Pharmacokinetics of angiotensin converting enzyme inhibitors

Transcription

1 Br. J. clin. Pharmac. (1989), 28, 133S-140S Pharmacokinetics of angiotensin converting enzyme inhibitors M. BURNIER, B. WAEBER, J. NUSSBERGER & H. R. BRUNNER Division of Hypertension and Cardiovascular Research Group, University Hospital, Lausanne, Switzerland 1 The pharmacokinetics of most ACE inhibitors have been evaluated indirectly by the measurements of plasma ACE activity and circulating levels of angiotensin I and II. 2 Although plasma ACE activity is very useful to study the degree and the time-course of ACE inhibition, one has to be aware that very different results can be obtained depending on the substrate employed in the assay. It is therefore impossible to compare the results of different inhibitors unless an identical methodology is used. 3 A clear dissociation between plasma angiotensin II levels and the antihypertensive effects of ACE inhibitors has been reported. This observation is in part linked to problems with the measurement of angiotensin II. New methods of determination of plasma angiotensin II have now allowed demonstration of the complete disappearance of plasma angiotensin II following acute ACE inhibition. During chronic treatment, however, angiotensin II generation is effectively blocked only during part of the day, but blood pressure remains controlled permanently. 4 Among the different pharmacokinetic characteristics of ACE inhibitors presently available, the route of excretion and to a lesser degree the half-life appear to be the most clinically relevant. However, the importance of the ability of ACE inhibitors to inhibit tissue renin-angiotensin systems remains to be defined. Keywords pharmacokinetics ACE inhibitors Introduction Prevention of angiotensin II formation by angiotensin converting enzyme (ACE) inhibitors is now a well accepted approach to the treatment of hypertension and congestive heart failure. Since the original description of teprotide and captopril (Ondetti et al., 1971), numerous new molecules have been developed which effectively block ACE activity (Brunner et al., 1985). The new compounds differ essentially by their pharmacokinetic characteristics. Whether there also exist differences in pharmacodynamics is less clear. The pharmacokinetics of ACE inhibitors have been evaluated in normal volunteers or hypertensive patients using various indirect and direct methods (Belz et al., 1988). With most compounds, the components of the renin-angiotensin system (RAS) including ACE activity, angiotensin I and II and plasma renin activity have been determined before and during ACE inhibition. Whenever possible, these biochemical determinations have been correlated with measured plasma drug concentrations to establish a concentration-effect relationship (Biollaz et al., 1982; Bussien et al., 1985; Nussberger et al., 1987). The in vitro measurement of plasma ACE activity appeared to be a useful means to determine the degree of RAS blockade and has been used extensively for the purpose of characterizing pharmacokinetics although evidence is accumulating which suggests that it is not necessary to suppress ACE activity permanently to decrease blood pressure (Boomsma et al., 1981; Waeber et al., 1980). Recently the reliability of conventional in vitro ACE activity measurements to assess the degree of ACE inhibition has been Correspondence: Dr M. Burnier, Division of Hypertension, C H U V, 1011 Lausanne, Switzerland 133S

2 134S M. Burnier et al. questioned because of potential technical problems. An important aspect of converting enzyme inhibition is the clinical dissociation between the time course of ACE inhibition and the duration of the antihypertensive effect (Unger et al., 1986; Waeber et al., 1980). Alternating normal and suppressed plasma angiotensin II levels have been reported during chronic converting enzyme inhibition in patients with a clearly continuous optimal blood pressure control (Nussberger et al., 1985). This observation has led some authors to postulate other mechanisms than the disappearance of circulating angiotensin II to be responsible for the antihypertensive effect of ACE inhibitors (Campbell, 1987; Unger et al., 1986). However, before considering other possible mechanisms of action, one has to take into account the difficulties linked to the determination of plasma angiotensin II. Finally, when confronted with the large number of ACE inhibitors presently available with their various chemical structures and their specific pharmacokinetic properties, an obvious question immediately arises i.e. are the differences between ACE inhibitors of any clinical relevance? The problems linked to plasma ACE angiotensin II determinations and the clinical significance of different pharmacokinetics will be discussed in the present review. Pharmacokinetics of ACE inhibitors: problems with the measurement of ACE activity Several indirect approaches have been used to study the pharmacokinetics of ACE inhibitors. At first glance, monitoring of the changes in blood pressure would appear to be the easiest and most direct way. However, the participation of the RAS in blood pressure maintenance may vary considerably from one individual to another depending mainly on the dietary salt intake (Brunner et al., 1972). Thus, some volunteers or patients may decrease their blood pressure, whereas others do not and this in response to an identical degree of RAS blockade (Case et al., 1977). Furthermore, it is well recognized today that particularly after prolonged therapy there exists a clear dissociation between the time course of ACE inhibition and that of blood pressure reduction (Waeber et al., 1980). Therefore, blood pressure recordings cannot be used easily to evaluate the pharmacokinetics of ACE inhibitor at least in normal volunteers and patients with essential hypertension. Blockade of the blood pressure response to exogenous angiotensin I has been used in the first studies of ACE inhibitors to assess the degree and the time-course of ACE inhibition (Biollaz et al., 1981; Burnier et al., 1981; Bussien et al., 1985; Fasanella d'amore et al., 1987; Ferguson et al., 1977). The results obtained in these experiments have allowed definition of the short duration of action of captopril which is now known to have a half-life of 1 to 2 h (Ferguson et al., 1977; Jarrott et al., 1982). Blockade of the pressor response to angiotensin I actually correlated closely with plasma ACE activity following administration of enalapril to normal volunteers (Biollaz et al., 1981). In the original reports using this technique, blood pressure was monitored continuously via an intra-arterial catheter to record the acute changes in blood pressure. This rather invasive method has recently been modified to make it more suitable and the intra-arterial device has been replaced by a recorder which allows non-invasive and continuous monitoring at the finger (unpublished data). The most convenient way to investigate the degree of ACE inhibition produced by a new agent is to measure the enzyme activity in plasma. This can be achieved in vitro using various synthetic substrates of ACE. For instance, Hip-Gly-Gly can be used in a radioenzymatic assay (Ryan et al., 1977) and Z-Phe- His-Leu for a fluorimetric assay (Piquilloud et al., 1970). The former has been utilized in our laboratory to measure plasma ACE activity following the administration of almost all inhibitors studied so far and a dose dependent decrease in plasma ACE activity has been found with all agents (Brunner et al., 1985). The results obtained with the intravenous administration of captopril are presented in Figure 1. The validity of this determination is suggested mainly by the close relationships found with either plasma drug concentrations or the decrease in blood pressure response to angiotensin I as discussed above. With this synthetic substrate, it became evident in our experience that plasma ACE activity has to be suppressed markedly (below 10% of the basal activity) to obtain a substantial blunting effect of the response to exogenous angiotensin I. There are, however, two problems with plasma ACE activity. The first is that angiotensin I is converted to angiotensin II primarily not in plasma but in endothelial cells and probably most of it takes place in the lung (Erd6s, 1976). One might therefore wonder whether plasma ACE activity adequately reflects the bulk of angiotensin conversion throughout the body. The second major problem is that the

3 Pharmacokinetics of ACE inhibitors 135S 1K 7 j, j. I. i di. ~~~~~~~~~~~~~~~~4~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..i - l f, r f W \ ;; x t i i ; r~~-1-v ; i *Ei %&*t.u.i* **} * h#..s. n, Fi. _ Ii ij 4~~~~~~~~~~~~~~~~~~~~~~~~ -L1V f l'i' i.,,' K J _ i+srtt 't ;i y - vs f..!&i t;fei;j,t i.,tjj.'it} ;0.t-ll-.;.t1.;i: j j ^ 2 f ftr Xil,,0 7 w 4E U; ;Ai? -:'ij.rix-ts,2,...t}sb.;! 'x. ;i -0} #,,...,. fjs;mh v z S 8'-'w w,sw1)! d-t...,i...w.s; <*~~~~~~~~~~~~~-7 T-I ~1 r, t.m R.- i r i' 4 t i. 1. X r ht.,r tet, i~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ji --%.&. Am 'I 05 I is_ I , r~ ol:- 6.' : 46'~~~~~~~~~~~~~~~~~~~~~~ 90, 120 T. " *~~~~~~~1 is Figure 1 Effect of intravenous bolus doses of captopril on plasma ACE activity of normotensive healthy subjects. Mean ± s.e. mean, n = 5. Placebo, 0; captopril 1 mg, A, 5 mg, *; 25 mg, A. determination is performed in vitro with synthetic substrates. The results may therefore vary depending on the substrate chosen for the assay (Nussberger et al., 1989). Under these conditions, particular claims such as 'the need to suppress ACE activity below 10% to achieve an effective ACE inhibition' is true only if identical methodology is always used. In an attempt to characterize better the in vivo inhibition of ACE, we have calculated in the past several years the ratio of angiotensin II to angiotensin I measured in plasma (Biollaz et al., 1982). This parameter should actually reflect not only the enzymatic activity taking place in the plasma but also the conversion occurring in endothelial cells. The relationship between in vivo and in vitro ACE inhibition has been compared recently (Nussberger et al., 1989). In this study, the effects of a single dose of 20 mg benazepril were compared with those of a single dose of 20 mg enalapril. Plasma ACE activity was determined in vitro using two substrates, i.e. Hip-Gly-Gly or Z-Phe-His-Leu. Plasma angiotensin I and angiotensin II levels were also measured to calculate the in vivo ACE inhibition. Very different results were obtained with both drugs depending on the substrate used for the in vitro plasma ACE activity measurement. Thus, when evaluated with one substrate (Hip-Gly-Gly) the two drugs appeared to be equally effective whereas with the other substrate (Z-Phe-His-Leu) enalapril seemed to be less effective. Interestingly, with benazepril, in vivo ACE activity followed very nicely the results obtained with Z-Phe-His-Leu as a substrate in vitro. In contrast, with enalapril, the in vivo measurement of the angiotensin II/angiotensin I ratio was closer to Hip-Gly-Gly than to Z-Phe-His-Leu. This example further emphasizes the problems linked to the determination of plasma ACE activity and demonstrates that it is impossible to compare the efficacy of ACE inhibitors when different methods are used. There is no doubt that in vitro plasma ACE activity is useful to assess the degree of ACE inhibition. It is however necessary to characterize for each tested compound the relationship between the in vitro and the in vivo indicators of ACE inhibition. Other potential problems of the in vitro

4 136S M. Burnier et al. measurement of plasma ACE activity have been recognized. Thus, one has to be aware of the possible dissociation of an ACE inhibitor from the enzyme during plasma storage which may lead to an underestimation of the degree of inhibition (Burnier et al., 1981; Roulston et al., 1980). Dissociation between ACE inhibition and the antihypertensive effect: Problems with the determination of plasma angiotensin II levels ACE inhibitors are administered with the intention to decrease the synthesis of angiotensin II and thereby to reduce the peripheral vascular vasoconstriction. Thus, during effective ACE inhibition, a complete disappearance of circulating plasma angiotensin II levels would be expected. In fact, very few investigators have been able to document the disappearance of angiotensin II after acute administration of ACE inhibitors and there is now considerable evidence that plasma angiotensin II levels are still detectable in hypertensive patients chronically treated with ACE inhibitors (Nussberger et al., 1985). Moreover, even when plasma angiotensin II levels return to baseline immediately before the daily readministration of the ACE inhibitor, blood pressure remains well controlled in the face of these intermittently normal angiotensin II levels. The principal reasons why in most instances plasma angiotensin II levels are still measurable after acute ACE blockade are due to methodological problems linked to the determination of angiotensin II (Nussberger et al., 1986). The first and most important source of error is the specificity of the antibody used in the radioimmunoassay of angiotensin II. In many radioimmunoassays, there exists a cross-reaction of the antibody with other angiotensin peptides and this leads to an overestimation of the true value of angiotensin II. During the last few years, we have developed a method combining high performance liquid chromatography with an extremely sensitive radioimmunoassay (Nussberger et al., 1985). With this procedure, the break-down products of angiotensin II as well as its precursors are separated and only the angiotensin-(1-8)octapeptide, i.e. the true angiotensin II, is determined 4' Co _- 0..-i a0 c._a 4)- 0 0) CD Detection limit ol_l l, I Time (min) Figure 2 Effect of intravenous bolus doses of captopril on plasma angiotensin II levels of normal subjects. Mean ± s.e. mean, n = 5. Placebo, 0; captopril 1 mg, a, 5 mg, *; 25 mg, A. * P <0.05, *** P <0.001 vs placebo.

5 by the immunoassay. This method has been used to evaluate the acute effects of several ACE inhibitors and interestingly, in contrast to earlier observations, angiotensin II indeed disappeared from plasma during peak inhibition (Nussberger et al., 1985, 1988). The results obtained with intravenous administration of captopril are shown in Figure 2 (Nussberger et al., 1988). Plasma angiotensin II levels were not modified by the vehicle of captopril. A dose-dependent decrease in circulating angiotensin II was seen with captopril and with the dose of 25 mg virtually no angiotensin II could be detected in plasma for a short period of time. Interestingly, 90 min after the administration of 25 mg captopril, some angiotensin II was present in the plasma despite the fact that at the same time plasma ACE activity determined in vitro with Hip-Gly-Gly as the substrate was still almost maximally inhibited (Figure 1). During chronic treatment with ACE inhibitors, some circulating angiotensin II was regularly found in plasma even with our improved methodology (Nussberger et al., 1985). As shown in Figure 3, plasma immunoreactive angiotensin II levels were higher than the true angiotensin (1-8)octapeptide in hypertensive patients treated with enalapril. The reduction in the plasma concentration of the angiotensin- (1-8)octapeptide observed 2 h after the morning 9 c 8 en 7 0-.aL 5 ce 4 C3 cn 2 F 1 0 ET > c 20r N C > m10 L Enalapril I 1 - Immunoreactive 'Angiotensin II' Angiotensin- (1-8) octapeptide o E 0 2 Time (h) Figure 3 Effect (mean ± s.e. mean, n = 9) of the morning dose of enalapril on plasma ACE activity and plasma angiotensin II levels in hypertensive patients chronically treated with this ACE-inhibitor. * P <0.05 vs time 0. Pharmacokinetics oface inhibitors 137S dose of enalapril was statistically significant (-68%) whereas only a slight change in immunoreactive angiotensin II (- 17%) could be demonstrated. These observations clearly established the persistence of measurable plasma angiotensin II during long-term ACE inhibition even at peak effect of the drug. Beyond the characteristics discussed so far, it is now also well accepted that permanent and consistent reduction of plasma angiotensin II formation is not a prerequisite to obtain a continuous control of blood pressure around the clock. Thus, with all ACE inhibitors available so far, when administered once a day, plasma angiotensin II levels always return to baseline levels 24 h later. Nevertheless, in placebo controlled investigations, blood pressure remains constantly reduced. This dissociation between the plasma angiotensin II levels and the antihypertensive effect necessarily implies that ACE inhibitors may act via mechanisms other than reducing plasma angiotensin II levels to lower blood pressure. In this context, it has to be remembered that angiotensin II seems to play an important role in inducing hypertrophy of the smooth muscle of arterioles (Campbell-Boswell & Robertson, 1981). The reduction in smooth muscle hypertrophy observed after chronic ACE inhibition most probably is the consequence of the blood pressure reduction as well as of the intermittent reduction of circulating angiotensin II which may possibly result in a reduced responsiveness to circulating angiotensin II. Therefore, even the apparent dissociation between the intermittently 'normal' angiotensin II levels and the continuously reduced blood pressure could still conceivably be the result of a chain of events triggered by the intermittent reduction of angiotensin II levels. Other possible mechanisms induced by chronic ACE-inhibition include attenuated sympathetic nerve activity, enhanced parasympathetic activity, raised depressor hormones and also a vascular or cerebral renin angiotensin system operating independently of the circulating components (Unger et al., 1988; Zimmerman et al., 1984; Zusman, 1984). The discussion of the potential of these various mechanisms is beyond the scope of the present review. Difference between ACE inhibitors; does it matter? The numerous new ACE inhibitors differ from the original molecules in several ways (Brunner et al., 1985). Some compounds have a longer duration of action and/or lack the SH-group of

6 138S M. Burnier et al. captopril. Others are characterized by other metabolic pathways, including the route of excretion or the need for the prodrug to be metabolized in order to form the active drug. Are these differences clinically relevant? Intuitively, an ACE inhibitor with a long halflife would be preferred to one with a short halflife because one wishes to reduce plasma angiotensin II levels throughout the day. However, the clear dissociation during chronic treatment between plasma angiotensin II and blood pressure reduction just discussed above demonstrates that this goal does not need to be reached. In fact, in some patients with congestive heart failure, it turned out that a marked and prolonged ACE inhibition may even be deleterious by increasing the incidence of renal failure (Packer et al., 1986). The possible advantages or inconveniences of having a SH-group in the molecule certainly require further investigations. Originally, it has been claimed that SH-groups were the major source of side-effects (Anonymous, 1980). With the use of much lower doses, the rate of sideeffects associated with captopril has fallen considerably and become quite comparable to that of other ACE inhibitors. Today, it is still uncertain whether the side-effects of captopril are related to the existence of the SH-group. On the other hand, recent observations have even suggested that the presence of the mercaptogroup improves the cardiac effects of this agent by preventing postischaemic reperfusion arrhythmias and also by reducing tachyphylaxis to chronic nitrate therapy (Pfeffer et al., 1988; van Gilst et al., 1986, 1987, 1988). Considering the difference in metabolism, the clinical advantage of a compound that does not need to be metabolized in order to become active still has to be demonstrated. However, the route of excretion of the drug may have important pharmacological and clinical implications. Most ACE inhibitors are cleared by the kidney and drug dosage may have to be adapted in patients with reduced renal function to avoid drug accumulation. For patients with reduced renal function, new drugs are becoming available which are excreted in a large proportion by the liver. Conclusions ACE inhibitors are effective antihypertensive agents which allow control of blood pressure in hypertensive patients even though the plasma levels of angiotensin II are not constantly reduced. The in vitro measurements of plasma ACE activity associated with the determinations of plasma angiotensin I and II levels can provide reliable means to investigate the degree and duration of inhibition induced by these agents as long as one is aware of the potential problems of these methods. Direct comparisons of the potency or efficacy of various inhibitors should be made with great caution. At the present time, it is still not clear to what extent pharmacokinetic differences among the ACE inhibitors are of any major clinical relevance if one excludes patients with reduced renal function in whom a drug with an extrarenal route of excretion might be preferable. Additional information on the capacity of these agents to inhibit specific tissue renin-angiotensin systems and to decrease organ damage are expected with great interest in the near future. References Anonymous (1980). Captopril, benefits and risks in severe hypertension. Lancet, ii, Belz, G. G., Kirch, W. & Kleinbloesem, C. H. (1988). Angiotensin-converting enzyme inhibitors. Relationship between pharmacodynamics and pharmacokinetics. Clin. Pharmacokin., 15, Biollaz, J., Burnier, M., Turini, G. A., Brunner, D. B., Porchet, M., Gomez, H. J., Jones, K. H., Ferber, F., Abrams, W. B., Gavras, H. & Brunner, H. R. (1981). Three new long-acting converting enzyme inhibitors: relationship between plasma converting enzyme activity and response to angiotensin I. Clin. Pharmac. Ther., 29, Biollaz, J., Schelling, J. L., Jacot des Combes, B., Brunner, D. B., Desponds, G., Brunner, H. R., Ulm, E. H., Hichens, M. & Gomez, H. J. (1982). Enalapril maleate and a lysine analogue (MK-521) in normal volunteers; relationship between plasma drug levels and the renin-angiotensin system. Br. J. clin. Pharmac., 14, Boomsma, F., de Bruyn, J. H. B., Derkx, F. H. M. & Schalekamp, M. A. D. H. (1981). Opposite effects of captopril on angiotensin I-converting enzyme "activity" and "concentration"; relation between enzyme inhibition and long-term blood pressure response. Clin. Sci., 60, Brunner, H. R., Laragh, J. H., Baer, L., Newton, M. A., Goodwin, F. T., Krakoff, L. R., Bard, R. H. & Btthler, F. R. (1972). Essential hypertension: renin and aldosterone, heart attack and stroke. New Engl. J. Med., 286, Brunner, H. R., Nussberger, J. & Waeber, B. (1985). The present molecules of converting enzyme inhibitors. J. cardiovasc. Pharmac., 7 (Suppl. 1), 2-11.

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8 140S Discussion M. Burnier et al. Pierre Corvol (Paris): Are you saying that there is no correlation between ANG II levels and blood pressure control under chronic administration of ACE inhibitors, and that that applies to every sort of ACE inhibitor which you have tested? Hans R. Brunner (Lausanne): I think that applies to all the ACE inhibitors, but we have not performed a comparative study of all the ACE inhibitors under similar circumstances. A review of the literature provides no evidence that ANG II levels must be reduced for a 24 h period with any of the ACE inhibitors in order to reduce blood pressure around the clock. On the other hand, in my opinion, there is no evidence that you can reduce BP with an ACE inhibitor without reducing ANG II at some point during the day. In other words, if insufficient drug is given to reduce ANG II levels, it is unlikely that blood pressure will be reduced in the long term. Herwig Holtzer (Vienna): Does it make any difference whether you give a drug with a short half-life, like captopril, in the evening or the morning, once a day? Hans R. Brunner (Lausanne): I am not aware it makes a difference. Although I'm very much in favour of captopril, I am not convinced that in all patients captopril given once a day will always be equivalent to one of the longer -acting drugs. I have seen a few patients for whom the shorteracting captopril is not enough.