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Journal of Clinical Pharmacology, 2004; 44:245-252
© 2004 the American College of Clinical Pharmacology

PHARMACOKINETICS AND PHARMACODYNAMICS

Rheumatoid Arthritis Does Not Reduce the Pharmacodynamic Response to Valsartan

Noriko Daneshtalab, BSc, Richard Z. Lewanczuk, MD, PhD, Anthony Russell, MD and Fakhreddin Jamali, PhD, FCP

From the Faculty of Pharmacy and Pharmaceutical Sciences (N. Daneshtalab, Dr. Jamali) and Faculty of Medicine (Dr. Lewanczuk, Dr. Russell), University of Alberta, Edmonton, Alberta, Canada.

Address for reprints: Dr. F. Jamali, Faculty of Pharmacy and Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Inflammatory conditions decrease the cardiovascular response to calcium channel and ß-adrenergics blockers due, likely, to down-regulation of the receptors mediated by pro-inflammatory mediators such as C-reactive protein (CRP), nitric oxide (NO), and tumor necrosis factor. The purpose of this investigation was to determine whether down-regulation is also evident in angiotensin II type 1 receptors (AT1R) during varying inflammatory states. Normotensive subjects were divided into three groups according to the severity of disease: 14 with active rheumatoid arthritis, 12 with controlled rheumatoid arthritis, and 12 healthy control subjects. The AT1R antagonist valsartan (160 mg) was given to all the subjects, and blood samples were taken for pharmacokinetic analysis. The systolic, diastolic, and mean arterial pressures were determined at all blood collection times. The degree of inflammation was measured using joint swelling, NO, and CRP. Plasma valsartan concentration was measured using high-performance liquid chromatography (HPLC). Patients with active disease had significantly higher joint swelling, NO, and CRP than other groups. Plasma valsartan concentration-time curves were remarkably similar in all groups. No reduced response was noticed. Our preliminary observation suggests a need for further studies to examine the possibility of AT1R antagonists as alternatives to other cardiovascular drugs so that their potency may be reduced by inflammation.

Key Words: Angiotensin II type 1 receptors • pharmacokinetics • pharmacodynamics • inflammation • rheumatoid arthritis • receptor down-regulation • drug-disease interaction • pro-inflammatory mediators • NO • C-reactive protein

Inflammatory conditions are associated with an increase in various pro-inflammatory mediators (e.g., interleukins, tumor necrosis factor {alpha} [TNF-{alpha}], C-reactive protein [CRP], and nitric oxide [NO]) proportionate to the severity of disease.1-3 Many cardiovascular conditions such as hypertension, congestive heart failure, and myocardial infarction4-7 are also associated with increased pro-inflammatory mediators. Indeed, elevated pro-inflammatory cytokines and C-reactive protein have been suggested to be independent risk factors for atherosclerotic vascular disease and myocardial infarction.8-13 Keeping with this hypothesis is the increased mortality due to the development of cardiovascular complications seen in patients with rheumatoid arthritis.14-17

Pro-inflammatory mediators have also been shown to reduce the clearance of efficiently metabolized drugs through down-regulation of the cytochrome P450 system.18 This results in increased drug plasma concentrations. Interestingly, however, this elevation of drug concentration is associated with the decreased rather than increased potency of selected cardiovascular drugs such as calcium channel blockers in patients19 with rheumatoid arthritis as well as ß-adrenergic antagonists and potassium channel blockers in animal models of arthritis.20-22 These effects are attributed to down-regulation of the receptors involved. A reduced effectiveness of cardiovascular drugs, therefore, may at least in part be contributing to the higher rate of mortality in cardio-inflammatory states.

The purpose of this study was to investigate whether the potency of the angiotensin receptor antagonists is also reduced by inflammation. We chose valsartan since its clearance does not depend on hepatic metabolism; hence, it is unlikely to be affected by inflammation. The possibility of altered pharmacodynamics can, therefore, be investigated in the absence of complications arising from altered pharmacokinetics. We chose rheumatoid arthritis patients as our model of inflammation as it is associated with an increase in cardiovascular events and because our previous studies on the down-regulation of calcium channel receptors revealed abnormalities in this group of subjects.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Materials
Valsartan was supplied by Novartis Pharma (Basel, Switzerland). Sodium hydroxide, potassium dihydrogen orthophosphate (minimum assay 99%), and orthophosphoric acid (minimum assay 85%) were all purchased from BDH Chemicals Canada (Edmonton, Canada). High-performance liquid chromatography (HPLC) grade methyl-tert-butyl ether and acetonitrile were obtained from Fisher Scientific (Edmonton, Canada). Asperigillus nitrate reductase 10 U mL-1, 0.1 mM nicotinamide adenine dinucleotide phosphate (NADPH), 1500 U mL-1 lactate dehydrogenase (LDH), and 100 mM pyruvic acid were purchased from Sigma Chemical Co. (St. Louis, MO).

Subjects, Study Protocol, and Assessment of Pharmacokinetics and Pharmacodynamics
Subjects were recruited from rheumatology clinics in the city of Edmonton, Alberta. A total of 38 subjects, in the age range of 22 to 74 years, were entered into the study. The subjects were divided into three groups: 14 patients with active flare-up of rheumatoid arthritis, 12 patients with controlled rheumatoid arthritis (in remission), and 12 healthy subjects as controls. Patients were selected independent of blood pressure. However, known hypertensives were excluded, and study subjects were not on any cardiovascular drugs. The study was performed in accordance with the Declaration of Helsinki. The protocol was approved by the University of Alberta Hospital Research and Ethics Committee. All participants provided written informed consent.

The subjects all underwent routine laboratory tests 1 week prior to the commencement of the study. The screening studies consisted of hematology, routine biochemistry, ECG, urinalysis, and C-reactive protein levels.

Patients were matched between groups based on the arthritis therapy used. They were diagnosed according to the American Rheumatism Association 1987 revised criteria.23 The arthritic index was calculated using number of joints involved and the severity. Subjects were dosed with 160-mg capsules of valsartan (Diovan, Novartis Pharma, Basel, Switzerland), which were purchased from the University of Alberta Hospital Pharmacy.

No arthritic medications were taken within 24 hours of the study, and all subjects fasted on the evening prior to the study. If necessary, acetaminophen was given for pain control. Acetaminophen does not interfere with the pharmacokinetic analysis of valsartan.

On the study day, subjects arrived before 0700 to the clinical investigation unit after at least an 8-hour fast. An intravenous line was inserted for blood sampling, and the patient was allowed to rest recumbent for 30 minutes prior to measuring baseline physiological variables. Physiological variables included mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP). All measurements were carried out using an HDI/PulsewaveTM Cardiovascular Profiling Instrument CR-2000 (Hypertension Diagnostics, Inc., Minneapolis, MN). The maximum percent effect and the area under the percent effect curve (AUEC) were calculated for the cardiovascular parameters.

After baseline measurements were carried out, the subjects received valsartan with 250 mL of distilled water. After drug administration, subjects were required to remain upright for a minimum of 2 hours. At 2 hours, subjects received 240 mL of orange juice. Thereafter, they were free to drink at will. At hours 4 and 9, standard meals were provided. No other food was consumed other than that provided.

Blood samples (approximately 10 mL) were taken, and pharmacodynamic measurements were carried out at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 12 hours. Blood was centrifuged immediately after collection and the plasma immediately frozen at -70°C. Pharmacokinetic indices were calculated using the model-independent approach. Oral clearance (CL/F), oral volume of distribution (Vd/F), area under the concentration versus time curve (AUC0-{infty}), terminal elimination rate (ß), terminal half-life (t1/2), and maximum concentration (Cmax) and the time of its attainment (tmax) were estimated. Plasma nitrite level was measured in the time zero blood samples.

Assay of Valsartan
A previously published validated HPLC assay was used for the measurement of valsartan.24 Briefly, a 100-µL aliquot of 5 µg/mL losartan (internal standard) was added to 0.5 mL of patient sample and brought to a 1-mL volume with blank human plasma. Samples were then acidified to pH 2.5 with 125 µL of 1 M phosphoric acid. To the analytes were added 10 mL of methyl-tert-butyl ether. The solutions were vortex mixed for 3 minutes and centrifuged at 1800g for 5 minutes. The organic solvent was transferred to clean tubes containing 200 µL of 0.05 M NaOH (pH > 10) and vortex mixed for 2 minutes. The aqueous layer was frozen by immersing the tubes in a dry ice-acetone bath. The organic layer was discarded and the aqueous layer thawed and neutralized with 75 µL of 0.2 M phosphoric acid. Aliquots of 125 µL were injected into the HPLC.

A Waters HPLC apparatus was used, consisting of a model 590 pump, a 712 Wisp autosampler, and a scanning fluorescence detector model 470 (Waters, Millipore, Mississauga, Canada). The excitation and emission wavelengths were set at 265 and 378 nm, respectively. The apparatus also included a model 3390A recorder integrator (Hewlett-Packard, Palo Alto, CA). A prepacked ODS 10-cm x 4.6-mm i.d. C18 analytical column packed with 5-µm particles (Phenomenex, Torrance, CA) attached to a NovaPak C8 Guard-Pak HPLC precolumn insert (Waters, Millipore, Mississauga, Canada) was used. The columns were operated at ambient temperature. The mobile phase consisted of 70% pH 2.8 phosphate buffer and 30% acetonitrile, pumped at a flow rate of 1.3 mL/min. The standard curve was linear over a 10- to 2000-ng/mL range. Limit for quantitation for valsartan was 10 ng/mL (coefficient of variation [CV] < 11%). The intra- and interday precisions were greater than 90%.

C-Reactive Protein Determination
The Dade-Behring (Deerfield, IL) assay kit was used to determine CRP. The assay was performed at the University of Alberta hospital.

Plasma Nitrite Assay
Total nitrite (, a stable breakdown product of nitric oxide) was measured in plasma of all rats using a method reported by Archer et al25 and Grisham et al.26 Briefly, 100 µL of plasma was incubated with Asperigillus nitrate reductase and treated with various chemicals to reduce all nitrate (NO3-) to nitrite (). The sample was then treated with the Griess reagent, and the absorbance was measured at 540 nm using a Powerwave x 340 plate reader (Bio-Tek Instruments, Fisher Scientific). Calibration was performed using standard solutions of NaNO2 and NaNO3. A comparison of NaNO2 and NaNO3 calibration curves was used to test the dehydrogenase efficiency. The assay was linear from 5 to 200 µM with a CV < 10%.

Statistical Analysis
Statistical significance of the observed differences was tested using the ANOVA followed by Duncan's new multiple-range test at {alpha} = 0.05 for two and more means. For AUEC in which each data point comprised multimeasurement, the standard error of mean was calculated. All other indices are expressed as mean ± standard deviation.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subject characteristics are shown in Table I. There were no significant differences between groups in age, height, and weight. The activity of the rheumatoid arthritis was based on the arthritis index, CRP, and nitrite levels (Figure 1). Active arthritis patients had significantly more joint swelling as well as higher levels of pro-inflammatory mediators, and CRP.


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  		Table I Characteristics of Subjects

 


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  		Figure 1. Markers of inflammation, arthritic index, C-reactive protein (CRP), and nitrite (). *Significantly different from control.

 

Valsartan pharmacokinetics were not significantly altered by rheumatoid arthritis. Indeed, the concentration-time profiles of valsartan were remarkably consistent among the three groups (Figure 2, Table II).



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  		Figure 2. Plasma valsartan concentration-time curves following oral administration of 160 mg. Experimental data points are mean ± SD.

 

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  		Table II Mean (±SD) Valsartan Pharmacokinetic Indices

 

There was no statistically significant difference in the baseline pharmacodynamic indices among groups. Valsartan administration was associated with a significant drop in blood pressure in all groups (Figure 3). No significant difference was observed among the groups in terms of the effect of valsartan on other measured cardiovascular parameters.



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  		Figure 3. Effect of a single 160-mg oral dose of valsartan on blood pressure. Bars represent mean ± SEM for area under the percent effect curve (AUEC, top) and mean ± SD for maximum percent change (bottom).

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
It has been shown that the calcium channel blocker verapamil has decreased potency in prolonging the PR interval in normotensive rheumatoid arthritis patients as compared with healthy subjects.19 Using animal models of inflammation, similar altered pharmacodynamics have been reported for verapamil27 as well as for the ß-adrenergic blockers propranolol22 and sotalol.21 Such findings are therapeutically relevant since these drugs are used in the treatment of cardiovascular diseases such as myocardial infarction (MI) and angina pectoris. As in the case of rheumatoid arthritis, the latter conditions are also associated with increased expression of pro-inflammatory mediators. There are significant increases in TNF-{alpha}, interleukin 1ß, interleukin 6, CRP, and NO in MI and angina.8,9,11,28 Our results also demonstrate an average two- to threefold increase in plasma , a stable breakdown product of NO, and up to fourfold increases in CRP levels (Figure 1) associated with active rheumatoid arthritis.

The observed changes in pharmacodynamics of these cardiovascular drugs in rheumatoid arthritis may have important therapeutic consequences.29 Rheumatoid arthritis patients have an increased mortality rate14,15 and die on average 2.5 years earlier in community-based studies16 and up to 18 years in hospital-based cohorts.17 The reason for this increased cardiovascular mortality in rheumatoid arthritis is not clear. However, in addition to the generally acknowledged risk factors (i.e., hypertension, smoking, high cholesterol, and obesity), elevated baseline diastolic blood pressure and a prothrombotic state have been suggested for arthritic patients.30,31 Very recently, in another other forms of inflammation—namely, MI and unstable angina—the presence of pro-inflammatory mediators such as C-reactive protein, TNF-{alpha}, and interleukin 6 have been identified as additional risk factors.12,28,32,33 Indeed, there appears to be a close association between death and elevated C-reactive protein, a pro-inflammatory marker, after myocardial infarction.32 Therefore, it is reasonable to question the influence of pro-inflammatory mediators in the high mortality rate in both rheumatoid arthritis and cardiovascular patients. This is particularly important since, based on the limited human data19 that are supported by observations made using experimental animals21,27 and in vitro tests,34-37 the presence of these mediators appears to reduce the potency of some drugs used in the treatment of cardiovascular diseases.

Reduced potency of some cardiovascular drugs may, at least in part, be due to a down-regulation and/or inactivation of the receptors and channels caused by inflammatory mediators. In fact, a decrease in ß-adrenergic receptor density and binding sites in the airway, heart, and blood mononuclear cells has been observed with an increase in inflammation.34-38 Recent observations made using a rat model of inflammation suggest down-regulation of the myocardial ß1 adrenoceptor, both at the level of receptor binding27 and density.39 Altered receptor function may also be due to receptor uncoupling of the ß-adrenoceptor from guanine nucleotide protein or intracellular modifications to protein kinases, adenylate cyclase activity and cAMP regulation, and changes in calcium trafficking.34-36,40

Our present data suggest that inflammation, at least as manifested in rheumatoid arthritis, does not reduce the pharmacodynamic response to valsartan, an angiotensin receptor antagonist. This is contrary to the reduced response reported for verapamil19 in humans as well as propranolol and sotalol in experimental animals.21,22 Indeed, patients with rheumatoid arthritis demonstrated even a trend toward increased response to the hypotensive effect of valsartan as compared to the control group (Figure 3). Although this increased potency did not reach statistical significance due, perhaps, to the limited study population size and high variability in response, it is supported by increasing evidence regarding the effect of CRP and TNF-{alpha} in up-regulating angiotensin II type 1 receptors (AT1Rs) in various inflammatory disease conditions, including atherosclerosis, MI, and congestive heart failure.41-45 For example, increased levels of TNF-{alpha} and interleukin 1ß increase the mRNA levels of the AT1R by up to fivefold in cardiac fibroblasts.41 There is also an up-regulation of the renin-angiotensin system during differentiation of monocytes to macrophages46 and increased angiotensin II levels in MI and left ventricular hypertrophy (LVH),41 which, combined with an increase in AT1Rexpression, may exaggerate the vascular response via AT1R47 on cardiovascular parameters.47

Valsartan is mainly eliminated through biliary excretion (~70%), with metabolism contributing only to approximately 20% of its clearance.48,49 This limited dependency of the drug clearance on metabolism may explain the observed lack of effect by rheumatoid arthritis on valsartan pharmacokinetics. It is mainly drugs with efficient hepatic clearance that have been influenced by inflammation.20 Valsartan is more than 92% bound to plasma albumin.50 This may result in enhanced clearance due to reduced plasma protein binding. This was not observed in our patients. Indeed, the plasma concentration-time curves of the three examined groups were remarkably close (Figure 2) and in agreement with those observed previously.49 A change in the plasma protein binding and, subsequently, clearance of drugs has been observed only with naproxen and in patients with severe arthritis (i.e., patients with CRP concentrations more than double of what we recorded for our patients).50

Our study had a few limitations. First, it was conducted after a single dose of valsartan, whereas the drug is usually intended for long-term therapy. However, it has been demonstrated that single-dose studies predict chronic pharmacodynamic responses.51 Second, all the subjects were normotensive. Nevertheless, although blood pressure reduction is proportionate to baseline levels, the drug's hypotensive effect can be studied, albeit with less of a magnitude of effect, in normotensive subjects.52,53 Hence, our data must be considered as preliminary in nature. The beneficial effect of increased AT1R antagonists in patients who are afflicted with both inflammatory conditions and impaired cardiovascular function remains to be studied using a larger population of patients.

In conclusion, inflammation as manifest in rheumatoid arthritis does not alter the pharmacokinetics and pharmacodynamics of valsartan. Thus, this class of drugs may be useful in treating cardiovascular conditions in rheumatoid arthritis, compared to calcium channel blockers or beta-blockers.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
This project was supported in part by Novartis, Switzerland and the Canadian Institute of Health Research. The authors thank Ms. E. Hutchings and Mr. G. Wade for their assistance with the clinical investigation.


   FOOTNOTES
 
DOI: 10.1177/0091270003262951

Submitted for publication August 26, 2003; Revised version accepted November 26, 2003.


   REFERENCES
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 METHODS
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 DISCUSSION
 ACKNOWLEDGEMENTS
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