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CLINICAL STUDIES |
From the Faculty of Pharmacy (Dr Daneshtalab, Dr Jamali) and Pharmaceutical Sciences and Faculty of Medicine (Dr Lewanczuk, Dr Russell), University of Alberta, Edmonton, Alberta, Canada. Financial support provided by the Canadian Institute for Health Research and Novartis Pharmaceuticals, Switzerland.
Address for reprints: Fakhreddin Jamali, PhD, #3118 Dentistry/Pharmacy Building, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada, T6G-2N8; e-mail: fjamali{at}ualberta.ca.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Inflammation • receptor downregulation • angiotensin II type 1 receptor • inflammatory mediators • C-reactive protein
(TNF), and C-reactive protein (CRP) have been implicated in the cause and exacerbation of cardiovascular complications such as myocardial infarction and left ventricular hypertrophy.1,2 Indeed, elevated proinflammatory cytokines and CRP are suggested to be independent risk factors for cardiovascular diseases.3,4 Cardiovascular complications are the primary causes of mortality in autoimmune diseases, such as rheumatoid arthritis (RA).5,6
Inflammation increases plasma concentration of drugs that are efficiently metabolized by the liver.7-9 This is due to elevation of plasma protein concentrations of such proteins as acid glycoprotein, responsible for drug-protein binding.10,11 The inhibition of cytochrome P450 (CYP450),7,12 as well as altered levels of P-glycoprotein,10 may also contribute to the increase in plasma drug concentration. However, at least for some cardiovascular drugs, this increase does not seem to result in increased pharmacologic effects. Indeed, despite elevated drug concentration, reduced potency has been reported under inflammatory conditions for the calcium channel antagonist verapamil in humans11 and for the ß-adrenergic antagonist propranolol in the rat.13,14 This reduced responsiveness, which appears to be linked to increased proinflammatory mediator levels, does not seem to be a general observation because the effect of the angiotensin II type 1 receptor (AT1R) antagonist valsartan is not downregulated in patients with RA.15
The objective of this work was to examine pharmacokinetics and pharmacodynamics of losartan in the presence of inflammation. Similar to valsartan, losartan is an AT1R antagonist. However, although pharmacologic activity of valsartan is attributed to the drug itself,16 that of losartan is mainly ascribed to its metabolite, EXP 3174,17 which is formed in the liver. We hypothesized that the extent of this conversion may be reduced by RA, leading to reduced hypotensive effect.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Subjects, Study Protocol, and Assessment of Pharmacokinetics and Pharmacodynamics
Subjects (n = 38, 22-74 years old, Table I) were recruited. Patients and healthy volunteers were recruited from the University of Alberta Hospital outpatients and the general population of the city of Edmonton, Alberta, respectively. They were aged-matched and divided into 3 groups: 14 with active RA, 12 with controlled RA, and 12 healthy subjects. Patients were selected independent of blood pressure. Active RA patients had an active flare-up as compared to patients whose arthritis was under control at the time of the study. 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. None of the other drugs taken by patients (Table I) was expected to interact with the pharmacokinetics or pharmacodynamics of losartan.
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The study was performed in accordance with the Declaration of Helsinki. The protocol was approved by the University of Alberta Faculty of Medicine Research and Ethics Committee. All participants provided written informed consent and underwent specific inclusion and exclusion criteria. The same group of subjects was involved in a previously reported study of valsartan.15
One week before the study, subjects underwent routine laboratory tests (hematology, electrocardiogram, urinanalysis), and their CRP levels were measured.
Patients were diagnosed according to the American Rheumatism Association 1987 revised criteria.18 Arthritic index was the number of swollen, inactive joints.
On the study day, subjects arrived before 7 AM 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 physiologic variables. Physiologic variables included mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP), pulse, cardiac ejection time, calculated stroke volume index, calculated cardiac index, peripheral vascular resistance, large and small artery compliance, and total vascular impedance. The focus of the study was, however, maintained on the SBP, DBP, and MAP, as the changes in blood pressure parameters encompass the total effect of AT1R antagonists on the cardiac and vascular parameters. All measurements were performed using an HDI/Pulsewave Cardiovascular Profiling Instrument CR-2000 (Hypertension Diagnostics Inc, Minneapolis, Minn). The experimentally observed maximum percentage effect and the time of its attainment were recorded and used in statistical analysis. The area under the percentage effect-time (0-12 hour) curve (AUEC) was calculated using the trapezoidal rule.
After the baseline measurements, subjects received 100 mg losartan (Cozaar, Merck Frosst, Montreal, Quebec, Canada) purchased from the University of Alberta Hospital pharmacy) with 250 mL distilled water. They remained upright for a minimum of 2 hours. Thereafter, they were free to drink water at will. At hours 4 and 9, standard meals were provided. No other food was consumed other than that provided.
Blood samples (10 mL) were taken, after waste tubes were drawn, into green cap vials containing heparin lithium, and pharmacodynamic measurements were performed at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 8, and 12 hours. Samples were centrifuged immediately, and plasma was stored at -70°C. Pharmacokinetic indices were calculated using the model independent approach: oral clearance (CL/F), oral volume of distribution (Vd/F), terminal half-life (t
), area under the concentration versus time curve (AUC0-
) calculated using the trapezoidal rule plus the last observed concentration divided by 0.693/t. The highest observed concentration and the time of its attainment were recorded as Cmax and tmax, respectively.
Total nitrite (NO2-) a stable breakdown product of both NO and nitrate (NO3-), is an indirect measure of reactive nitrogen species levels in plasma. As the ultimate metabolic fate of NO in vivo is nitrate, plasma nitrite level was measured in the time zero blood samples.
Drug Assay
A published HPLC assay was used to measure losartan and EXP 3174.19 Briefly, internal standard was added to 0.5 mL patient plasma and quesced to 1 mL with blank human plasma. Samples were acidified to pH 2.5 with phosphoric acid. To the analytes were added 10 mL of methyl-tert-butyl ether. Solutions were vortex-mixed and centrifuged. The organic solvent was transferred into clean tubes containing NaOH (pH > 10). After vortex-mixing and centrifugation, the aqueous layer was frozen by immersing the tubes in dry ice-acetone. The organic layer was discarded; the aqueous layer was thawed and neutralized with phosphoric acid. Hexane was added, followed by vortex-mixing to wash the aqueous fraction. Hexane was discarded by further centrifugation and freezing in dry ice-acetone. To improve solubility, isopropanol was added to the aqueous residual, and aliquots were injected into HPLC.
The HPLC consisted of a 590 pump, a 712 Wisp autosampler, and a 470 UV detector (Waters, Millipore, Mississauga, Canada) set at 254 nm, a 3390A recorder integrator (Hewlett-Packard, Palo Alto, Calif), a prepacked ODS 10 cm x 4.6 mm I.D. C18 analytical column packed with 5-µm particles (Phenomenex, Torrance, Calif) and a NovaPak C8 Guard-Pak HPLC Precolumn insert (Waters). The mobile phase consisted of 0.015 M H3PO4, acetonitrile, and TEA in a ratio of 71:29:0.078 and pumped at a flow rate of 1.3 mL/min. Standard curve was linear over a 10 to 2000 ng/mL range with a coefficient of variation (CV) <10%. The minimum quantifiable concentration was 2.5 ng/mL with a CV <15%.
C-Reactive Protein Determination
The Dade-Behring (Deerfield, Ill) assay kit was used to determine CRP. The assay was performed at the University of Alberta Hospital.
Plasma Nitrite Assay
Total nitrite (NO2-, a stable breakdown product of nitric oxide) was measured in plasma using a method reported by Archer et al.20 Briefly, 100 µL plasma was incubated with Asperigillus nitrate reductase and treated with various chemicals to reduce all nitrate (NO3-) to nitrite (NO2-). The sample was then treated with the Griess reagent, and the absorbance was measured at 540 nm using a Powerwavx 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%.
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= .05 for 2 and more means using the SAS program (SAS Institute, Cary, NC). The power of the study was calculated to detect a significant difference in the pharmacokinetic and pharmacodynamic parameters. At the power of 0.8, the study will be able to detect a significant difference in Cmax and AUC0-, a difference of 6.3 mm Hg in blood pressure, and a 20% difference in other cardiac parameters, assuming usual measurement standard deviations and an of .05. For AUEC, in which each data point comprised multiple measurements, the standard error of mean was calculated. All other indices are expressed as mean ± standard deviation. The unpaired and paired Student t test was used to compare whether the baseline and posttreatment blood pressure measurements were significantly different from one another. The significance of correlations between the degree of inflammation and various parameters was tested using the least squares linear regression.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Rheumatoid arthritis did not significantly alter losartan pharmacokinetic parameters (Figure 1, Table II). However, the disease significantly decreased the AUC of the pharmacologically active metabolite, EXP 3174. The ratio of EXP 3174 AUC over losartan AUC exhibited a significant correlation with disease severity (r = -.35, P < .05, n = 37).
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Losartan administration was associated with a significant drop in blood pressure in all groups (Figure 2). The treatment also led to a significant increase in the maximum change from baseline value of large and small artery elasticity and drop in systemic vascular resistance and total vascular impedance as compared to baseline in all groups (data not presented). There was also a significant decrease in cardiac ejection time and increase in the calculated stroke volume index in healthy and controlled arthritis subjects following losartan administration. The pulse and the calculated cardiac output index, however, were not affected with losartan administration in any of the groups (data not presented).
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The mean percentage change from baseline for SBP, DBP, and MAP were plotted versus concentration for both losartan (Figure 3) and EXP 3174 (Figure 4). There was an immediate drop in blood pressure coinciding with the rise in losartan concentration. The effect continued as EXP 3174 concentration increased.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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as risk factors in cardiovascular events.1-4 In addition, in the elderly, ß-adrenergic antagonists are less efficacious in treating hypertension,21,22 and verapamil has been shown to be less potent in PR interval prolongation in the elderly,23 obese,18 and RA subjects11 as compared with the general population. The latter conditions are associated with higher proinflammatory mediator expression.24 Interestingly, a recent report indicates that RA patients who are treated with Anti-TNF antibodies, hence reduced TNF concentration, demonstrate a lower incident of first cardiovascular event.25 The mechanism behind the association between the anti-inflammatory mediators and cardiovascular events is not known. However, it has been shown that inflammation alters pharmacokinetics and pharmacodynamics of various cardiovascular drugs. Rheumatoid arthritis decreases potency of the calcium channel antagonist, verapamil, in prolonging PR interval despite increased plasma drug concentrations.11 Similarly, animal data indicate reduced response to ß-adrenergic13,26 and potassium channel antagonists.26 Diminished receptor responsiveness to the drug secondary to reduced drug-receptor binding have been suggested to be among the plausible causes.27 The extent of the contribution of a reduced response to pharmacotherapy in the reported cardiovascular events remains to be explored.
A previous report suggests the response to angiotensin receptor antagonists may not be affected by inflammation15; neither pharmacokinetics nor hypotensive effect of valsartan is affected by RA. Losartan, however, differs from valsartan in having a potent metabolite that is formed in the liver. Because inflammation is known to reduce hepatic drug metabolism activity,7-9 we hypothesized that the formation of the active metabolite of losartan was diminished. Hence, we expected a reduced potency for losartan in RA patients. Indeed, concentrations of EXP 3174 were significantly reduced in both arthritis groups to approximately half as much as that observed in healthy subjects (Table II, Figure 1). This, however, was not accompanied by a reduction in the potency of the administered dose (Figure 2). A 50% reduction in the concentrations of EXP 3174 with no reduction in hypotensive potency cannot be attributed to an increased bioavailability of the parent drug. Indeed, inflammation did not influence pharmacokinetics of losartan (Table II, Figure 2). Only about 14% of losartan is converted to EXP 3174 and over 80% to other metabolites with no hypotensive activity.28 A change in the activity of such a minor metabolic pathway, therefore, is unlikely to have any significant consequence on the bioavailability of the parent drug. Neither does attainment of the ceiling effect, that is, the maximum possible effect, can explain this observation because of the small size of the dose.
A plausible explanation for our observation is that increased proinflammatory mediators appear to have an opposite effect on AT1R receptors than what has been reported for ß-adrenergic, potassium, and calcium channel receptors, that is, reduced responsiveness.11,13,26 Increased CRP and TNF have been shown to upregulate AT1Rs by various mechanisms in cardioinflammatory conditions including atherosclerosis, myocardial infarction, and congestive heart failure.29-31 AT1R upregulation with increased inflammatory mediators may lead to an increased blood pressure-lowering effect in the presence of inflammatory conditions. Interestingly, according to a previously reported set of data, although the potency of valsartan is not significantly altered by RA, a trend toward increased potency of the drug is evident.15 Angiotensin II, the major effector molecule produced from the renin-angiotensin-aldosterone axis, is a vasoconstrictor contributing to hypertension. Recent evidence, however, has shown that angiotensin II is also a potent proinflammatory mediator with growth and remodeling effects. Interruption of angiotensin II activity, such as AT1R antagonist therapy, has been shown to be of benefit in inflammatory diseases such as atherosclerosis, heart failure, and diabetes. Much of this benefit is independent of the antihypertensive effect of angiotensin II interruption suggesting a unique protective mechanism.32
The observed reduced concentrations of EXP 3174 may be attributed to several factors. Because the elimination half-life of EXP is not affected by inflammation, the significant decrease in EXP AUC can be postulated to be due to the reduced extent of formation of the metabolite. Losartan conversion to EXP 3174 involves P450 enzymes CYP2C9 and CYP3A4.28 The CYP450 enzyme system has been shown to lose activity in the presence of inflammation.7-9 Interestingly, the pharmacokinetic profile of both losartan and EXP 3174 seen with the RA patients is analogous to the reported effect of fluconazole.33 Fluconazole, a selective CYP3A4 and CYP2C9 inhibitor, decreases the formation of EXP 3174 with no significant influence on the pharmacokinetics of losartan. Selective inhibition of CYP enzymes by cytokines may therefore inhibit losartan biotransformation to EXP 3174, yet not hinder alternate elimination pathways for losartan to alter its pharmacokinetics.
The concentration versus percentage effect from baseline for losartan and EXP 3174 (Figures 3 and 4) makes apparent the initial and immediate control of blood pressure by losartan, followed by the more stable and potent blood pressure control provided by EXP 3174. It appears that the therapeutic efficacy of losartan is uncompromised by the presence of inflammatory mediators due to the combined antihypertensive effect of losartan and EXP 3174. The results, coupled with the previously reported data on valsartan, suggest that AT1R antagonist effects are not downregulated under inflammatory conditions and may be suitable alternatives to the calcium channel and ß-adrenergic blockers in patients with inflammatory conditions. Indeed, clinical studies indicate the benefits of losartan over certain ß-blockers in the treatment of isolated systolic hypertension and left ventricular hypertrophy,34-36 both of which being diseases that exhibit increases in inflammatory mediator levels.24
One of our healthy subjects exhibited no detectable concentrations of EXP 3174 in plasma (Figure 5). This may be explained by genetic polymorphism. The major isozyme involved in formation of EXP 3174 is CYP2C9,37-39 which is subject to polymorphism due to isozyme-specific mutations. The CYP2C9*3 variant allele has been observed in some persons and population groups leading to only less than 1% formation of EXP 3174 from losartan.37,38 Despite the lack of EXP 3174, however, the blood pressure response to losartan administration in this subject confirms the pharmacologic activity of losartan.
Our study had 2 main limitations. It was conducted after a single dose of losartan whereas the drug is intended for long-term therapy. However, single-dose studies have been shown to predict chronic pharmacodynamic responses.37 Secondly, all the subjects were clinically normotensive. However, as the blood pressure reduction by AT1R antagonists is proportional to baseline levels, the hypotensive effect of losartan can be consistently extrapolated to normotensive subjects.
Our data must be considered preliminary in nature. A larger population of patients, afflicted with both inflammatory conditions and impaired cardiovascular function remains to be studied.
In conclusion, increasing inflammatory mediators, as seen in RA, alters the conversion of losartan to EXP 3174, most likely because of the inhibition of the metabolizing enzymes CYP2C9 and CYP3A4. However, the decrease in AUC of EXP 3174 did not result in a decrease in response, due possibly to pharmacologic effect of the parent drug and/or the AT1R upregulatory mechanisms of inflammatory mediators. Overall, RA appears to have no downregulatory effect on the pharmacodynamics of AT1R antagonists, a characteristic that differentiates this class of drugs from ß-adrenergic receptor and calcium channel antagonists.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: Dr Lewanczuk has received honoraria for CME events and has sat on advisory boards for Novartis and Merck.
This project was supported in part by Novartis, Switzerland, and Canadian Institute of Health Research.
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REFERENCES |
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