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Introduction
The renin-angiotensin-aldosterone system (RAAS) is a direct contributor to both hypertension and the associated
pathological changes that develop in the heart and vasculature. Angiotensin II (Ang II), a multi-functional hormone and
major effector molecule of the RAAS, has a pivotal role in regulating extracellular volume and vascular
resistance[1,2]. Telmisartan inhibits
AT1 receptor selectively and inconvertibly, which is used for treatment of hypertension without action on other
receptor, especially those in the cardiovascular system. Its efficacy, tolerability, and clinical uses are reviewed in several
reports[3_5]. In humans, telmisartan 40 mg provided rapid-onset, well-tolerated, and certain inhibition of Ang II-induced
hypertension, with maintenance of the inhibitory effect for
48 h[6].
In recent years, the pharmacokinetic (PK) and the
pharmacodynamic (PD) properties of telmisartan have been
reported[7]. It is evident that telmisartan resides in the plasma
for a long time and has a slow dissociation rate from the
AT1 receptor, which extends the occupancy time of the receptor
protein and duration of action. However, very little
information is available on the relationship between PK and PD of
telmisartan. For antihypertensive agents, a suitable
relationship of dose-concentration-effect is helpful for clinical
application. A proper PK-PD model has made it possible to
predict the time course of plasma concentration and the
intensity of the pharmacological effect just based on clinical
dosage. In this study, a PK-PD model based on the
hypotensive mechanism of telmisartan was proposed in
spontaneously hypertensive (SH) rats after oral drug
administra-tion. The objective of the current report was to resolve the
PK and the PD characteristics of telmisartan.
Materials and methods
Chemicals and animals Telmisartan and candesartan
were supplied by the Department of Pharmaceutical
Analysis of China Pharmaceutical University (Nanjing, China).
Acetonitrile (Merck Corporation, Darmstadt, Germany) was
of HPLC grade, and all other reagents were of analytical grade.
Male SH rats (200_230 g) were obtained from Beijing Vitalriver
Experiment Animal Corporation (Beijing, China). The
animals were kept on a 12 h light/dark cycle for a minimum of
three days before the experiments with free access to water
and a standard diet. The studies were approved by the
Animal Ethics Committee of China Pharmaceutical University.
Animal study Twenty male SH rats with systolic blood
pressure (SBP)>200 mmHg, diastolic blood pressure
(DBP)>150 mmHg were randomized into one control and three
experimental groups for oral administration of 2, 4, and 8
mg/kg of telmisartan. At 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96
h after administration, blood pressure was measured by
tail-cuff manometry (BESN-II BioSystems, Nanjing, China), and
the blood samples (0.2 mL) were collected by puncture of
retro-orbital sinus simultaneously.
Drug assay The quantitative analysis of telmisartan,
according to the established method with little
modifications[8], was performed using a Shimadzu HPLC/ESI/MS 2010 EV
system (Shimadzu Corporation, Kyoto, Japan) with a
Shim-pack C18 column (150×2.0 mm ID, 5 mm, Shimadzu, Japan).
The mobile phase was acetonitrile-5 mmol/L ammonium
acetate (50:50, v/v), and the column temperature was maintained
at 40 ºC. A constant mobile phase flow rate of 0.2 mL/min
was employed throughout the analyses. Target ions were
monitored at m/z 515.1 for telmisartan and
m/z 611.1 for candesartan (internal standard) in the positive ion-selected
ion-monitoring mode. The samples were prepared as follows:
50 mL plasma samples together with 10 µL (2 µg/mL) internal
standard were mixed after vortex shaking; 4 mL of ether was
added and the mixture was vortexed for 3 min. After
centrifugation at 1500×g for 10 min, the upper organic layer was
quantitatively transferred and evaporated to dryness using
an evaporator at 50 ºC. The residue was reconstituted in 100
mL of the mobile phase, and a 10 mL aliquot of the solution
was injected into the HPLC/ESI/MS system for analysis.
Under these conditions, the method was also validated
according to the requirement of the biopharmaceutical analysis.
The limit of quantitation for telmisartan was 2 ng/mL; at this
concentration the accuracy was 92.9% while precision was
12.7%. During validation, within-batch accuracy ranged from
91.5% to 112.0%, while within-batch precision remained
below 10.6%. The between-batch accuracy was between
94.6% and 109.1%, while precision remained below 13.7%.
Short-term stability showed that telmisartan was stable in plasma
for at least 16 h at room temperature, while long-term
stability studies showed that telmisartan was stable in plasma for
at least 7 d when stored at -20 ºC.
Pharmacokinetic analysis The PK parameters were
estimated by the BAPP2.3 software package (Nanjing, China).
The terminal half-life (t1/2) was determined by linear
regression of the terminal elimination of the plasma concentration.
The mean residence time (MRT) was calculated by a moment
method. The area under the plasma concentration-time curve
from 0 to the last measurable plasma concentration point
(AUC0_t) was calculated by the linear trapezoidal method.
Extrapolation to time infinity
(AUC0_¥) was calculated as follows:
AUC0_¥=AUC0_t+C
t/ke. The maximum drug plasma
concentration (Cmax) and the time to reach the maximum
concentration (Tmax) were taken directly from the observed data.
According to the observed data, the hypotensive curve was
fitted using a nonlinear least-squares regression analysis
after oral doses.
Pharmacodynamic analysis Microsoft Excel software
(Microsoft, Redmond, WA) was used to develop the
algorithm[10]. The hypotensive effect was assessed by
measurement of SBP and DBP, and then the mean arterial blood
pressure (MABP) was evaluated as follows:
MABP=DBP+(SBP-DBP)/3. The relationship between the plasma concentration
and pharmacological effect was quantified by a
physiological indirect effect model that was similar to the indirect
suppression model proposed by Dayneka et
al[9]. The diagram of the model is shown in Figure 1.
The PD modeling was based on a scheme that blood
pressure was produced with a zero-order input rate constant
(Kin) and dissipated with a first-order output rate constant
(Kout). Telmisartan inhibited the input rate of production
(Kin), thus, the effect of telmisartan was modeled as an inhibitory
factor of input rate, and the changes of blood pressure in SH
rats can be expressed as:
The response variable (R) begins to a predetermined
baseline value (R0), changes with time following drug
administration, and eventually returns to
R0. Thus,
R0=Kin/K
out, where IC50 is the concentration which yielded 50%
effect of the maximum inhibition effect. The effect
compartment model uses a modified
Emax model to calculate the PK-PD
parameters[11]. An equation of the modified
Emax model is:
The goodness of fitting are determined by the Akaike's
information criterion (AIC) values.
Statistical analysis The statistical difference of PK and
PD parameters at three doses was tested by ANOVA.
Results
Pharmacokinetics The plasma concentration-time
profiles of telmisartan after oral administration were shown in
Figure 2, and the PK parameters were summarized in Table 1.
The analysis of variance of the
t1/2 and clearance (CL) showed no differences
(P>0.05), while the AUC had significant
differences among the three doses of treatments after oral
administration (P<0.05). These results indicated that
t1/2 and CL did not vary with doses. The AUC increased with
increasing doses for oral administration, and the regression
analysis of the AUC-dose plot indicated good linearity
(r>0.98).
Pharmacodynamics The observed and fitted
hypotensive effects by various PK-PD models after oral
administration were displayed in Figure 3. Telmisartan caused a slow
onset and marked reduction of blood pressure at three
experimental doses. Blood pressure levels were lowered by
13.4%±4.0%, 23.5%±6.3%, and 33.2%±5.8% of the basal
levels after doses of 2, 4, and 8 mg/kg respectively. The
analysis of variance of the hypotensive effect showed
statistical differences among the three doses of treatments
after oral administration (P<0.05). The hypotensive effects
rose to a peak at 12 h and were still observed at 72 h. Blood
pressure returned to baseline at 96 h at all doses. As shown
in Figure 4, the peak level of hypotensive effects occurred
later than the plasma peak concentration, indicating a delay
in eliciting the pharmacological effect. The PK-PD
parameters simulated by the indirect response model and
effect-compartment model at three different doses were shown in
Table 2. The determined AIC values for the indirect response
model were lower than those for the effect-compartment
model at three dose levels, respectively. This suggested
that the indirect response model was more adequate for the
PK-PD modeling of telmisartan than the effect-compartment
link model. The analysis of variance of AUEC showed
statistical analysis at three doses in two models. There was no
significant difference in the other parameters at different dose
levels, which suggested that these parameters were
dose-independent.
Discussion
A link model (effect-compartment model) was used to
describe the PD of the AT1
inhibitor[12]; however, this model is physiologically unrealistic for the mechanism of this class
drug which may be largely determined by the elimination
rate of the physiological substance rather than the
distribution of the drug to the site of
action[13,14]. An indirect response model has been proposed for many
drugs[15_17], such as the inhibition or simulation of the growth or decline of
factor controlling the response measured experimentally.
Despite the fact that the PK character and the mechanism
of the hypotensive action of telmisartan have been
described[7], the relationship between its PK and PD has not yet been
established with a proper model. Based on the mechanism of
telmisartan hypotensive action, the indirect response model
was introduced for the investigation of the PK-PD
relation-ship. As the present results indicated, the indirect response
model provided a good prediction of the time course of the
pharmacological effect. One of the objectives for this
investigation was to compare the indirect PD response model with
the effect-compartment link model for the PK-PD modeling
of telmisartan based on the resultant AIC data listed in Table
2. The relationship between plasma concentrations of
telmisartan and its hypotensive effect has been better fitted
by the indirect PD response models than by the
effect-compartment link model. The results suggested that the
hypotensive effect of telmisartan could be better described by
an indirect response mechanism.
An important issue regarding any PD model is its ability
to reflect the underlying mechanism. Drugs/ligands that
interact with the corresponding receptor have gained
considerable interest for therapeutic use. It is reported that the
hypotensive effect of telmisartan are mediated by blocking
the AT1 receptor as the case for other sartans. The
hypotensive mechanism of telmisartan is caused by the inhibition of
adenylate cyclase (AC) by the AT1 receptor at many target
sites, which inhibits the formation of cyclic adenosine
monophosphate (cAMP) from cytoplasmic adenosine
tripho-sphate. A decrease in the cAMP inhibited the
cAMP-mediate protein kinase, which exhibits the blood pressure lowering
through several routes, such as decreasing vasoconstriction,
renal sodium re-absorption, aldosterone secretion, and
sympathetic nervous system activity. It is assumed that
production of cAMP is a zero-order process with a rate constant
(Kin), whereas cAMP is eliminated by phosphodiesterase with
a first-order rate constant
(Kout). Telmisartan induces the
blood pressure lowering through the inhibition of the
production of cAMP with an inhibition constant of
IC50. Hypotensive effect in turn is assumed to be proportional to the
cAMP level. Therefore, the PD part of the model was also
based on the scheme that blood pressure was produced by
an input function (Kin) and dissipated by an output function
and that telmisartan inhibits the factor of input of response.
The initial decline of blood pressure reflected the inhibition
of Kin values, whereas the return to baseline was controlled
by the disappearance of telmisartan. In the present study,
the change rate of the plasma concentration and
hypotensive effect were fitted to a time-dependent function.
The investigation employed an indirect response PD
model to describe the hypotensive effect dependent on the
concentration of telmisartan. The study had provided the
parameters (ie Kin,
Kout, IC50) to estimate the duration, the
intensity, and the rate of the hypotensive effects. In the PD
profile, the blood pressure returned to the basal level in a
relatively long time. This may be attributed to close
drug-receptor binding, as well as slow dissociating from the
receptor. In addition, the long duration of the
pharmacological effect was justified by the finding that the
IC50 of telmisartan was low, which suggested that telmisartan was
a potent and longer acting blood pressure-lowering drug.
The Cmax and AUC increased in proportion to the
administered doses (r=0.98 and 0.99, respectively), while the
DMABPmax and AUEC did not increase proportionally with
dose increasing. This finding could be explained by the fact
that antihypertensive drugs have a flat dose-response curve
for the hypotensive effect[18].
In conclusion, we have characterized the PK and PD
profiles of telmisartan, an AT1 receptor antagonist, in SH rats.
An integrated indirect response PK-PD model was
successfully developed to characterize the PK-PD profile after oral
administration. The hypotensive response to telmisartan
could be predicted accurately by using the indirect response
model than the effect-compartment link model. The
modeling procedure employed here may be useful for optimizing
the therapeutic schedule of telmisartan.
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