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The Effect of Candesartan on the Pharmacokinetics of Enalaprilat in Nephrotic Rats

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The Effect of Candesartan on the Pharmacokinetics of Enalaprilat in Nephrotic Rats European Review for Medical and Pharmacological Sciences 2012; 16: 2162-2170 The effect of candesartan on the pharmacokinetics of enalaprilat in nephrotic rats B.-T. BI, Y.-B. YANG*, A.-D. MA**, T. LIN***, H.-B. LIN, X.-M. YANG**, J.-P. XU Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China *Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Southern Medical Universi- ty, Guangzhou, China **Hygiene Detection Center of Southern Medical University, Guangzhou, China ***Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China Abstract. – BACKGROUND AND OBJECTIVES: Introduction The adverse reactions in combination of an- giotensin-converting enzyme inhibitors (ACEIs) The renin-angiotensin system (RAS) plays an and Ang II receptor blockers (ARBs) were severer than that in monotherapy for patients with important role in the progress of renal disease. nephropathy. The effect of candesartan on phar- The principal bioactive peptide in RAS is an- macokinetics of enalaprilat in nephrotic rats was giotensin II (Ang II), which may contribute to investigated to make references for the clinical vascular endothelial dysfunction, atherosclerosis, therapy in patients with nephropathy to avoid relat- remodeling and hypertrophy of renal tissue, and ed adverse effects. cell death. These changes represent a pathophysi- MATERIALS AND METHODS: Nephrotic rats 1,2 were prepared by adriamycin injection. Control ologic basis of renal diseases . group and one nephrotic group received Evidences have pointed out that blockade of enalapril alone, another nephrotic group received RAS can delay the progress of renal diseases3,4. The enalapril and candesartan simultaneously. Blood general RAS blockers in clinical application in- samples were drawn at time points after a single clude angiotensin-converting enzyme inhibitors oral administration. The concentration of enalaprilat was determined using LC-MS/MS. (ACEIs) and Ang II receptor blockers (ARBs). RESULTS: Compared with control group and ACEIs are able to reduce Ang II production by in- nephrotic group received enalapril alone respec- hibiting angiotensin-converting enzyme (ACE), and tively, Tmax of enalaprilat in nephrotic group re- ARBs can bind the specific receptor of Ang II, ar- ceived both enalapril and candesartan cilexetil resting its biological effects5. Because of the emerg- prolonged about 21.43% and 6.224%, respectively; ing “angiotensin escape phenomenon” in the use of AUC increased by 185.3% and 60.63%, respec- (0-t) ACEIs alone4, the combination of ACEIs and tively; Cmax increased by 219.4% and 56.64%, re- spectively; t1/2 incerased by 163.7% and 30.05%, ARBs has been proposed for clinical application. respectively; CL/F reduced by 65.12% and 40.78%, Studies found that the combination of ACEIs and respectively. There were no significant differences ARBs was more effective than the single entity of the V1/F of enalaprilat between three groups. alone in depressing systemic blood pressure and The CL/F and t1/2 of enalaprilat showed significant 6,7 correlations with serum creatinine (Scr) respec- treating albuminuria in diabetic nephropathy . The tively (r = –0.7502; r = 0.5626). joint use of them would lead to a dual RAS block- DISCUSSION: The combination with candesar- ade and a greater clinical benefit theoretically3,5-7. tan in nephrotic rats significantly changed the However, clinical observations revealed that ad- pharmacokinetics of enalaprilat, showing in- verse reactions in the combined therapy were sever- creased accumulation and decreased elimination. er than that in monotherapy, including hypotension, In view of these findings, we should lower dosage and prolong dosing interval for nephrotic patients hyperkalemia, and renal function deterioration, 8-11 in the combination of enalapril and candesartan. even if consciously reduced the dosages . Phar- macodynamic studies indicated that these adverse Key Words: reactions were related to the excessive inhibition of Angiotensin II, Candesartan, Enalaprilat, Nephrosis, Pharmacokinetics. RAS. However, the pharmacokinetic changes in the combined use of both drugs remain unclear. Corresponding Authors: Jiang-Ping Xu, MD, Ph.D.; e-mail: [email protected]; and 2162 Ying-Bao Yang, MD, Ph.D.; e-mail: [email protected] The effect of candesartan on the pharmacokinetics of enalaprilat in nephrotic rats Enalapril is a widely-used ACEI. Its active tology, the normal rats and nephrotic rats were metabolite enalaprilat is mainly excreted by the treated as the following: control group (n=6) and kidneys. Studies found elevated concentrations of one model group (n=6) received enalapril (15 enalaprilat in nephrotic patients with convention- mg/kg, p.o.) alone, and another model group al dosages12. Candesartan is a commonly used (n=6) received simultaneously enalapril (15 ARB. It is cleared via kidneys, biliary and in- mg/kg, p.o.) and candesartan cilexetil (3 mg/kg, testinal route. Whether the physiological disposi- p.o.). Blood samples were drawn under ether tion of enalaprilat and candesartan would be anesthesia from orbital venous plexus before ad- changed in their combined use for nephrotic pa- ministration and 1, 2, 3, 4, 6, 8, 12, 24, and 48 h tients is unknown. Compared with ARBs, ACEIs after single dosing. Blood samples were collect- have been used more generally, but can result in ed using heparinized tubes, centrifuged for 20 more adverse effects13. Accordingly, in this study min at 450 × g at 4°C. Plasma samples were we chose enalaprilat as the monitoring object, stored at -20°C before analysis. and investigate the effect of candesartan on phar- macokinetics of enalaprilat in nephrotic rats to Determination of Serum Creatinine make references to the clinical application for pa- Before injection with ADR or saline and 7 tients with nephropathy for avoiding related ad- weeks after injection, blood and serum collection verse effects. was carried out. Avoiding hemolysis during the collection process, the Scr was measured using corresponding kit with enzymatic method. Material and Methods Sample Preparation Chemicals The preparation of samples was carried out as Adriamycin was purchased from Main Luck described17 with adjusted. A 200 µL of plasma Pharmaceuticals Inc, ShenZhen, China. Kit for sample was mixed with 20 µL internal standard measuring creatinine was purchased from Shang- (3 µg/ml benazepril) and 10 µL formic acid. The hai Mind Bioengineering Co. Ltd., Shanghai, mixture was vortexed with 370 µL methanol by China. Enalapril and candesartan cilexetil were oscillator followed by centrifuging for 15 min at purchased from YiBang Pharmaceutical Technol- 10,000 × g at 4°C. The supernatant was collected ogy Development Co. Ltd., GuangZhou, China. and filtered. 3-µL aliquot of supernatant was in- Enalaprilat was purchased from USPC Inc., jected to LC-MS/MS system for analysis. Rockville, MD, USA. Benazepril was supplied by the National Institute for the Control of Phar- LC-MS/MS maceutical and Biological Products. All chemi- LC-MS/MS was carried out as described18 cals were at least analytical grade. with adjusted. The mobile phase composed of methanol-water-formic acid (70:30:0.03, v/v/v) Animals and Treatment at a flow rate of 0.3 mL/min. An API 4000 Q Male and female Sprague-Dawley rats TRAP LC-MS/MS system (Applied Biosystems, (250~280 g) in this study were obtained from the Foster City, CA, USA) was used for analyses. Experimental Animal Center, Southern Medical The mass spectrometer was operated in positive University, Guangzhou, China. The animals were ion detection mode. Nitrogen was used as the ion housed in at 25 ± 2°C with water and standard source gas at 55 psi, the collision gas at medium, diet accessible ad libitum. All procedures were and the curtain gas at 25 psi. The ion spray volt- performed in accordance with the NIH Guide for age was adjusted to 5,500 V and the temperature the Care and Use of Laboratory Animals. After of vaporizer was at 350°C. The declustering po- one week of acclimatization, the rats were divid- tentials were set at 63 V and 100 V for enalapri- ed into control group (n=8) and model group lat and benazepril, respectively. (n=18). As adriamycin (ADR) has been reported to be able to induce renal impairment14-16, rats in Pharmacokinetic Analysis model group received injection of ADR (3 Non-compartmental pharmacokinetic parame- mg/kg, once every two days, thrice in total) ters were calculated from the plasma concentra- through the tail vein. Control rats received injec- tions of enalaprilat in each time point of each rat tion of saline (2 mL/kg). After confirming the using DAS 2.0 Program registrated from Mathe- nephropathy rat model in biochemistry and his- matical Pharmacology Professional Committee 2163 B.-T. Bi, Y.-B. Yang, A.-D. Ma, T. Lin, H.-B. Lin, X.-M. Yang, J.-P. Xu Table I. Precision, recovery and accuracy of enalaprilat (n = 3 days, five replicates per day). Concentration (ng/ml) R.S.D. (%) R.E. Extraction recovery Added Found Intra-day Inter-day (%) (%) 50 59.63 ± 3.05 11.44 2.03 19.26 85.80 500 599.9 ± 12.23 5.00 1.12 19.98 84.26 5000 5277 ± 65.74 2.79 0.80 5.54 74.53 of China. This program has been applicated in capsule, and nephric tubule dilatation in compari- other pharmacokinetic studies19-21. The non-com- son to the rats in control group (Figure 2). These partmental pharmacokinetic parameters includ- biochemical and histological changes indicated ing area under the concentration-time curve from that ADR administration successfully induced a zero to last quantifiable time (AUC(0-t)), half-life nephropathy model. of elimination (t1/2), total clearance (CL/F), vol- ume of distribution (V1/F) were calculated using Enalaprilat Detection and statistical moments22-24. The maximum plasma Method Validation concentration (Cmax) and the time to maximum The detection of enalaprilat was carried out concentration (Tmax) were measured according to by LC-MS/MS.
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