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Vol. 286, Issue 3, 1152-1158, September 1998
Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Uppsala University, Uppsala, Sweden
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Abstract |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The concentration-effect relationship of l-propranolol and
dl-metoprolol were investigated in spontaneous hypertensive
rats using reduction in exercise-induced tachycardia as a
pharmacodynamic endpoint. The influence of protein binding on the
effect relationship was also assessed. The rats were assigned to
treatment or placebo groups, where each group received three randomly
selected consecutively increasing steady-state infusions. Different
pharmacodynamic effect models were fitted to the data, using nonlinear
mixed effect modeling. The data were best described by a combined
effect model, with a sum of an ordinary Imax and a linear
model. At the lower concentration range, the ordinary Imax
model dominated, although at higher concentrations, the effect was
linearly related to the antagonist concentration. The Imax
were 83 ± 6 and 103 ± 6 beats · min
1
and the IC50 were 18.1 ± 4.3 and 50.6 ± 15.2 ng/ml for l-propranolol and dl-metoprolol,
respectively. The slope in the linear model was steeper for
l-propranolol than for dl-metoprolol, 28.9 ± 2.8 and 4.48 ± 0.39 beats · ml · (min · µg)1, respectively. Plasma protein binding of
l-propranolol was saturable. The unbound IC50
for l-propranolol was 1.14 ± 0.27 ng/ml. The concentration-effect relationship of l-propranolol was
altered at higher plasma concentrations, due to saturable protein
binding. The Imax and the linear concentration-effect
relationship may be interpreted as a specific 
-antagonist effect and
a membrane-stabilizing effect, respectively. Using exercise-induced
tachycardia as a pharmacodynamic endpoint, to study the effect of
-antagonists in spontaneous hypertensive rats, seems to give
reliable results and can be a useful model to extrapolate to humans.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The beta antagonists are among the most widely prescribed drugs for treatment of diverse cardiovascular diseases such as hypertension, angina pectoris, ischemic heart disease and arrhythmias. Propranolol was the first clinically used beta receptor antagonist and is the standard to which other beta antagonists are compared. A number of beta antagonists have been developed with different properties, such as relative affinity for beta-1 and beta-2 receptors, intrinsic sympathomimetic activity, membrane-stabilizing activity, differences in lipid solubility and general pharmacokinetic disposition properties. Despite their long use, the pharmacodynamic relationships have often been poorly characterized, mainly due to the restricted concentration ranges used in clinical studies. Other factors that have hampered the characterization of pharmacodynamic characteristics have been data with high variability and the use of dose rather than concentration.
The beta-1 and beta-2 receptors are present in
most tissues, the former is dominant in myocardial tissues and the
latter is more common in peripheral vessels and bronchial tissue. The
effect of beta-1 blockade is a reduction of myocardial
contractility and heart rate, resulting in a decreased cardiac output,
although beta-2 blockade causes bronchial constriction and
decreased vascular tone (Hoffman and Lefkowitz, 1996
). In the absence
of sympathetic stimuli, there is only a poor correlation between drug
plasma concentration and the decrease in heart rate (Hager et
al., 1981). This is not surprising, because heart rate at rest is
regulated by the parasympathetic system, whereas exercise increases the adrenergic innervated activity. Many models have been developed to
quantify the reduction in heart rate caused by beta
antagonists after a controlled pharmacological (e.g.,
isoproterenol) or physiological (e.g., exercise) stimulus.
It is important to state that these two methods do not yield equivalent
mechanistic responses. Heart rate reduction by an isoproterenol
stimulus is mediated by both beta-1 and beta-2
receptors (Pringle et al., 1988), whereas exercise is purely
beta-1 mediated (Arnold et al., 1985).
Exercise-induced tachycardia is the most widely used method of
measuring the drug effect in humans (Wellstein et al.,
1992), but corresponding animal studies have been few. SHR have been shown to be an appropriate animal model in studying essential hypertension in humans, and was used in this study to evaluate the
concentration-effect relationship of two beta antagonists, using exercise-induced tachycardia as a pharmacodynamic endpoint.
One of the most widely prescribed beta antagonists,
metoprolol, was selected, using propranolol as a reference. Because of the large difference in disposition between the two enantiomers of
propranolol (Walle et al., 1988), the
l-enantiomer was selected in this study. There is also a
large difference in protein binding between the two beta
antagonists. Propranolol is extensively bound (95%) to plasma
proteins, a binding that decreases at higher concentrations (Smits and
Struyker-Boudier, 1979), whereas the more hydrophilic metoprolol is
negligibly bound (12%) (Brogden et al., 1977).
Consequently, when an effect model is evaluated over a large
concentration interval, the impact of protein binding on the
concentration-effect relationship has to be considered.
Our objectives were to determine the concentration-effect relationships of l-propranolol and dl-metoprolol in conscious SHR, and to evaluate the use of exercise-induced tachycardia as a pharmacodynamic endpoint for future studies. The influence of plasma protein binding of l-propranolol was also determined.
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Animals and drugs. Male SHR weighing 300 ± 10 g (S.D.) were used (Möllegaard, Ejby, Denmark). The animals were housed under standardized conditions; room temperature 22 ± 1°C (S.D.), humidity 55 ± 5% (S.D.) and controlled light (7:00 A.M. to 7:00 P.M.) with free access to food and water. At least 1 wk before start of experiment, the rats were acclimatized to these conditions. During the experiment, the rats were kept in individual cages (CMA/120, CMA, Solna, Sweden). The study was approved by the Animal Ethics Committee of the University of Uppsala.
Crystalline l-propranolol hydrochloride (99% purity) and dl-metoprolol tartrate (Sigma Chemical Co., St. Louis, MO) were completely dissolved in a physiological saline solution (Pharmacia & Upjohn AB, Stockholm, Sweden).Surgical procedure and drug infusion. Two days before drug administration, two indwelling polyethylene catheters (PE50, Intramedic, KEBO, Spånga, Sweden) were implanted under light ether anesthesia. The left carotid artery was used to monitor heart rate and to sample blood while the study drugs were administered through the right jugular vein. The animals were trained during these two days to be accustomed to the handling and equipment.
The study was conducted in two separate parts. In each part, the rats were randomly assigned to receive drug or placebo treatment, and were given three consecutive intravenous infusions to steady-state (Harvad Apparatus Syringe Infusion Pump 22; B & K, Sollentuna, Sweden), where l-propranolol was given to 17 rats, dl-metoprolol to 13 and the corresponding placebo groups were five and six animals each. The steady-state levels were randomly picked among different aimed steady-state levels. Although, they were always attained from between the lowest up to the highest target concentration level. The desired steady-state plasma concentrations (Css) were; 20, 70, 200, 400, 800, 1400, 2200, 3000 and 3500 ng/ml for l-propranolol and 50, 100, 200, 400, 800, 1600, 3200, 6400, 12800 and 25600 ng/ml for dl-metoprolol. A technique using two consecutive intravenous infusions (Wagner, 1974)
was implemented so that different pseudo steady-state plasma
concentrations were rapidly attained. The following equations for calculating the infusion rates (Q1 and
Q2) were used:
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(1) |
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(2) |
and are pharmacokinetic macro-constants
(Gibaldi and Perrier, 1982). The pharmacokinetic parameters used to
calculate the rate of infusion required for a given steady-state concentration were derived from Terao and Shen (1983) and Vermeulen et al. (1993). A 30 min (T) loading infusion was followed by
a maintenance infusion over 2 hr and 20 min, for each of the three desired levels. The drug solution was given in such a concentration that the rats received less than 3 ml during the total 8.5-hr infusion.
Effect measurements and blood sampling. Mean arterial blood pressure was measured by a pressure transducer (Statham P23 DC, Grass Instruments Co., Quincy, MA). Heart rate was captured from the pressure signal, which triggered a tachograph (7P4DE) and the signals were recorded by a polygraph (Grass model 7). The recorded data were instantly converted in a MacLab interface (ADInstruments, Castle Hill, Australia) and fed into a Macintosh LC IIvi computer. The data were stored on a hard disk for off-line analysis, using the MacLab software Chart, version 3.2.6 (AdInstruments, Castle Hill, Australia).
Exercise-induced tachycardia was obtained by having the animals run in a motorized wheel for 10 min (6 m · min1). Mean
arterial blood pressure and heart rate were measured continuously for
15 min after exercise. In each rat, two effect measurements were
recorded before start of infusion (baseline) and at each concentration
level (effect values taken between 10 to 15 min postexercise). A mean
value of each was used in the pharmacodynamic analysis.
Arterial blood samples, 200 µl, were collected in heparinized
Eppendorf tubes. A total of 1200 µl was drawn from each animal. Two
blood samples were drawn at each steady-state level after the effect
measurement, and a mean value was used in the pharmacodynamic analysis.
The samples were centrifuged at 7200 × g for 10 min whereby plasma was separated and frozen immediately (
70°C) until analysis.
Protein binding.
The binding of l-propranolol to
rat plasma was determined by equilibrium dialysis. Pooled plasma
obtained from eight untreated rats that had undergone the same surgical
procedure previously described, including time in the restraining cage,
was frozen (70°C) pending equilibrium dialysis. The plasma sample
was adjusted to pH 7.40 using carbogen gas and spiked in triplicate
with known amounts of l-propranolol to achieve the following
concentrations: 20, 60, 100, 200, 300, 400, 600, 1000, 2000 and 3500 ng/ml. The Teflon chambers were filled with 0.8 ml plasma and 0.8 ml of
0.13 M phosphate buffer (pH 7.40). Before dialysis, the Spectrapor 4 membranes (Spectrum Medical Industries Inc., Houston, TX; cut-off value
of 12-14,000) were soaked in buffer for 2 to 3 hr. The cells were kept
rotated at 37°C for 4.5 hr, by which time equilibrium has been
reached. Volume shift was assessed by weighing the plasma/buffer solutions before and after equilibrium dialysis.
1-Acid glycoprotein and drug analysis.
The
AGP concentrations were determined by using a modification of a
previous published method (QR method) (Imamura et al., 1994). The analytical system consisted of a pump (ESA-580 Chelmsford, MA), a Triathlon autoinjector (Sparc Holland Emmen, the Netherlands), a
fluorescence detector (Shimadzu RF-551, Kyoto, Japan), and an integrator (Schimadzu C-R5A Chromatopac). The detector was set at
excitation and emission wavelengths of 496 nm and 590 nm, respectively. A 1/15 M phosphate buffer (pH 7.40) was used as mobile phase with a
flow rate of 0.5 ml/min. All volumes used were one-fourth of that
described in the original method, when preparing standard curves and
samples. Standards and samples were placed in the autosampler, where 50 µl were injected. The difference in height of the chromatograms, with
and without QR solution, gave the fluorescence of AGP alone and was
used as the response in the standard curves. Rat AGP showed a lower
fluorescence response than human AGP. Human AGP standards were used to
check the linearity of the system and rat AGP standards were used in
the standard curve. The method was highly reproducible with a interday
variability of <8%. The limit of quantification was 0.08 mg/ml with a
coefficient of variation of 17% (n = 6).
, with some modifications. The
analytes were extracted from 100 µl samples and standards in a 10-ml
round-bottomed test tubes. Internal standard, 50 µl, (12 µM
metoprolol tartrate or 4 µM propranolol HCl in distilled water) was
added to the 100-µl sample followed by 100 µl sodium hydroxide (4 M) and mixed briefly. Three mLs of diethyl ether was then added to the
mixture. The contents of the test tube were vortexed for 2 min and
centrifuged at 1400 × g for 10 min. The organic phase
(upper layer) was transferred into a 10-ml conical glass tube and
evaporated to dryness under a steam of oxygen free nitrogen, at 35°C.
The residue was dissolved in 150 µl of 5 mM
H2SO4, vortexed and then centrifuged (10 min 2000 × g) before injection. In the protein binding
study, the phosphate buffer samples were diluted with 5 mM
H2SO4 and the plasma samples with blank plasma,
when necessary, up to a total volume of 100 µl, to end up within the
range of the standard curve. All solvents and reagents were of
analytical grade.
The chromatographic equipment consisted of a pump (Shimadzu LC-9A,
Kyoto, Japan), a µBondapak colonn (C18 column, 30 cm × 3.9 mm i.d., Waters Associates Milford, MA), a fluorescence detector (Shimadzu RF-535 or Jasco FP-920 Tokyo, Japan) and an integrator (Schimadzu C-R5A Chromatopac). The excitation and emission wavelengths were 235 nm and 335 nm using Shimadzu RF-535 for
l-propranolol, and 280 and 305 nm using Jasco FP-920 for
dl-metoprolol, respectively, in the animal study. For the
protein binding analysis, the l-propranolol plasma and
phosphate concentrations were analyzed using Jasco FP-920 with
excitation and emission wavelengths of 222 and 350 nm, respectively.
All sample injection was performed using a CMA/200 autoinjector (CMA,
Solna, Sweden) fitted with a 100-µl sample loop. The composition of
the mobile phase was a 65:35 mixture of solution A and B, respectively,
when running plasma samples and changed to 70:30 when running samples
of phosphate buffer (pH 7.40). Solution A contains 25 ml of
l-heptanesulfonic acid (5 mM) in 1 liter acetic acid (1%)
and solution B contains 25 ml of l-heptanesulfonic acid (5 mM) in 1 liter acetonitrile. The flow rate was 2.0 ml/min. Retention
times for plasma samples were 2.7 and 4.7 min for metoprolol and
propranolol.
Peak area ratios of drug/internal standard were calculated and used in
single-level calibration curves drawn through origin with replicates
(n = 5) of the highest calibrator. The standard curves
were linear within the range of 1.8 to 400 ng/ml and 3.9 to 800 ng/ml
for l-propranolol and dl-metoprolol,
respectively. The interday variation for l-propranolol in
the concentration range 1.8 to 330 ng/ml was 
5% and the accuracy
varied between 92 to 100%. The interday variation for metoprolol in
the concentration range 9.8 to 490 ng/ml was 11% and the accuracy
varied between 90 and 100%. The absolute recovery was between 100%
(1.8 ng/ml) to 96% (326 ng/ml) for l-propranolol, although
it varied between 112% (3.9 ng/ml) and 93% (780 ng/ml) for
dl-metoprolol. The limit of quantification was 1.8 ng/ml for
l-propranolol and 3.9 ng/ml for dl-metoprolol,
respectively.
Data analysis.
Population models describing the
concentration-effect relationships of the two -antagonists were
performed by relating the reduction of induced exercise-tachycardia
directly to the measured steady-state plasma concentrations
(time-independent) of the drugs. Both a linear (equation 3) and an
ordinary Imax model (equation 4) were first fit to the
data.
|
(3) |
|
(4) |
; Holford and Sheiner, 1982; Paalzow, 1990)
were also considered. Both a linear (equation 5) and an ordinary
Imax model (equation 6) were tested as the dual effect.
|
(5) |
|
(6) |
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(7) |
). The
NONMEM program is based on a statistical model that explicitly takes
into account both the inter-animal variability in the parameters as
well as intra-animal residual error. All data will be fitted
simultaneously although preserving the individuality. This approach is
particular suitable in cases where some of the concentration-effect
curves are not completely defined, as all available information may
provide reasonable estimates of the missing parts. The graphic analysis
was performed using the Xpose package (Jonsson and Karlsson, 1998)
running under Splus, version 3.3 (Statistical Sciences, 1993). An
additive error model (equation 8) was used to characterize the residual
error:
|
(8) |
ij represents the residual error of variance
for the ith individual, its distance between the
jth observation and prediction. The values for
ij are assumed to be symmetrically distributed, with
mean zero and variance 
2. A proportional error model was
used in the protein binding study:
|
(9) |
|
(10) |
is the population mean parameter value, and
exp(
i) expresses the (random) difference between
Pi and . The values for i
are assumed to be independently multivariate distributed, with mean
zero and diagonal variance-covariance matrix 
with diagonal elements
(
12, ... ,
m2). The values of the population parameters
, 2, and are estimated from the data, where is the population parameter estimate.
Discrimination between different models was calculated via comparison
of the objective function values (2log likelihood) by NONMEM and by
visual inspection of the goodness of fit plots. The difference between
the objective function values for two hierarchical models is
approximately chi-square distributed and may consequently be used for
model selection purposes. In this study, P < .05 was used as the
significance level. All data are given as mean ± S.E. unless
otherwise stated.
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Protein binding.
The relationship between unbound fraction and
total plasma concentration of l-propranolol was described by
a binding model for different independent sets of equivalent binding
sites (fig. 1). The number of binding
site was 1.08 ± 0.07 and the association constant was 0.736 ± 0.059 µM1 at an AGP concentration of 22.6 µM (MW
43,500). The fraction unbound of l-propranolol was 5.3 ± 0.5% (mean ± S.D.) and linear in the 60 to 1400 ng/ml
concentration range (fig. 1). At more than 1400 ng/ml, the free
fraction increased, and at 3500 ng/ml, it was 10 ± 0.7%
(mean ± S.D.). No results were obtained for the lowest studied
concentration (20 ng/ml) because of assay limitations. No apparent
volume shift was seen during the 4.5-hr equilibration time.
|
Concentration-effect relationship.
The baseline variation
between the two treatment groups was not significantly different. The
maximal observed decrease in heart rate for l-propranolol
and dl-metoprolol was 168 and 216 beats · min1, respectively. At concentrations higher than 3000 ng/ml of l-propranolol, acute bradycardia occurred, and
consequently the highest steady-state level has been excluded in this
evaluation.
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1. The first-order (FO) and first-order
conditional estimation (FOCE) methods performed equally, and therefore
only the results of the former are presented.
|
). About a 20-fold difference in the IC50u
values was found when the two drugs were compared. There were large
differences between the slopes of the linear model; 343 ± 51 and
28.9 ± 2.8 beats · ml · (min · µg)1 for unbound and total l-propranolol and
4.48 ± 0.39 beats · ml · (min · µg)1 for dl-metoprolol.
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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In earlier pharmacodynamic studies of -antagonists, simplified
concentration-effect relationships such as linear or log-linear models
have frequently been used, mainly due to the small dose/concentration range studied in humans. In this study, we clearly demonstrate that the
concentration-effect relationship of l-propranolol and metoprolol is more complex and better described by a combined relationship of at least two different components. This was obtained by
using a well-defined stimulus (exercise-induced tachycardia) in
combination with a large drug concentration interval.
When using a large dose/concentration interval, saturation processes
might be revealed, such as nonlinear protein binding. Differences in
the free fraction are of minor importance in experiments with only one
compound, but when a highly bound agent is compared to a virtually
unbound drug, this needs to be accounted for. The protein binding in
this study was linear at low plasma l-propranolol concentrations, which is in agreement with previous findings in Wistar
rats (Chindavijak et al., 1988). An increase in free
fraction has earlier been found for dl-propranolol in SHR
(Smits and Struyker-Boudier, 1979), where the nonlinearity started at
around 100 ng/ml in rats with a normal AGP level. From the literature
it is known that the AGP level can increase 6-fold 2 days after surgery
(Yasuhara et al., 1983; Lin et al., 1987),
suggesting that the nonlinearity in this study would occur at higher
drug concentrations.
In addition to surgery, infections, inflammations and stress, are
important conditions that will increase the AGP concentration. It has
been shown that the AGP level has a large influence on both the
pharmacokinetics and the apparent pharmacodynamics of propranolol when
total plasma concentrations are used in the evaluation (Yasuhara
et al., 1983), and consequently the levels of AGP is essential to quantify and explain interindividual variability. The
saturation of the protein binding in our study affects the response of
l-propranolol at high plasma concentrations. It increases the steepness of the concentration-effect relationship at high plasma
levels, suggesting a nonlinear increase of the effect at high doses.
During saturated protein binding the half-life is likely to increase,
because the relative change in the volume of distribution is expected
to be larger than in clearance (Evans et al., 1973). In
addition, the -antagonists at these high concentration levels will
decrease the blood flow and thereby the clearance, which suggest that
an even longer half-life should be observed. The consequence on
duration of action is difficult to interpret, but changes in kinetics
is suggested to be larger than the difference in the effect slope.
The maximal response after exercise-induced heart rate in humans
occurred at plasma dl-propranolol concentrations from 100 ng/ml and above (Hager et al., 1981; Lalonde et
al., 1987; Sowinski et al., 1995), which is in
agreement with our data. The Imax value was 21.3% for
l-propranolol in this study, which is lower in comparison values reported from human studies, 33.3 to 38.3%, where
dl-propranolol was given orally (Lalonde et al.,
1987; Sowinski et al., 1995). The estimated IC50
value in our study, 18.1 ng/ml (l-propranolol), was within
the range reported in these human studies (10.2-24.4 ng/ml,
dl-propranolol). The unbound IC50 values in
these human studies were 1.29 to 2.77 ng/ml, which is similar to our
observation (1.14 ng/ml). The corresponding values reported for
dl-metoprolol are in agreement with the present findings
(Abrahamsson et al., 1990).
In a study performed on dogs, both propranolol and metoprolol
equipotently reduced exercise-induced heart rate in a similar fashion
(Åblad et al., 1980). In our study, we did not find large differences in the pharmacodynamics between the two drugs either. However, a 20-fold difference appears when the IC50 values
are corrected for protein binding, making propranolol the more potent drug. The difference in IC50 values of different studies
could be due to the exercise test used, i.e., duration,
power and type. As the drugs are competitive antagonists, a higher
degree of exercise (agonist) will shift the effect relationship toward
higher concentrations (Wellstein et al., 1985).
Except for the large difference in protein binding between propranolol
and metoprolol, they also differ in such factors as their respective
affinities to the beta-1 and beta-2 receptors, membrane stabilizing activity and lipophilicity. Selectivity is a
relative rather than an absolute property, because increasing doses of
1-selective antagonists results in a dose-related
beta-2 adrenoceptor blockade (Lipworth et al.,
1991) and because higher doses of a beta-2 adrenoceptor
selective antagonist will reduce exercise-induced tachycardia (Harry
et al., 1988). The different roles of beta-1 and
beta-2 receptors in the genesis of cardiovascular responses
have proved to be more complex, because of their coexistence in the
heart (Brodde et al., 1983). The rat's left ventricle
contains about 74% beta-1 and 26% beta-2
adrenergic receptors (Vago et al., 1984). Due to the high
density of beta-1 receptors in the heart, one would expect
that they would contribute more to the positive inotropic and
chronotropic responses than would beta-2 (Molenaar and
Summers, 1987), and that the latter would play only a minor role in the
heart rate alteration.
A major effect of beta antagonist therapy is increased AV
nodal conduction time resulting in a prolonged AV nodal refractoriness (increased PR interval). Hence, beta antagonists are useful
in terminating reentrant arrhythmias that involve the AV node and in
controlling ventricular response in atrial fibrillation or flutter
(Roden, 1996). As it is difficult to standardize and use arrhythmias as
pharmacodynamic endpoints, many studies have been performed in
vitro. Pruett and coworkers (1977, 1980) found that d-
and dl-propranolol shortened action potential duration with similar potency at a concentration as low as 100 ng/ml. The
antiarrhythmic activity correlated better with the tissue propranolol
concentration, and when this was taken into account, the minimum plasma
concentration expected to produce an electrophysiologic effect in
patients was 150 ng/ml. This was confirmed when 40% of the patients
with ventricular arrhythmias responded to the drug at plasma
concentrations in excess of 150 ng/ml, a level associated with a high
degree of beta receptor blockade (Woosely et al.,
1979). When d-propranolol was given separately, it
suppressed ventricular arrhythmias both through
non-beta-mediated effect (includes membrane-stabilizing activity) and beta-mediated effect (Murray et
al., 1990).
Propranolol and metoprolol display a large difference in partition
coefficient, where propranolol is much more lipophilic (logD 20.2) than
metoprolol (logD 0.98). The large difference in lipophilicity could
explain the difference in membrane-stabilizing activity, due to
membrane dissolving capacity. The steeper slope of propranolol should
then indicate that it would display more membrane-stabilizing activity
as compared to metoprolol, which is in agreement with the literature
(Hoffman and Lefkowitz, 1996). Concluding that the linear component in
the dual effect model could be membrane-stabilizing activity.
In conclusion, using spontaneous hypertensive rats to study the concentration-effect relationship of beta-blockers, with exercise-induced tachycardia as the pharmacodynamic endpoint, gives reliable results and may be a useful model to extrapolate to humans. The combined Imax and linear concentration-effect relationship can be interpreted as a specific beta antagonist effect and a membrane-stabilizing effect, respectively.
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Acknowledgments |
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The authors thank Mrs. Britt Jansson for her analytical expertise and Beatrice Nilsson and Marika Segerström for hard work during their undergraduate studies. The authors thank the section of Pre-Clinical Pharmacokinetics, Pharmacia & Upjohn AB, Uppsala, Sweden, for placing the protein binding equipment at our disposal. Janet Wade, PhD, is cordially thanked for discussion of the manuscript.
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Footnotes |
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Accepted for publication April 24, 1998.
Received for publication December 22, 1997.
1 This study was supported in part by the Swedish Pharmaceutical Society, Sweden. This study has been presented at the meeting of the Annual American Pharmaceutical Society (AAPS), Boston, 1997.
Send reprint requests to: Dr. Lena Brynne, Department of Pharmacy, Division of Biopharmaceutics and Pharmacokinetics, Box 580, S-751 23 Uppsala, Sweden.
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Abbreviations |
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AGP, 1-acid glycoprotein;
SHR, spontaneous hypertensive rat.
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References |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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2-adrenoceptor antagonist ICI 118,551 on exercise tachycardia and isoprenaline-induced -adrenoceptor responses in man.
Br J Clin Pharmacol
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an S-PLUS based population
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Drug Metab Dispos
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138-140[Medline].1-adrenoceptor selectivity of bisoprolol.
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513-520This article has been cited by other articles:
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  L. Brynne, L. K. Paalzow, and M. O. Karlsson Consequence of Exercise on the Cardiovascular Effects of l-Propranolol in Spontaneously Hypertensive Rats J. Pharmacol. Exp. Ther., September 1, 2000; 294(3): 1201 - 1208. [Abstract] [Full Text]
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L. Brynne, L. K. Paalzow, and M. O. Karlsson Mechanism-Based Modeling of Rebound Tachycardia after Chronic l-Propranolol Infusion in Spontaneous Hypertensive Rats J. Pharmacol. Exp. Ther., August 1, 1999; 290(2): 664 - 671. [Abstract] [Full Text]
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)
and predicted (
