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Impact of Disease States on the Pharmacokinetics and Pharmacodynamics of Angiotensin-Converting Enzyme Inhibitors

From the College of Pharmacy at The Ohio State University, Columbus, Ohio (Dr LeBlanc, Mr Dasta, Dr Pruchnicki), and the University at Buffalo School of Pharmacy and Pharmaceutical Sciences, and the Clinical Pharmacokinetics Laboratory, University at Buffalo, Buffalo, New York (Dr Schentag).

	ABSTRACT

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 
The pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors (ACE) in elderly patients and patients with renal and hepatic impairment were examined, and a role for an AUC/EC₅₀ ratio to guide dosing was evaluated. A Medline and International Pharmaceutical Abstracts search was used to identify human studies and abstracts. Relevant data were evaluated and summarized. Dosing regimens were compared using an AUC/EC₅₀ ratio. Most studies evaluating ACE inhibitors in renal impairment report a strong linear correlation between creatine clearance and drug elimination. AUC and EC₅₀ values for these drugs in elderly subjects appear similar to younger and hypertensive patients. There is increased AUC in some patients with hepatic impairment. Pharmacodynamic data are conflicting. Prolonged ACE inhibition is evident in renal impairment but not necessarily other disease states. ACE inhibitor dosing for hypertension is reasonable based on pharmacokinetics and EC₅₀ values. Further individualization of therapy may improve outcomes, and using the threshold AUC/EC₅₀ ratio may help guide appropriate dosing.

Key Words: Angiotensin-converting enzyme inhibitors • elderly • renal dysfunction • hepatic dysfunction • review

ACE inhibition causes plasma angiotensin (Ang) I concentrations to rise and Ang II concentrations to fall, which may be used as an alternative approach to estimating the degree of inhibition in patients. The degree of inhibition in vivo can be estimated by using the ratio Ang II/Ang I detected in the plasma. A clear dose-response relationship for ACE inhibitors can be illustrated in normal volunteers, and it is assumed that a similar relationship exists in hypertensive patients.¹ ACE inhibitors administered once daily usually show a decline in efficacy toward the end of the dosing interval. The trough to peak (T:P) blood pressure response ratio is a measure of the variability in blood pressure during a dosing interval, whereby a trough effect should be at least half of the peak effect.^2,3 It has been shown that benazepril, quinapril, and ramipril do not achieve the required T:P ratio of 50%. However, enalapril, lisinopril, and trandolapril have T:P ratios greater than 50%, suggesting that not all ACE inhibitors can be dosed once a day.⁴

Potency differences among the ACE inhibitors can be offset by individual dose adjustments, but comparative potency and dose in relation to achieved serum concentrations following various dosage regimens have not been critically evaluated. Thus, ACE inhibitor dosing strategies have not been linked to receptor affinity and simultaneous human pharmacokinetics. These associations are important determinants of dose and duration of action for other classes of compounds, such as antibiotics, and should be evaluated to effectively compare the dosages of ACE inhibitors.

Some ACE inhibitors appear to produce excessive blood pressure reduction in elderly and renally impaired patients,^5,6 suggesting that the augmented response may be a consequence of disease-specific changes in drug sensitivity. Alternatively, the changes in response could be due to patient factors that alter the disposition of the drug and result in higher serum concentrations. To date, most studies attribute augmented responses to disease states that alter ACE inhibitor pharmacokinetics.^7-9 In this setting, determining the optimal dosage for the elderly population or patients with renal and hepatic compromise using the index ratio AUC/EC₅₀ may have some clinical utility.

Many research reports have been scrutinized to attempt relative comparisons between the following active moieties of the ACE inhibitors: benazeprilat, captopril, enalaprilat, fosinoprilat, lisinopril, quinaprilat, ramiprilat, and trandolaprilat, and several review articles have been published.^9-13 Available data were often conflicting. To date, there are very few published crossover comparative pharmacokinetic or pharmacodynamic studies in the same volunteers or animal models. The purpose of this article was to compare pharmacokinetics and pharmacodynamics of ACE inhibitors in elderly and patients with renal and hepatic impairment, and to suggest a role for the AUC/EC₅₀ index ratio to guide appropriate dosing.

	METHODS

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 
A search of the English-language literature via Medline (1966-April 2006) and International Pharmaceutical Abstracts (1971-April 2006) was used to identify human studies, addressing pharmacokinetic and pharmacodynamic differences between normal volunteers and patients receiving ACE inhibitors. Pharmacokinetic differences were focused on elimination pathways and activity profiles of the active diacid form (or the active moiety for captopril and lisinopril) of the ACE inhibitors; pharmacodynamic differences were searched with regard to blood pressure effect and hormonal changes induced by the ACE inhibitors. Relevant data were evaluated and summarized for comparative review. Dosing regimens were compared using a general index ratio of AUC/EC₅₀.

For the purposes of this review, the AUC was defined as the area under the time-concentration curve for an ACE inhibitor (prodrug or metabolite) preferably over a 24-hour dosing interval (AUC_0-24h). When the AUC comprised a different time period, it is noted in the subscript. The EC₅₀ of an ACE inhibitor was defined as the serum concentration that produced 50% of maximum ACE inhibition.

	PHARMACOKINETICS OF ACE INHIBITORS IN HUMANS

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 
With few exceptions, ACE inhibitors have a relatively long half-life, particularly with trandolapril (eg, 11 hours for enalaprilat, 16-24 hours for trandolaprilat).¹⁴ This factor may be an advantage, resulting in less frequent dosing and improved patient compliance. However, in some patient populations, especially the elderly and those with organ dysfunction, slowly eliminated drugs like these agents may produce adverse drug reactions such as prolonged hypotension. Therefore, in these populations, a dual route of elimination may be a desirable characteristic, because accumulation is less likely to occur. There are only a few studies that have evaluated elimination pathways of ACE inhibitors, and no data were found with enalaprilat, quinaprilat, and trandolaprilat. With the exception of fosinopril, the active moiety of each ACE inhibitor is predominantly eliminated renally.^21,40-46

The minimum effective dose of an ACE inhibitor can be approximated by examining the ratio of the AUC of the active moiety to the corresponding EC₅₀. Previously, this concept of having the AUC exceed the EC₅₀ over 80% of the dosing interval has been applied to extensively model the actions of antibiotics on bacteria, demonstrating clear relationships of cure and failure in the infectious disease setting.^47-49 Theoretically, the dose at which the AUC/EC₅₀ ratio reaches a value of 100 to 200 should be the initial point at which a clinically significant reduction in blood pressure is observed.⁴⁷ Regardless of the individual AUC or EC₅₀ values, when approximately 80% of the AUC exceeds the EC₅₀, the ratio of these 2 parameters will be approximately 100. Thus, a dosage that produces a ratio of 100 exceeds the EC₅₀ for most (80%-100%) of the dosing interval and is an intuitively logical initial dose for any drug that acts on a receptor.⁴⁷ There is evidence that 80% of plasma ACE must be inhibited for plasma Ang II concentrations to decline.⁵⁰

Available EC₅₀ and AUC data gathered from ACE inhibitor pharmacokinetic and pharmacodynamic studies performed in various patient populations are presented in Table I. Theoretically, a listing of equipotent ACE inhibitor doses can be constructed using AUC_0-24h and EC₅₀ data. If the patient populations studied have similar characteristics, the dose at which one ACE inhibitor is equipotent to the dose of another ACE inhibitor can be determined using the AUC/EC₅₀ of each drug's active moiety. The dose that produces an AUC/EC₅₀ of approximately 100 for one ACE inhibitor's active moiety is equipotent to the dose that produces the same value for another ACE inhibitor's active moiety.

	EFFECTS OF RENAL IMPAIRMENT

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 
Most studies evaluating ACE inhibitors in patients with renal impairment have reported a strong linear correlation between creatinine clearance (Cl_Cr) and some measure of drug elimination.^51,52,62-65 For the active moiety, the intercept for these relationships is not significantly different from zero, suggesting that the elimination is entirely renal and that the clearance of the active compound declines in relation to Cl_Cr.

The effects of varying degrees of renal impairment on ACE inhibitor accumulation are shown in Table II. Many ACE inhibitors elicit large, unpredictable increases in AUC in patients with severe renal dysfunction. As renal function declines, maximum serum concentrations rise, particularly evident in patients with Cl_Cr less than 30 mL/min. Very few of these studies described the methods used to determine the Cl_Cr of the patient groups.

In contrast to renally excreted ACE inhibitors, there is relatively little increase in AUC for ACE inhibitors with dual routes (renal and hepatic) of elimination as renal function declines. As the degree of renal impairment worsens, the percentage recovered in the urine declines, whereas the percentage of the dose recovered in the feces progressively increases. The elimination of fosinoprilat in renal dysfunction relies on the nonrenal (primarily hepatobiliary) elimination pathway, suggesting that biliary excretion plays a larger role in the hepatic elimination of fosinopril in these patients.⁴²

	EFFECTS OF AGING

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 
Consistent with the behavior of many drugs, pharmacokinetic data from elderly patients usually follow that of patients with mild renal compromise, in that most age-related declines in drug clearance can be explained by reductions in renal function. Table III demonstrates the effect of age on the AUC of ACE inhibitors. EC₅₀ values for elderly subjects appear similar to those of younger and hypertensive patients (Table I); thus, any changes in effect of the drug at the same dose in the elderly are probably related to higher AUC values. Data with ramipril are conflicting, with one study reporting little difference in ramipril AUC between elderly subjects and young historical controls.⁶⁸ Other investigators observed increased mean maximum plasma concentrations of ramiprilat between 8 elderly subjects and 12 young subjects following a 20-mg dose of ramipril.⁶⁹

Some ACE inhibitors show increased bioavailability (eg, perindoprilat: 35% vs 19%, P < .025),⁶ as well as modest declines in renal clearance in the elderly. Assuming that sensitivity of the receptor is not reduced in this population, these pharmacokinetic changes may lead to a functional increase of effective dose and a greater decrease of blood pressure, as well as a longer duration of action. Several studies have shown associations between plasma ACE activity and ACE inhibitor concentration that did not differ between young and elderly subjects.^6,16,23 This finding suggests that pharmacokinetic differences observed between elderly and young patients may be responsible for differences in effect.

	EFFECTS OF HEPATIC IMPAIRMENT

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 
Table IV presents AUC ratios for both the active metabolite and prodrug in subjects with hepatic dysfunction. AUC ratios for the active moieties range from 0.46 for enalaprilat and quinaprilat to 2.2 for perindoprilat. The nonrenally excreted agent, fosinoprilat, also shows some increase in AUC ratio. More drug is excreted renally, in part because of the loss of hepatic excretion of fosinoprilat, but the renal excretion does not return the AUC to normal volunteer values.

A major concern with the use of ACE inhibitors in patients with hepatic insufficiency is that the prodrug will not undergo bioactivation in a diseased liver. Of those ACE inhibitors studied in this patient population, enalapril and quinapril have been shown to have a reduced rate and extent of hydrolysis. In cirrhotic patients, the deesterification of enalapril to enalaprilat was impaired compared to healthy counterparts,⁷² although the impairment was not reported in another study.⁷³ Fosinopril showed a slower rate of conversion in hepatically impaired patients compared to healthy volunteers, although the extent of conversion to the active moiety was similar.⁷⁵

In reviewing these data, it is important to recognize that typical patients with hepatic disease who participate in pharmacokinetic studies often have mild hepatic disease. Study designs may require biopsyproven liver disease, which assures that the patient can tolerate a liver biopsy. Furthermore, a diagnostic liver biopsy alone does not dictate the severity or extent of hepatic disease. Many of the hepatic disease patients who participate in these studies are elderly and may also have concomitant renal insufficiency. Thus, the increased AUC sometimes attributed solely as a consequence of hepatic disease may in fact be the combined impact of some hepatic impairment in a setting of older age and appreciable concomitant renal insufficiency. This may explain why certain renally dominated ACE inhibitors, like enalapril, accumulate in "hepatic disease" patients.^72,76

	PHARMACODYNAMICS OF ACE INHIBITORS IN HUMANS

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 
Dose-response relationships have been extensively studied in an effort to predict the blood pressure response from varying dosages of ACE inhibitors in specific patient populations. Investigators have examined correlations between effects on hemodynamics and peak plasma concentrations of the ACE inhibitors, as well as the relationship with ACE inhibitory activity. Plasma levels of aldosterone, Ang II, and renin have also been measured to try to demonstrate, and subsequently predict, blood pressure response. For the purposes of the following pharmacodynamics section, ACE inhibition and blood pressure response will be discussed. Table V presents examples of the effects of ACE inhibitors on the hormonal pharmacodynamic parameters of aldosterone, Ang II, and renin.

Evaluation of blood pressure response to the ACE inhibitors in healthy volunteers is hampered by the observation that subjects with normal resting blood pressures often will not demonstrate any pharmacologic effect. As an example, escalating doses of quinapril given to healthy volunteers showed no effect on supine or erect blood pressure.³² Some data are available in hypertensive patients without renal or hepatic impairment. In hypertensive patients, cilazapril and perindopril demonstrated a relationship between the maximum decrease in blood pressure with the percentage inhibition of ACE and maximum serum concentration.⁸⁰ In another study, enalapril elicited a decrease in blood pressure in 13 essential hypertension patients and significantly decreased ACE from baseline; both of these effects were correlated through kinetic-dynamic analysis to plasma enalaprilat concentration.²⁴

	EFFECTS OF RENAL IMPAIRMENT

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 
AUC/EC₅₀ ratios demonstrate that with decreasing renal function, lower dosages are needed to attain the target ratio of >100 (Table I). Dose-response relationships have been studied in patients with renal impairment to determine appropriate dosage of ACE inhibitors for this group of patients. Fruncillo et al illustrated that the magnitude of blood pressure changes showed no correlation with peak enalaprilat concentrations; however, blood pressure was significantly decreased in patient groups with a Cl_Cr < 15 mL/min.⁵⁵ Conversely, data with cilazapril demonstrated falls in blood pressure were comparable in hypertensive and nonhypertensive patients with normal and impaired renal function.^18,54 Conflicting data have also been published with lisinopril. Blood pressure decreased in 3 groups of patients with differing renal function after administration of this ACE inhibitor, with a more prolonged duration of effect in patients with the most severe renal insufficiency, although this finding was not statistically significant.⁸¹ However, another study showed the blood pressure decrease was similar in normal and renally impaired hypertensive patients after 10 mg lisinopril despite higher plasma concentrations of the drug in the renally impaired group.²⁷ Studies involving ramipril,³⁶ quinapril,⁶² and trandolapril³⁹ have not demonstrated an association between the change of blood pressure and decreasing Cl_Cr. These studies illustrate the conflicting data available in the literature. Overall, most data support no correlation between the effects on blood pressure and the degree of renal impairment.

Van Schaik et al reported that after a single dose of lisinopril in patients with normal and impaired renal function, ACE activity was still depressed 25% (clearance > 30 mL/min) and 50% (clearance < 30 mL/min) at 168 hours.⁵⁹ A recent study evaluating perindopril in 26 hypertensive patients also demonstrated that the extent and duration of plasma ACE inhibition was augmented in those with severe renal failure (Cl_Cr < 15 mL/min).²⁹ Cilazapril,¹⁸ enalapril,⁵⁶ lisinopril,⁸¹ and quinapril⁶² have all demonstrated prolonged duration of ACE inhibitory activity in patients with impaired renal clearance. This was also shown with trandolapril, with one reporting no correlation between Cl_Cr and ACE inhibition.^38,39 There are data, however, that after a single dose of cilazapril, Cl_Cr was correlated with ACE inhibition at 24 hours.⁵⁴ ACE inhibition occurred in patients with renal impairment given ramipril, with prolonged effect in the severest group.³⁶ A correlation was seen with plasma ramiprilat and ACE inhibition, suggesting accumulation of the drug in this population may have affected response. Generally, there is an association between decreased renal function and prolonged ACE activity, although there are few studies supporting that this results in a change in blood pressure response.

	EFFECTS OF AGING

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 
Interpreting hemodynamic outcomes of studies in the elderly is particularly difficult because of a number of issues, including generally higher resting blood pressures, which can confound the results. Both benazepril and enalapril have demonstrated greater blood pressure reduction in elderly patients compared to younger ones; however, this response was not statistically significant when adjusted for baseline blood pressure.^82,83 In another study, elderly and young patients were given enalapril, enalaprilat, or placebo, and the fall in blood pressure was significantly greater in the elderly for both active treatments.⁵ At 24 hours, the effect was gone in the young, but persisted in the elderly; when initial pressures were normalized, the differences lost statistical significance. This result was possibly related to reduced clearance, greater AUC, and decreased volume of distribution in the older group. Although most of the evidence with enalapril suggests no differences in the hemodynamics related to age, oral perindopril and intravenous perindoprilat both caused decreases in mean arterial pressure (MAP) in elderly and young subjects, whereas baseline MAP only accounted for some of the differences in blood pressure response.⁶

Perindopril and perindoprilat caused comparable ACE inhibition between elderly and young subjects, with peak effects at about 1 hour after intravenous infusion and 4 to 6 hours after oral administration,⁶ whereas older patients showed more prolonged inhibition with benazepril (31% ± 16% vs 16% ± 9% at 24 hours for elderly vs young, P < .005).⁸² Results with enalapril have been contradictory, showing both prolonged and similar ACE inhibition between elderly and young groups.^5,16,83 The magnitude of ACE inhibition was shown not to be different between elderly and young subjects with trandolapril and cilazaprilat.^22,37 In general, results are conflicting about the effect of age on ACE activity.

	EFFECTS OF HEPATIC IMPAIRMENT

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 
Pharmacodynamic data with the ACE inhibitors in patients with liver impairment are lacking. One study demonstrated no differences in mean blood pressure change, even though the AUC of enalaprilat was lower in the cirrhotic group than in the normal subjects,⁷² whereas another showed no change in systolic blood pressure, but the decrease in diastolic blood pressure was comparable.⁷³ Ford et al showed no effect of fosinopril on blood pressure in either alcoholic cirrhotic patients or healthy volunteers, perhaps explained by these patients being normotensive at baseline.⁸⁴ Enalaprilat and lisinopril caused comparable decreases in blood pressure in normal subjects and cirrhotic patients; however, the mean baseline blood pressure was higher in the patients.⁷⁶

Cilazaprilat concentrations were higher in patients with mild-moderate hepatic impairment than in normal volunteers; however, the response of degree of inhibition of ACE to a given concentration was similar in both groups.⁷¹ In 2 comparative studies of enalapril in patients with mild liver impairment versus normal volunteers, the decrease in ACE activity was also similar in both groups.^72,73 Few data are available with regard to inhibition of ACE in this population; therefore, conclusions cannot be reached.

	CONCLUSIONS

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 
For the disease states described, it appears that the EC₅₀ for most ACE inhibitors is not altered; therefore, it is possible to use the target AUC/EC₅₀ ratio of 100 to estimate the minimally effective antihypertensive dosage. The dosage that achieves a ratio of 100 is likely to be associated with the minimal detectable antihypertensive effects of the drug, although it is clearly not the highest dosage possible. Additional effects may be demonstrated as dosages are increased. However, adherence should also be investigated in patients whose blood pressure is not responding to dosages targeting the AUC/EC₅₀ ratio before increasing them. All ACE inhibitors, except fosinopril, require dosage adjustments in patients with moderate to severe renal impairment. Because the EC₅₀ is similar in normal and renal failure patients, dosage reductions should be designed to lower AUC in renal failure patients to values similar to patients with normal renal function.

Our evaluation revealed that the ACE inhibitor dosing actually employed for the treatment of hypertension is reasonable, based on the known pharmacokinetics and EC₅₀ values for these drugs. Dosage adjustments are necessary in patients with Cl_Cr less than 30 mL/min. There appeared to be conflicting data with the dose-response relationship in renally impaired patients, although it was apparent that ACE inhibitory activity was prolonged. The blood pressure response in elderly patients was difficult to evaluate because of higher resting blood pressure, and conflicting data are published with regard to ACE inhibition. Data are lacking in hepatically impaired patients, with few studies showing no differences in ACE inhibition. An index such as the AUC/EC₅₀ ratio provides a means of estimating dose equivalency across current and investigational ACE inhibitor doses, half-lives, clearances, elimination pathways, and EC₅₀, and can potentially serve as a method of adjusting dosages in special patient populations.

	REFERENCES

TOP ABSTRACT METHODS PHARMACOKINETICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT PHARMACODYNAMICS OF ACE... EFFECTS OF RENAL IMPAIRMENT EFFECTS OF AGING EFFECTS OF HEPATIC IMPAIRMENT CONCLUSIONS REFERENCES

 

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