibition. The decrease in GFP can severely impair renal function in the fetus. Renal function is present prenatally in humans as well as in animal species. In the human fetus, urine formation, glomerular filtration, and tubular function start at approximately 10 weeks (between 9 and 12 weeks) of gestation [63]. The greater sensitivity of the immature kidney to vasoactive drugs is accounted for by certain functional characteristics of the kidney during gestation and postnatal maturation. Renal blood flow and perfusion pressure are physiologically low in the human fetus during gestation [77] and in early postnatal life [69]. This has also been confirmed in the fetal lamb [78]. When renal perfusion pressure is low, the renin-angiotensin system is important in regulating the glomerular filtration rate [79,80]. To maintain glomerular filtration rate and urine output, A II mediates efferent renal arteriolar constriction, which is critical for maintaining glomerular filtration and urine output in the low perfusion pressure conditions of the fetal kidney [77]. High concentrations of A II are physiologically necessary to maintain glomerular filtration rate at low perfusion pressures. Correspondingly, the activity of RAS is physiologically high in fetal and early postnatal life [69]. ACE inhibitors reduce the concentration of angiotensin II, thus reducing glomerular filtration [76,80], which in turn causes a decrease in fetal urine output and reduction in amniotic fluid volume (oligohydramnios), the most frequent
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feature of the ACE fetopathy syndrome. A prolonged reduction in glomerular filtration rate can impair renal tubular development and further diminish urine production [81]. Renal tubular defects (distal tubular hypoplasia) have been observed in infants exposed in utero to enalapril [2,76]. These renal defects are secondary to reduced renal blood flow rather than a direct effect of the drug on renal development [76]. Fetal renal dysfunction is the initial and leading event in the pathogenesis of the fetopathy syndrome induced by ACE inhibitors, including enalaprilat, and triggers the development of other specific features of this syndrome. The clinical manifestations of this fetopathy in humans (renal tubular dysgenesis, oligohydramnios and its sequelae—limb contractures, delayed development of calvarial bones, pulmonary hypoplasia, intrauterine growth retardation, neonatal anuria) are secondary to the dysfunction of the fetal kidney and RAS as a result of ACE inhibition [2,16,31]. They are a consequence of the pharmacologic effect of this class of drugs on fetal functions, and not a result of a direct dysmorphogenic effect. Therefore, the observed adverse fetal effects are not manifestations of teratogenicity (i.e. malformations characteristic of exposure during organogenesis)— hence the term “fetopathy” is used to describe the syndrome in humans [16]. There are several conclusions to be drawn with regard to animal-human comparisons: (a) if the drug is not teratogenic in the classic sense in humans, an absence of teratogenic effect in experimental animals would be concordant with the human situation; (b) because altered fetal renal function is the primary event, treatment during the period of organogenesis would not be likely to produce morphologic effects in either humans or experimental animals since renal and RAS functions develop after the period of major organogenesis; (c) because this fetopathy is induced by a direct pharmacologic action on fetal physiology, the fetal effect would depend on species sensitivity to the pharmacologic action of the agent, and (d) the drug should be present in the fetal compartment in order to induce an effect (thus, species with absent transplacental passage of enalapril, would not be expected to develop fetal pathology comparable to the human). The primary mechanism by which ACE inhibitors (including enalapril) impair fetal renal function is through a decrease of blood flow [76]. Human evidence suggests that fetal and neonatal mortality and fetopathy manifestations are related to severe fetal hypotension during the second and third trimester [2,31]. Animal studies indicate that ACE inhibitors reduce uterine blood flow and induce fetal hypotension in the rabbit [35], lamb [82], and guinea pig [83]; the rat has not been studied in this respect. In the rhesus monkey, exposure to a single i.v. dose of enalaprilat during the third trimester of pregnancy produces fetal hypotension even in the absence of maternal hypotension or alteration of any other maternal cardiovascular parameter [14], suggesting that in this species, similarly to the human, the fetal effect is not secondary to a maternal effect. The end result
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of these pharmacodynamic effects is a decreased afferent fetal renal blood flow leading to decreased glomerular filtration pressure [76]. Fetal hypotension has been considered to be the cause of fetotoxicity (intrauterine growth retardation and fetal mortality) induced in the rabbit and the baboon by maternal enalapril treatment during gestation [84, 85]. Therefore, there is a similarity between humans and some animal species in the fetal pathophysiologic response to ACE inhibitors, which provides justification for comparison of human data with data obtained from these species. The best concordance in fetal pharmacodynamic response to the human is seen in the rhesus monkey, suggesting that this species may be a good model for ACEI fetopathy in humans. We have not found data from similar studies in the fetal rat, nor information to indicate if the same fetal pathophysiologic mechanism is valid for this animal model, although renal histopathologic changes (juxtaglomerular cell hyperplasia) have been observed in the rat with prenatal exposure to an ACE inhibitor, quinapril [17]. The adverse effect on fetal kidney is specific for ACE inhibitors. ACE inhibitors, including enalapril, produce fetopathy not merely through fetal hypotension, but by selectively affecting the renal perfusion pressure [14]. For example, calcium channel blockers, such as nifedipine, are commonly used to treat hypertension in pregnancy but have not been reported to produce the fetopathy described with ACE inhibitors, although they produce fetal hypotension at maternal therapeutic doses [86,87]. These agents produce hypotension by dilation of coronary and peripheral vessels with minor effects on fetal renal vascular tone [14]. By contrast, ACE inhibitors act primarily on renal vascular tone. The precapillary arteriolar constriction, a primary microvascular effect of angiotensin II, is strongest in the kidney [88]. Therefore, unless a decrease of fetal renal vascular tone is involved, fetal hypotension alone is not sufficient to produce the adverse renal effects and fetopathy syndrome typical for ACE inhibitors. This specificity of effect is important in evaluating outcomes in case of maternal coexposure to other antihypertensive drugs in addition to enalapril during pregnancy and comparing them to outcomes in animal studies. Co-exposure to other drugs is often the case in human studies, while animal studies commonly involve exposure to a single agent. The fetal effects of enalapril are time-specific. Fetal sensitivity to ACE inhibitors increases with the maturation of renal development and the RAS in both human and animal species. Renal tubular function begins in the human kidney between gestational weeks 9 and 12 [89]. Loss of glomerular filtration likely would not be significant until tubular function begins. This may explain why there are no reported cases of renal dysfunction in infants whose mothers discontinued ACE inhibitors in the first trimester [76]. Similarly, in experimental animals (sheep, rabbit), ACE inhibition has different effects on renal hemodynamics and function in early and near-term fetuses [21]. Lamb fetuses of less than
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120 days gestation (term 147 days) are insensitive to the effect of ACE inhibition on renal hemodynamics because plasma A II levels are low and the tonic effect of A II on renal vasculature is minimal early in gestation, but increases later as plasma A II rises. In near-term fetuses (⬎130 gestation days), ACE inhibition decreases renal vascular resistance, arterial blood pressure, and plasma aldosterone concentrations. Similarly, in the fetal rabbit, renal ACE activity and intrarenal formation of A II are low early in gestation but increase as the kidney matures [66]. The period of sensitivity of the rabbit fetus to the toxic effects of enalapril is limited to middle- and late gestation, with treatment on gestational day 26 resulting in 100% fetal death [84]. This is after the period of typical organogenesis treatment in segment II rabbit studies (g. days 6 through 19). Therefore, the timing of gestational exposure to enalapril would be of crucial importance for producing fetal renal impairment and the associated syndrome of fetopathy. Exposures during the period of major organogenesis are not likely to produce fetal renal impairment in either humans or animals. The timing of typical treatment in the segment II rat developmental toxicity studies (gestation day 6 through 17) would be inadequate for producing an effect by enalapril. Such an effect would be expected with exposures during late gestation, and even after birth, corresponding to the time of development and maturation of renal function and the RAS in this species [16,31]. RAS development in humans starts around the end of the first trimester of pregnancy but it develops much later in the rat, gestation day 19 being the critical period of fetal rat renin synthesis [57,59,90]. Renal development (nephron formation) in humans is completed before birth (gestational days 224 through 252), while in the rat it extends into the postnatal period, and the end of nephron formation takes place about postnatal day 10 [91]. This probably accounts for the fact that in the rat, postnatal (lactational) rather than prenatal enalapril exposures have produced functional and morphologic renal abnormalities, manifested in adult life [92], while in humans such effects are induced by prenatal exposures and manifested prenatally and at birth [93]. It is possible that the unique feature of human fetopathy produced by ACE inhibitors—i.e. excessive calvarial hypoplasia— could be explained by earlier maturation of renal and RAS function relative to bone development in the human. In humans, the permanent kidney (metanephros) begins to develop early in the fifth gestational week and starts functioning about four weeks later, well before the beginning of calcarial ossification that starts by the end of the twelfth week of pregnancy [63]. In contrast, in the rat, the onset of metanephric function is on day 17 of gestation (term day 21), after ossification has already begun [91]. Thus, in the human, the critical period for affecting the renal system and RAS would precede the period of calcarial bone formation. There is
an increasing body of evidence that angiotensin II may act as a local growth factor with respect to bone cell proliferation in human and rat cell populations [94,95]. The importance of the RAS in vascular development could also be of greater consequence for skull membranous bones that, in contrast to long bone formation, require abundant vascularization [16]. In the rat near the end of gestation, membranous bone formation is well advanced. It is likely that the interspecies differences in the relative developmental timing of target organ systems rather than interspecies differences in the mechanism of action of the drug are responsible for these animal-human differences in enalapril developmental toxicity manifestations. This view is based in part on reports that angiotensin II has a potent stimulatory effect on the proliferation and function of osteoblastic precursor cells from both rodent and human bone tissue in vitro. These effects have been observed in fetal rat calvarial bone cells [94], murine osteoblast-rich cells [95] as well as in human bone cells [94], indicating that they are not limited to a certain species. Therefore, the interspecies differences in the relative developmental timing of critical organ systems and how they relate to the timing of exposure should be taken into account in any animal-human or interspecies comparison of enalapril prenatal effects.
4. Summary The adverse prenatal effects of enalapril are a result of its pharmacologic effects on maternal-fetal physiologic functions rather than of a specific dysmorphogenic activity of the agent. The similarity of pharmacodynamics of the drug in humans and animals justifies animal-to-human comparisons of developmental effects and implies a similarity in the pathogenesis (mechanism of induction) of adverse effects on the conceptus. However, animal-human differences in fetal response to enalapril stem from differences in pharmacokinetics of the drug, as well as in fetal sensitivity, which is dependent on the relative developmental stage of vulnerable systems (RAS, renal, and skeletal) at the time of exposure. Because the primary event in the pathogenesis of adverse human developmental effects specific for enalapril is the direct impairment of fetal renal function and urine production leading to decreased amniotic fluid volume and features of fetal damage secondary to oligohydramnios, the agent must directly reach the fetus in order to induce the specific effects that characterize enalapril fetopathy. If the agent does not reach the fetus, it can possibly affect its development through maternal pharmacologic effects (most likely by affecting maternal and uteroplacental hemodynamics), but the specific features of the enalapril fetopathy syndrome are not likely to be produced.
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The development of specific fetal damage would therefore depend on availability of enalapril to the fetus and the timing of this availability relative to the critical period of development of fetal renal function and RAS. There are animal-human differences in both availability (because of different pharmacokinetics) and critical periods of exposure (because of developmental time differences of systems that play a key role in the pathogenesis of enalapril fetopathy). In general, the human fetus would be expected to be more vulnerable to enalapril in comparison to experimental animals for the following reasons: Y Greater placental transfer in humans in comparison to other species. Because of the higher rate of placental transfer of enalapril, the direct effect on the fetus would be greater in humans in comparison to animal species with lesser or uncertain placental passage of the agent, such as sheep and rat. In these species, adverse prenatal effects would be predominantly, or even exclusively, maternally mediated. If there is no direct effect on fetal kidney, fetal renal function would not be impaired, fetal urine production would not decrease, and oligohydramnios with its related sequelae (constituents of the typical human fetopathy syndrome) would not develop. Therefore, clinical manifestations similar to ones noted in humans would not be expected, although embryo/fetal survival and development may be impaired through the effect of enalapril on maternal hemodynamics and uteroplacental blood flow. There is no information available on enalapril placental transfer in the rabbit, but if it exists, this species might be more appropriate as a model because of its higher sensitivity to enalapril pharmacologic effects in comparison to rat, sheep, and dog. Y Earlier development of renal function and the reninangiotensin system in the human fetus in comparison to other species. In the human, development of renal function and RAS occurs immediately after major organogenesis, by the end of the first trimester, while in animal species, e.g. sheep and rat, the critical period for prenatal RAS development is near term. In the rabbit, fetal sensitivity to enalapril begins a little earlier—at mid to late gestation, suggesting that the rabbit would be a more appropriate experimental model compared to the rat and sheep. The earlier development of organ systems that are specific targets for enalapril pharmacologic action in the human, would make the human fetus vulnerable to enalapril at an earlier developmental stage and for a longer period of time. Y Background maternal health state. Pregnancy-induced hypertension, which is a typical indication for enalapril treatment, provokes by itself pathophysiologic changes in RAS and ACE activity and increases
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the risk of associated adverse fetal effects. This unfavorable background would aggravate and augment enalapril-induced effects in the human fetus, while experimental animal studies, typically done in healthy animals, do not provide a comparable background. Other factors that are expected to interfere with animalhuman comparisons include: Y Greater variability of enalapril developmental effects would be expected in human populations because of genetic heterogeneity in the ACE gene and different background levels of ACE activity in different population groups. Y Co-exposure to other drugs is likely in human populations. Hypertension in pregnant patients is most often treated with a combination of drugs, in contrast to animal developmental toxicity assessment studies that routinely use single agent exposures. Discerning the effects of ACE inhibitors may be possible however, because of their specificity for the human fetopathy syndrome which is not induced by other antihypertensive drugs.
5. Conclusion In conclusion, the pharmacokinetic and pharmacodynamic characteristics of enalapril in humans and in animal species are suggestive of a higher vulnerability of the human fetus compared to animal models. On the basis of existing data, there is no animal model that would be an “ideal” predictor of enalapril (and ACEI) developmental toxicity in humans. Among animal species, the best concordance in fetal pharmacodynamics to the human is seen in the rhesus monkey, but further studies are necessary to determine if similar developmental pathology is induced in this animal model upon repeated administration of the drug during the relevant period of intrauterine development. The human fetus is at a disadvantage with regard to in utero enalapril exposure (essential for enalapril developmental toxicity) in comparison to some of the animal species for which gestational pharmacokinetic data are available. Important reasons for the higher vulnerability of the human fetus are its accessibility by enalapril and the earlier (relative to animal species) intrauterine development of organ systems that are specific targets of ACEI pharmacologic effect (the kidney and the renin-angiotensin system). In humans, these systems develop prior to calcarial ossification at the end of first trimester of pregnancy. The specific pharmacodynamic action of enalapril on these systems during fetal life is the chief determinant of the etiology and pathogenesis of ACEI fetopathy in humans. In contrast, in most of the studied animal species, these target systems are not developed until close to term when the fetus is relatively more mature (and therefore less vulnerable), so that the
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window of vulnerability is narrower in comparison to the human. Animal-human concordance of developmental toxicity is least likely in the rat because of greater disparities in enalapril availability to the fetus and the relative development of the kidney and skeletal ossification compared to other animal species. The above conclusions for animal to human comparisons of enalapril prenatal effects rest on pharmacokinetic/pharmacodynamic inferences and remain to be verified by a comparison of actual manifestations of enalapril developmental toxicity in humans and animal species, which is a subject of our ongoing study.
Acknowledgments The authors are grateful to James Laborde and Drs. John Young and William Slikker, National Center for Toxicological Research, Jefferson, AR, who have reviewed an earlier version of this paper.
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