Abstract
The pharmacokinetic disposition of benazeprilat, an angiotensin-converting enzyme (ACE) inhibitor (ACEI), was assessed with a nonlinear binding model in dogs. A single oral benazepril dose, a single i.v. benazeprilat dose, or a daily oral dose of benazepril for 14 consecutive days was administered. The activity of benazeprilat was assessed by measuring plasma ACE inhibition with an ex vivo assay. Benazeprilat data were fitted to equations corresponding to a monocompartmental model with a volume equal to the extracellular space (∼0.2 l/kg) in which a fraction of benazeprilat was nonlinearily bound to ACE with both a saturable tissue and nontissue binding. The half-life of benazeprilat elimination determined from this physiologically based model was 39 ± 6 min. The estimated maximal binding capacity of benazeprilat to ACE was ∼23.5 nmol/kg, 90% of which was tissular. The estimated equilibrium constant of dissociation (Kd) of benazeprilat to ACE was 2.7 to 4.5 nM. IC50 values were one order of magnitude lower thanKd values (i.e., ∼0.27 nM). The nonlinear disposition of benazeprilat raised several issues and it was concluded that the benazeprilat concentration profile was only relevant to definition of an optimal dosage regimen if the appropriate kinetic model was used to interpret the plasma data.
Benazepril is a prodrug of benazeprilat, an inhibitor of angiotensin-converting enzyme (ACE). Benazepril was developed to circumvent the poor absorption of benazeprilat. It is assumed that benazepril is rapidly and relatively well absorbed by the gastrointestinal tract after an oral administration. After absorption, benazepril is rapidly de-esterified (hydrolyzed) by carboxyesterase to form the active moiety benazeprilat. Most of this metabolic transformation is considered to occur in the liver (Balfour and Goa, 1991).
The pharmacokinetics of benazepril, benazeprilat, and the effect of benazeprilat on plasma ACE activity has been recently evaluated in the dog (King et al., 1997). In this experiment, the data were described with a biexponential equation, the two phases being considered as “fast” and “terminal” elimination phases.
It has been shown in humans that many ACE inhibitor (ACEI) dispositions cannot be appropriately explained by interpreting multiexponential equations in terms of conventional compartmental models. Till et al. (1984) were the first to state that conventional pharmacokinetic approaches were inappropriate for characterizing ACEI disposition. They showed that a classical compartmental model was unable to describe drug (enalaprilat) disposition during repeated administration, particularly that accumulation was lower (r = 1.3) than expected from the drug's long terminal half-life (∼35 h). This apparent discrepancy was tentatively explained by the fact that the prolonged terminal phase of enalaprilat disposition did not represent an elimination phase but was due to the saturable binding of enalaprilat to serum ACE (Till et al., 1984).
Francis et al. (1987) were the first to take into account the saturated binding of ACEI to ACE and to suggest a physiologically realistic model that was able to relate the dynamics of an ACEI (cilazaprilat) to its kinetics. The validity of these classes of saturated binding models was verified for perindoprilat (Lees et al., 1989), and it is now known that the plasma concentration-time profile for ACEI exhibits two principal phases: an initial elimination phase that reflects clearance of (free) drug and a protracted phase that reflects the release of drug mainly from tissue-binding sites before elimination by the kidney and/or liver (MacFadyen et al., 1993). Thus, the protracted terminal half-life reflecting saturable binding to tissue and plasma ACE is not a conventional half-life and does not in consequence, control the rate of drug accumulation.
Despite these sound physiologically based views of ACEI disposition, most authors continue for convenience to analyze ACEI kinetics with a multiexponential or noncompartmental approach [e.g., with the plasma area under the plasma concentration curve (AUC) as an index of drug exposure with respect to ACE inhibition or to relate pharmacodynamic effects to the measured plasma concentrations rather than to free ACEI plasma concentrations]. Thus, biological interpretations of the plasma-drug concentration profiles are made difficult, confusing, or misleading with regard to drug efficacy or in predicting the therapeutic consequences of pathological conditions such as renal insufficiency.
Dogs are largely used in preclinical studies of cardiovascular drugs, including ACEIs, and we carried out an experiment to compare the influence of experimental renal insufficiency on both pharmacokinetics and pharmacodynamics of benazeprilat (a drug eliminated by both kidney and liver) and enalaprilat (a drug mainly eliminated by the kidney). When we used a classical multiexponential approach to model our data, we observed an almost systematic inconsistency, namely, a longer lag time to absorption (and/or biotransformation) of benazepril or enalapril than the first ex vivo observable effect of benazeprilat or enalaprilat. This prompted us to reconsider the disposition model of ACEI in dogs and to extend the physiological concepts developed in humans to this species.
Herein, we present original data on i.v. disposition of benazeprilat in dogs and reanalyze the raw data already published by King et al. (1997)on benazeprilat after single and multiple oral benazepril administrations. We also explored the relationship between free and bound concentrations of benazeprilat to the inhibitory action of this drug with a pharmacokinetic/pharmacodynamic approach. The influence of renal insufficiency on benazeprilat and enalaprilat disposition and ex vivo effects is addressed in Toutain et al. (2000), based on the modeling framework developed in the present article.
Materials and Methods
Study Design and Animals
The materials and methods have been extensively described in the original paper (King et al., 1997), except for information related to the i.v. benazeprilat administration, which was not published. Briefly, eight dogs (four females and four castrated beagle dogs), aged 14 to 15 months and weighing 12.7 to 15.5 kg, were studied.
Benazepril hydrochloride (mol. wt. 460.9) was supplied in the form of a 5-mg film-coated tablet (Fortekor; Novartis Animal Health, Basel, Switzerland). Benazeprilat (mol. wt. 396.4) was supplied as powder that was dissolved in 1% NaHC03 and then diluted 1:10 in isotonic 0.9% NaCl.
All the dogs received the same treatment beginning by a single oral benazepril or an i.v. benazeprilat administration according to a crossover design. The two administrations were separated by a washout period of 14 days. Fourteen days after completion of the crossover design, all the dogs received a single daily oral dose of benazepril for 14 days, 1 h after the morning feed.
Benazeprilat was administered by i.v. route (cephalic vein) at a mean dose of 0.463 mg/kg (1168 nmol/kg). Blood samples were obtained before (0 h) and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.5, 6.0, 8.0, 10, 12, 16, 24, 30, 36, 48, and 72 h after administration. Blood samples were obtained after the single oral dose of benazepril at a mean dose of 0.54 mg/kg (1168 nmol/kg), as in the i.v. study. For the multiple oral benazepril administration at a mean dose of 0.54 mg/kg/day (1168 nmol/kg/day), blood samples were taken before (0 h) and 2 h after the administration of benazepril on days 1, 2, 3, 4, 7, and 11 and before (0 h) and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10, 12, 16, 24, 30, 36, 48, and 72 h after the final benazepril administration.
Benazeprilat was measured in plasma with a gas chromatography-mass spectrometry method adapted from that described by Sioufi et al. (1988). Between-day coefficient of variation for precision was <10% and the limit of quantification was 1 ng/ml.
The activity of ACE was determined in plasma obtained after oral administrations (single- or multiple-dose regimen) with a commercial kit according to the manufacturer's instructions (ACE Radioassay System; Ventrex Labs, Portland, ME). This involved hippuryl-glycyl-glycine as substrate, one unit of activity corresponding to the amount of hippuric acid generated per minute per 1 ml of plasma. The coefficients of variation within and between days were 4.4 and 9.7%, respectively.
Pharmacokinetic Analysis
The data were analyzed with the class of models proposed and developed by Lees et al. (1989) (Fig.1). Briefly, a compartmental model can be constructed assuming that unbound drug is the sole form eliminated with a rate constant K10(h−1) from a central compartment with a volume Vc (liters per kilogram); benazeprilat binds specifically and saturably to ACE (circulating and tissular) (high affinity, low capacity) and nonspecifically and nonsaturably only to the plasma albumin (low affinity, high capacity). ACE is an ectopeptidase that appears in a soluble form in blood (circulating form) but that is mainly bound to the plasma membrane of vascular endothelium (the so-called tissular form). Thus, the plasma benazeprilat concentrations (hereafter termed measurable benazeprilat) measured by analytical techniques correspond to the sum of free benazeprilat, the benazeprilat specifically bound to the circulating ACE, and the benazeprilat bound nonspecifically to albumin.
The ACE (circulating and tissular) is immediately accessible to benazeprilat and for modeling purposes, all the ACE is located in the central sampling compartment. However, the benazeprilat bound to tissular ACE (i.e., at the luminal surface of vessels) is not measured by the analytical technique. Because the soluble form of ACE is assumed to originate from the membrane-bound forms by proteolytic action (Hooper, 1993), the circulating and noncirculating forms of ACE share the same binding parameters [Bmax (in nanomoles) that is the maximal binding capacity andKd (in nanomoles) that is the dissociation constant, i.e., the free plasma benazeprilat amount corresponding to half-saturation of the entire ACE pool]. The circulating fraction (fcirc) of ACE, from 0 to 1, was estimated as a parameter of the model given the sharing of binding capacity between circulating ACE (i.e., fcirc × Bmax) and tissular ACE (i.e., (1 − fcirc) ×Bmax).Bmax andKd were estimated in terms of amount (nanomoles) but have been expressed in terms of concentration (nanomoles per liter) by dividing the estimated amount by the volume of distribution (liters per kilogram) of the free fraction, i.e., Vc (seeDiscussion).
When exploring models that included both specific and nonspecific binding parameters, we observed a structural unidentifiability, i.e., the impossibility of separately estimatingK10,Kd and the nonspecific binding parameter (NS) linking the free fraction (Free) to the nonspecifically bound fraction (i.e., NS × Free). Consequently, in our model, NS was ignored so that the free benazeprilat corresponds to truly free benazeprilat plus benazeprilat that was not specifically bound to albumin. Francis et al. (1987) adopted this simplification for cilazaprilat. However, it must be realized that whether the NS parameter is included or not in the model influences the value ofKd and if the numerical value ofKd is of interest, the values of these parameters for matrix without albumin (e.g., in vitro buffer) should beKd/(NS + 1).
A fifth-order Runge-Kutta method with variable step size was used to solve the model numerically. The parameters were obtained with REVOL, a derivative-free Monte Carlo minimizing algorithm (Koeppe and Hamann, 1980). The goodness of fit of the described model was assessed with least-square criteria. The data points were weighted by the inverse of the squared observed value (1/Ŷ2). AnF test was used to select the appropriate number of compartments (1 or 2) and a monocompartmental model was selected.
The plasma clearance (Cl, milliliters per kilogram per minute) of free benazeprilat was calculated with
The half-life corresponding to the rate constant of elimination of the free benazeprilat was calculated as
The nontissular ACE binding capacity (Pmax) (nanomoles) was calculated with
Concentration Effect Modeling.
Individual data obtained after oral benazepril administration (single- or multiple-dosage regimen) were analyzed. Because a total inhibition of ACE was observed, the relationship between plasma benazeprilat concentrations (free or measured) and the ex vivo ACE activity (in arbitrary units) was described by the fractional Emax model according to the equation
Simulations.
Simulations were performed with parameters obtained from a representative dog after single oral administration to describe the dose-effect relationship and the influence of the dosing interval.
Statistical Analysis.
Statistical analysis was performed with STATGRAPHICS (5STSC, Rockville, MD). The values are reported as means ± S.D. or as median and range. The influence of time on the benazeprilat inhibition of ACE was analyzed with an ANOVA for repeated measurements. When homogeneity of variance was rejected (Bartlett test), a nonparametric test was used. P < .05 was considered as significant.
Results
Intravenous Administration.
The data were well fitted with a monocompartmental physiologically based model as is shown for representative dog in Fig. 2. The adjunction of a peripheral compartment was not required (P > .05, F test). Estimates of pharmacokinetic parameters are given in Table1. The free benazeprilat Cl was 0.216 ± 0.046 l/kg/h, and the volume of distribution of the free fraction was 0.197 ± 0.022 l/kg. The half-life corresponding to the rate constant of elimination of the free fraction was 39 ± 6 min, i.e., much shorter than the apparent terminal half-life (seeDiscussion for explanation).
Single Oral Administration.
The plasma benazeprilat profile after the single oral benazepril administration was apparently well fitted for all dogs (Fig.3). There was a short lag time (11.0 ± 10.8 min) and the systemic availability was low (2.57 ± 1.23%) and explained the computation of high apparent clearances and volumes of distribution (Table 1). The half-life corresponding to the rate constant of elimination of the free fraction was 31 ± 12 min, a similar value to that calculated after the i.v. administration (paired ttest, P > .05) (Table 1).
Multiple Oral Administrations.
The data obtained after the multiple drug administrations were well fitted with the physiologically based monocompartmental model (Fig. 4). The minimal plasma benazeprilat concentration observed 24 h after the 14th administration was 5.24 ± 0.93 nM, a value not significantly different from that observed 24 h after the first dose administration, i.e., 5.08 ± 2.36 nM (paired t test, P > .05).
Kinetic parameters obtained from the multiple-drug administration were very similar to those of the single-dose administration (Table 1). The estimated systemic availability was 3.95 ± 0.83%, i.e., close to that obtained after a single-dose administration.
Binding Parameters.
The total binding capacity for benazeprilat (Bmax) expressed after scaling by the volume of distribution was similar after the i.v. administration (119 ± 17 nM) and the single oral administration (112 ± 23 nM) but significantly lower than after the multiple-dose administration (160 ± 38 nM) (ANOVA, Bonferroni test, P < .005). Most of the binding ACE capacity was located in the tissue, the nontissular (or so-called circulating) fraction of ACE activity being only 10.5 ± 3.5% after the i.v. administration, 10.7 ± 3.9% after the single oral administration, and 8.4 ± 5.5% after the multiple-dose administration (ANOVA, Bonferroni test, P > .05). The absolute tissular-binding capacity was 23.5 ± 3.79 nmol/kg and the nontissular (circulating)-binding capacity was 2.37 ± 0.56 nmol/kg (i.v. study). Assuming an even distribution in the plasma and in the entire volume of distribution, the estimated plasma ACE molar concentration was 12.4 nM (i.v. study), 11.7 nM (single oral administration), and 12.8 nM (multiple-dose administration) (Table 1).
The Cl of the free benazeprilat at 50% binding saturation (Kd), which is a measure of benazeprilat affinity for ACE, was 4.5 ± 1.9 nM after the i.v. administration, 2.7 ± 1.4 nM after the single oral administration, and 3.9 ± 1.5 nM after the multiple-dose administration (Table 1). The differences were not significant (ANOVA, Bonferroni test, P > .05). The total plasma (measurable) benazeprilat concentrations at 50% binding saturation (i.e., concentration corresponding to the free fraction plus the fraction bound to circulating ACE) were 10.3 ± 6.0, 10.7 ± 3.8, and 8.6 ± 3.0 nM after i.v., single oral, and multiple oral drug administrations, respectively.
Pharmacodynamic Effects.
Fig. 5illustrates the observed and fitted time course of ACE inhibition after the single administration of benazepril for a representative dog. Before benazepril administration, the mean (±S.D.) baseline plasma ACE activity value was 18.1 ± 4.8 U of activity. A single oral benazepril administration caused a rapid, nearly total, and long-lasting inhibition of plasma ACE activity. The reduction of ACE activity was already statistically significant at the first sampling time (0.5 h) and attained its lowest point 1 h after drug administration; a progressive return to basal activity began 16 h after benazepril administration, but the ACE activity was only 13.8% (range 0–29%) of the control values 24 h after the drug administration and a significant inhibition (P < .05) can still be observed 72 h after benazepril administration (65.7% of control value, range 49–94%). With the predicted free plasma benazeprilat concentration obtained from the physiologically based model, as independent variable for eq. 4, the IC50 of benazeprilat was 0.27 ± 0.21 nM, which was significantly lower than the corresponding in vivoKd, i.e., 2.7 ± 1.4 nM (ANOVA,P < .001). When the total (measurable) plasma concentration was used, the IC50 was 1.25 ± 0.60 nM. The slope factor calculated with the free fraction was 1.48 ± 0.58.
For the multiple-drug administration, the inhibition of ACE activity was total or near total over the 14 days of treatment and had not returned to pretreatment value 72 h after the final administration (44.2% of control value, range 12–59%). The estimated IC50 based on the model predicted free plasma concentration was found to be much more variable than after a single oral administration: 0.089 (median) or 0.16 ± 0.19 nM (mean ± S.D.). The slope factor was 1.09 ± 0.48. The IC50 based on the measurable plasma concentration was 0.46 nM (median) or 0.53 ± 0.46 nM (mean ± S.D.). The IC50 (free benazeprilat plasma concentration) obtained from the multiple benazepril administration was significantly lower than that obtained after a single-dose administration (Friedman test, P < .05).
Simulations.
Fig. 6 illustrates the dose-effect relationship of benazepril on the time course of plasma benazeprilat concentrations and the plasma ACE activity. It can be seen that whatever the dose, plasma concentrations were similar after a delay of 12 h and there was no supplementary effect on ACE inhibition when the benazepril dose was increased from 0.25 to 1 mg/kg. Figure 7 shows the possibility of obtaining the same overall ACE inhibition either with a single benazepril dose of 0.5 mg/kg or a twice-daily dose of 0.125 mg/kg benazepril, i.e., by reducing the total daily benazepril administration by a factor of 2. Figure 7 also shows that a relevant ACE inhibition can be obtained during a multiple-drug administration with a very low dose (0.0313 mg/kg b.i.d.) but that effect is maximal only after 10 administrations.
Discussion
The main result of this new data analysis of benazeprilat disposition in dog is that equations corresponding to a physiologically based model are appropriate to fit benazeprilat data and that the choice of physiological based models is not only of academic interest but also of practical relevance when interpreting the plasma concentration profile and predicting the consequence of disease on ACEI disposition.
The same data also were analyzed with classical multiexponential equations that gave an apparent adequate fit (data not shown). This indicates that visual inspection alone of the fitted curves and the apparent goodness of fit may be misleading in selecting an appropriate model for the analysis of ACEI disposition curves.
Lees et al. (1989) showed the sigmoidal shape of the initial plasma concentrations curve when the perindoprilat was administered as a constant rate infusion. In the present experiment, the first sample was obtained 0.5 h after the oral benazepril administration and an initial sigmoid-shaped curve was not actually observed. However, we were faced with a consequence of this phenomenon, i.e., the estimation of a relatively long lag time (mean value of ∼30–40 min) when the data were fitted by classical exponential analysis (data not shown). InToutain et al. (2000), the first sampling time was earlier (0.25 h) and the calculated lag time was systematically longer than 0.25 h, whereas a pharmacodynamic effect was already clearly apparent at this first sampling time. This was the main reason why we decided to reconsider exponential fitting for benazeprilat. Actually, the physiologically based model shows that there is no or short lag time to absorption/bioconversion (∼10 min).
The estimated clearance of free benazeprilat (i.e., the actually free benazeprilat and that bound to albumin) was ∼3 to 4 ml/kg/min, i.e., nearly equal to that calculated with a classical compartmental model (data not shown); this was not unexpected as the dose administered by i.v. route was very high with respect to the specific ACE-binding capacity and most of the AUC after i.v. administration reflected the elimination of the free fraction. It must however be understood that the clearance calculated with a classical compartmental model is a variable that is dose-dependent, whereas the clearance calculated with the physiologically based model is a parameter.
One practical consequence of the aforementioned consideration is that the systemic bioavailability of benazeprilat after an oral benazepril administration can only be obtained from the ratio of AUC for free benazeprilat after i.v. benazeprilat and oral benazepril administrations. In contrast, use of the ratio of AUC of the measured plasma concentrations (free benazeprilat plus benazeprilat specifically bound to circulating ACE) is not acceptable because the calculation of bioavailability from an AUC ratio implicitly requires that the oral and i.v. clearance are the same, which is not the case when clearance is estimated from the measurable benazeprilat concentrations. This is shown when the systemic availability is calculated from AUC derived from the compartmental model, which is about twice the true value (data not shown). From the physiologically based model, it can be predicted that estimating absolute bioavailability from measurable rather than free plasma AUC benazeprilat led to a bias that is dose (concentration)-dependent; the higher the plasma concentration (i.v., oral administration) the less biased the estimates.
The volume of distribution calculated with the physiologically based model (0.2 l/kg) was small and similar in value to the extracellular fluid volume space. In addition, free benazeprilat is distributed immediately, evenly, and only in this volume (monocompartmental model). This is relevant to the pharmacodynamic effects because the ACEs are ectopeptidases anchored to the cell surface with the catalytic site exposed at the extracytoplasmic surface (Hooper, 1993). Thus, benazeprilat is mainly distributed in its biophase, which is extracellular.
The terminal half-life is not a half-life of benazeprilat elimination (i.e., the time necessary to eliminate half the drug that is still present when the terminal phase begins to decay) but is governed by the nonlinear binding of benazeprilat to the ACE. The elimination process is rather reflected by the initial phase of decay. During this phase, which is interpreted as a distribution phase in the classical multiexponential model, the ACE is saturated and the decay reflects clearance of free drug. Actually, half-life is a hybrid parameter depending on clearance and volume of distribution. The very short half-life calculated for free benazeprilat with the physiologically based model (∼39 min) was mainly due to the small volume of distribution. One practical consequence of this very short half-life is that an induced renal and/or hepatic impairment is unlikely to lead to drug accumulation during multiple drug dosing.
The physiologically based model allows determination of the major components of the dog's ACE system, namely, the ACE maximal binding capacity with its tissular and circulating components. From our model, we estimated Bmax to ∼22 to 24 nmol/kg after a single i.v. dose of benazeprilat or benazepril administration (oral). Assuming a 1:1 binding relationship for benazeprilat and ACE, as is generally accepted for all ACEIs, the estimated pool of ACE in the dog would be ∼23 nmol/kg b.wt. Ninety percent of the ACE pool was noncirculating and only 10% distributed in the extravascular space, thus supporting the general view that the majority of ACEI is tissue-bound (Lees et al., 1989).
The Kd, i.e., the estimated amount of free benazeprilat required to saturate half the maximal binding capacity, was 0.90 nmol/kg (i.v. study). Assuming an even distribution of the free benazeprilat fraction in plasma and the entire volume of distribution (extracellular fluid and plasma), the estimated benazeprilat plasma concentration, corresponding to half-ACE saturation was ∼4.5 nM, corresponding to a measurable plasma concentration of ∼10 nM.
It should be noted that Bmax (i.e., the total amount of ACE) is not a drug parameter but a dog-specific parameter for all ACEIs having 1:1 binding relationships with ACE. Similarly, the fraction of nontissular (circulating) ACE as opposed to the tissular fraction is a dog-specific parameter. In contrast,Kd, which measures the drug affinity to ACE, is a drug parameter and can be used to compare different ACEIs. If it is realized that the terminal phase that governs the effect is directly controlled by the binding parameters (Bmax,Kd, fcirc), and that the volume of distribution of many low-lipophilic ACEIs is probably the extracellular space (i.e., 0.2l/kg), then it can be suggested that an in vitro binding assay (for measuring Kd, i.e., affinity) may provide a relevant screening tool for predicting kinetic properties of a new ACEI.
We evaluated the potency of benazeprilat ex vivo by measuring its IC50 with a classical sigmoid inhibitory model (eq. 4). In eq. 4, the independent variable, i.e., concentration, has to refer to the unbound and not the measured plasma drug concentrations (Francis et al., 1987). In most publications, the measured drug rather than the free drug concentrations have been considered and the IC50 calculated in the present experiment is not directly comparable with those generally reported in the literature. The calculated benazeprilat IC50 after a single oral benazepril administration was low (0.27 nM) in terms of free drug and ∼1.25 nM in terms of measurable benazeprilat concentration; this last value is almost equal to that estimated in dog by King et al. (1995), i.e., 1.39 nM.
The estimated IC50 was 10 times lower than the corresponding in vivo Kd (2.7 nM); this was unexpected from a theoretical point of view (Francis et al., 1987). The origin of the large discrepancy between the in vivoKd and the ex vivo IC50 is probably due to the ex vivo conditions that were shown to influence optimum conditions for the enzyme reaction (Hurst and Lovell-Smith, 1981; Alhenc-Gelas et al., 1983).
If ACEI efficacy is solely related to ACE inhibition, any concentration above the target plasma concentrations can be considered as wasteful; it can be suggested from the present experiment (Fig. 6) that pharmacological action (ACE inhibition) is relatively independent of doses >0.2 mg/kg and administration of benazepril twice a day rather than once daily could enable the total dose per day required to obtain an equivalent ACE inhibition to be reduced by a factor of 2 (Fig. 7). Such a dosage regimen would be less practical but would merit attention when a reduction of systemic exposure to ACEI is in order. Figure 7also shows that it is possible to inhibit ACE activity with a very low dose due to the progressive saturation of ACE by benazeprilat. In contrast, this physiologically based model predicts that a loading dose could be administered to immediately saturate ACE and then a small maintenance dose could be used to maintain the concentrations above the targeted concentrations.
In conclusion, the present modeling approach addresses several relevant issues when interpreting the plasma profile of an ACEI, such as the computation of accurate bioavailability, potential consequence of a clearance reduction on drug accumulation, and influence of dose and interval of administration on ACE inhibition. It can be concluded that although there was no obvious relationship between plasma benazeprilat concentrations and effects on ACE inhibition, this relationship does exist and the plasma kinetic profile provides relevant information for defining an optimal dosage regimen provided that an appropriate kinetic model is used to interpret the plasma data.
Footnotes
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Send reprint requests to: P.-L. Toutain, Ecole Nationale Vétérinaire de Toulouse, Laboratoire de Physiologie, 23, chemin des Capelles, 31076 Toulouse Cedex, France. E-mail:pl.toutain{at}envt.fr
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↵1 This work was supported by Novartis Santé Animale, Case postale, CH-4002 Bâle, Switzerland.
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↵2 Current address: Novartis Santé Animale, Case Postale, CH-4002 Bâle, Switzerland.
- Abbreviations:
- ACE
- angiotensin-converting enzyme
- ACEI
- ACE inhibitor
- AUC
- area under the plasma concentration curve
- fcirc
- circulating fraction of ACE
- Received May 20, 1999.
- Accepted December 2, 1999.
- The American Society for Pharmacology and Experimental Therapeutics