Long-Term Plasma Levels and Dose Modulation of Alacepril in Patients with Chronic Renal Failure

29 Hypertens Res Vol.31 (2008) No.1 p.27-34 Original Article Long-Term Plasma Levels and Dose Modulation of Alacepril in Patients with Chronic Renal Failure Hiroshi NONOGUCHI1), Shigeru KIYAMA2), Kenichiro KITAMURA1), Masahiro NARUSE3), Masao TOMITA4), Noboru TAZOE5), Munemasa TAJIRI5), Yushi NAKAYAMA1), Yukimasa KOHDA1), Takeaki INOUE1), and Kimio TOMITA1) Because most angiotensin-converting enzyme inhibitors are excreted into urine, any decrease in renal function increases the plasma levels of these drugs. This study was designed to investigate the appropriate doses of alacepril in patients with chronic renal failure. The total plasma concentration of captopril, an active metabolite of alacepril, was measured in 47 patients with chronic renal failure or normal renal function. Fifteen patients on chronic hemodialysis were also enrolled in this study. In patients treated with 12.5, 25 and 50 mg alacepril, the plasma concentration of captopril was linearly correlated with serum creatinine and creatinine clearance (Ccr). There was an approximately 40% decrease of the plasma captopril concentration after 4 h of hemodialysis. Among patients treated with 25 or 50 mg alacepril for 4.5 years, the plasma concentration of captopril gradually increased along with an increase in serum creatinine (from 2.0 to 5.8, and from 1.9 to 7.1 mg/dL, respectively). Although the plasma concentration of captopril was higher in the 50 mg group, the increase in serum creatinine during this period was not different between the two groups. The plasma aldosterone concentration did not increase during this period. These data suggest that alacepril should be reduced from 50 to 25 and 12.5 mg/day in patients with a serum creatinine level of greater than 2–3 and 4–6 mg/dL, respectively, in order to maintain a plasma level equivalent to that in subjects with normal renal function receiving 50 mg/day alacepril. For patients on chronic hemodialysis, 12.5 mg alacepril is the appropriate dose. (Hypertens Res 2008; 31: 29–36) Key Words: angiotensin-converting enzyme inhibitor, chronic renal failure, dose modulation, hypertension Introduction Angiotensin-converting enzyme (ACE) inhibitors exert renoprotective effects mainly by decreasing intraglomerular pressure and, subsequently, proteinuria (1, 2). The widespread use of ACE inhibitors has revolutionized the treatment of patients with chronic kidney disease (CKD) (3–6). Proteinuria and blood pressure are the main determinants of the progression of CKD, and thus the appropriate doses of ACE inhibitors are determined by the effects on proteinuria and blood pressure, by safety (i.e., lack of side effects), and by cost (7–10). Most of the ACE inhibitors are excreted into urine, and their doses have to be titrated depending upon the renal function. ACE inhibitors suppress the synthesis of angiotensin II and aldosterone, which can sometimes induce hyperkalemia in patients with reduced renal function (11). Therefore, it is generally recommended that the doses be reduced under certain circum- From the 1)Department of Nephrology, Kumamoto University Graduate School of Medical Science, Kumamoto, Japan; 2)Kiyama Nakamura Clinic, Amakusa, Japan; 3)Tamana Daiichi Clinic, Tamana, Japan; 4)Department of Nephrology, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan; and 5)Nagamine Clinic, Kumamoto, Japan. This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (19590955, 18590895, 17590833, 16790466, 16590792, 16590791, 16390246, 15590852). Address for Reprints: Hiroshi Nonoguchi, M.D., Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1–1–1 Honjo, Kumamoto 860–8556, Japan. E-mail: Received September 11, 2006; Accepted in revised form August 3, 2007. 30 Hypertens Res Vol. 31, No. 1 (2008) stances, especially in patients with a serum creatinine level of more than 2.5 mg/dL, to avoid excess doses and the resultant hyperkalemia (12). However, it is very difficult to use ACE inhibitors in patients with moderate to severe renal failure. The decrease in serum ACE activity by the administration of ACE does not correspond to the renoprotective effect of ACE inhibitors but is known to be a marker of drug regimen compliance (13). Plasma levels of ACE inhibitors have been examined to determine the appropriate concentrations of ACE inhibitors (14– 17). However, the plasma concentration of ACE inhibitors has been studied mainly after short-term administration. It is not known whether the plasma concentration of ACE inhibitors is stable after long-term administration, especially in patients with chronic renal failure. ACE inhibitors are divided into two groups according to the presence of sulfhydryl groups in the compound. Alacepril and captopril belong to the sulfhydryl-containing group. Alacepril (DU-1219) is desacetylated to form desacetylalacepril (DU1227) and is then converted to captopril (18–20), an active metabolite of alacepril. However, DU-1227 is readily transferred to the vascular wall and also has a direct effect on sympathetic nerve activity, such that alacepril has a 1.5 to 2 times longer antihypertensive effect than captopril (18). The initial aim of the present study was to investigate whether the plasma concentration of captopril is stable after long-term administration of alacepril in patients with CKD, and to determine whether the decline of renal function over time affects the plasma concentration of captopril. The ultimate goal of our investigation was to determine the appropriate doses of alacepril in patients with chronic renal failure. To accomplish these goals, we examined the plasma concentration of captopril in CKD patients taking alacepril for more than 1 year. Methods Patients The study group included 47 patients (25 males and 22 females) with CKD who had been treated with alacepril for more than 1 year. All patients were diagnosed as having hypertension (hypertension without proteinuria: 4 patients) or chronic glomerulonephritis (immunoglobulin A [IgA] and other primary nephropathy, 22 patients; diabetic nephropathy, 11 patients; hypertensive nephrosclerosis, 7 patients; amyloidosis, 3 patients). The percentage of patients with hypertensive nephrosclerosis in our study was lower than the estimated percentage of such individuals in the general population in the United States (21). All of our patients had a normal or reduced renal function. In some patients, long-term follow-up was performed to examine the relationship between the gradual decrease in renal function and the increase in plasma level of captopril. Additionally, 15 patients on chronic hemodialysis were enrolled. These patients were Table 1. Baseline Characteristics of the Patients Start End No. of patients (male/female) 47 (25/22) Age (years old) 55±2 Height (cm) 158±1 Weight (kg) 55±1 Period (months) 25.0±1.7 Serum creatinine (mg/dL) 2. (...truncated)