ORIGINAL INVESTIGATIONS
Renal Handling of Enalaprilat Salim K. Mujais, MD, Antonio Quintanilla, MD, Mohammed Zahid, MD, Kevin Koch, PhD, Wayne Shaw, BS, and Thomas Gibson, MD • Most converting enzyme inhibitors share a predominantly renal dual elimination pathway consisting of glomerular filtration and tubular secretion. Since enalaprilat has two functional acidic groups, it is likely that it may be secreted via the proximal tubule organic acid system and, thus, its clearances would exceed that of glomerular filtration rate markers. We therefore examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances to explore the contribution of tubular secretion to the renal elimination of the drug. Twelve healthy male subjects with an age range of 24 to 58 years (mean ± SE, 33.1 ± 2.8) were studied. They had representative height (178.6 ± 1.99 cm) and weight (73.3 ± 2.1 kg) and had normal renal function as judged by blood urea nitrogen (BUN) (6 ± 0.3 mmol/L [17 ± 0.8 mg/dL]), plasma creatinine (88 ± 3 p.mol/ L [1.0 ± 0.03 mg/dL]), and creatinine clearance determined by a prestudy 24-hour urine collection (123.2 ± 6.2 mL/ min). Results are as follows: mean creatinine clearance, 2.12 mL/s (127 mL/min); mean inulin clearance, 119.1 ml/min mean creatinine clearance/inulin clearance, 1.07 mean enalaprilat protein binding, 37.9% unbound enalaprilat clearance, 222.4 ml/min; and the mean fractional enalaprilat clearances were: enalaprilat clearance/creatinine clearance, 1.72 (P < 0.05, difference from 1.0); enalaprilat clearance/inulin clearance, 1.85 (P < 0.05, difference from 1.0). Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin and creatinine, suggesting that elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion. © 1992 by the National Kidney Foundation, Inc. INDEX WORDS: Enalaprilat; converting enzyme inhibitors; renal clearance; tubular secretion.
C
ONVERTING ENZYME inhibitors are becoming a mainstay of therapy for hypertension I and congestive heart failure. 2 In addition, experimental studies in animals 3-6 and preliminary clinical trials? suggest a potential role for this class of agents in reducing the progression of chronic renal disease, notably the inexorable deterioration of diabetic nephropathy.? This widening use of the drugs could entail their coadministration with agents that may interfere with their phamacokinetics, and their use in patients who may have renal insufficiency. Consequently, a detailed understanding of the renal handling of these agents becomes imperative for rational dosing. Most converting enzyme inhibitors share a predominantly renal elimination pathway8,9 consisting of glomerular filtration and tubular secretion,8,IO the latter probably occurring through the organic acid secretory pathway of the proximal tubule. Since enalaprilat has acidic functional groups, II it is likely that it may be secreted via the proximal organic acid system, and thus its clearance would exceed the glomerular filtration rate. In addition, coadministration of similarly transported drugs, such as the penicillins, cephalosporins, furosemide, and other compounds, could reduce the clearance of enalaprilat and set the stage for potential drug-drug interactions at the level of the kidney. Therefore, to
explore the contribution of tubular secretion to the renal elimination of the drug, we examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances. METHODS
Subjects Twelve healthy male subjects with an age range of24 to 58 years (mean ± SE, 33.1 ± 2.8 y) were studied. They had representative height (178.6 ± 1.99 cm) and weight (73.3 ± 2.1 kg), and had normal renal function as judged by blood urea nitrogen (BUN) (6 ± 0.3 mmo1jL [17 ± 0.8 mgJdL]), plasma creatinine (88 ± 3 p.mo1jL [1.0 ± 0.03 mgJdL]), and creatinine clearance determined in a prestudy 24-hour urine collection (2.05 ± 0.10 mL/s [123 ± 6 mL/min]).
Inulin and Enalaprilat Administration Subjects were studied in the morning after an overnight fast. Two indwelling intravenous catheters were placed, one in each arm, and water diuresis was induced by giving an oral water load (20 mL/kg) followed by replacement of all urine losses with an equal volume of water. Simultaneous adminFrom the Department ofMedicine, Northwestern University, and Veterans Administration Lakeside Medical Center, Chicago, IL; and Merck, Sharp and Dohme Research Laboratories, West Point, PA. Address reprint requests to Salim K. Mujais, MD, Section of Nephrology, VA Lakeside Medical Center, 333 H. Huron St, Chicago, IL 60611. © 1992 by the National Kidney Foundation, Inc. 0272-6386/92/1902-0002$3.00/0
American Journal of Kidney Diseases, Vol XIX, No 2 (February), 1992: pp 121-125
121
122
MUJAIS ET AL
istration of inulin and enalaprilat was performed as loading boli, followed by maintenance infusions piggy-backed into one of the indwelling catheters. Inulin was administered as a priming dose (50 mgJkg), followed by a sustaining infusion calculated to maintain a stable plasma concentration. A loading dose of enalaprilat of 1.5 mg was administered, followed immediately by a sustaining infusion (5 mL/min) of 0.475 JtgJkgJmin diluted in 5% dextrose in water. After a 45-minute equilibration period, the subjects were asked to void spontaneously. This was followed by three consecutive 3D-minute urine collection periods. Blood was drawn (from the catheter in the arm contralateral to the sustaining infusions) at the end of the equilibration period and subsequently at 15-minute intervals until the end of the third collection period. Sitting blood pressure (standard sphygmomanometer) and heart rate were monitored before and at 15-minute intervals after the start of enalaprilat administration.
Analytical Methods Clearances were calculated using standard formulas relating the amount recovered in urine and the corresponding area under the curve for the timed collection plasma concentrations. For the clearance of enalaprilat, the free plasma concentration was used in the calculation. Inulin concentration was determined by the method of Schreiner with minor modifications,12 and creatinine by a modification of the method of Jaffe. 13 Enalaprilat was determined by radioimmunoassay. 14 Total drug was measured in serum diluted fivefold with normal serum. This dilution placed the samples in the most accurate portion of the assay curve. Standards were diluted similarly with normal serum. Free drug was measured in an ultrafiltrate obtained by the Centrifree Micropartition System (Amicon). The ultrafiltrate was diluted fivefold with assay buffer for the radioimmunoassay.
Statistical Analysis Equivalence results of the ratio for enalaprilat to creatinine and enalaprilat to inulin were analyzed using the posterior Enalaprilat level (ng/m!) total
200
150 free
100
40
60
• •
•
100
120
80
......
%free
140
Time (min)
Fig 1. Profile of plasma enalaprilat levels during the clearance study. Levels of total and free enalaprilat increased progressively and in parallel.
Renal Cle arances (mVmio)
250
*
*
200 150 100 50
o Period 1
Period 2
Period 3
Fig 2. Clearances of • creatinine, 0 inulin, and 0 tree enalaprilat tor the three clearance periods. At every interval, the clearance of free enalaprilat s ignificantly exceeded the corresponding clearances of inulin and creatinine .•p < 0.05 v inulin and creatinine.
probability method of Rodda and DavisY Changes from baseline in heart rate and blood pressure were assessed using a paired t test. All tests were two-sided.
RESULTS
Plasma Levels of Enalaprilat Plasma levels and protein binding of enalaprilat were monitored at 15-minute intervals for the duration of the urinary collections (Fig 1). A slow, progressive, and parallel increase of total and free plasma enalaprilat was observed. The percent free enalaprilat (mean, 62.1 %) was constant at all plasma concentrations. Renal Clearances Renal clearances of inulin, creatinine, and enalaprilat for each of the collection periods are provided in Table 1 and illustrated in Fig 2. Values obtained in the three collection periods were remarkably similar for each subject. The coefficient of variation for inulin clearance was 4.2% ± 0.57%, for creatinine clearance 5.0% ± 0.72%, and for enalaprilat clearance 11.2% ± 1.70%. The clearance of creatinine determined in the collection periods was similar to that determined on a previous 24-hour collection for each subject (2.12 ± 0.25 v 2.05 ± 0.10 mLls [127 ± 15 v 123 ± 6 mL/min]). The creatinine to inulin clearance ratio exceeded unity in nine of the 12 cases, indi-
CLEARANCE OF ENALAPRILA T
123
Table 1. Renal Clearances by Collection Period for Each Subject
Subject
Creatinine clearances (mL/min) 1 2 3 4 5 6 7 8 9 10 11 12 Mean
SO
Inulin clearances (mL/min) 1 2 3 4 5 6 7 8 9 10 11 12 Mean
SO
Unbound enalaprilat renal clearances (mL/min) 1 2 3 4 5 6 7 8 9 10 11 12 Mean
SO
1st Interval (0-30 min)
2nd Interval (30-60 min)
3rd Interval (60-90 min)
Cumulative (0-90 min)
165 121 116 121 96 128 128 143 130 140 120 124 127.6 16.8
143 126 120 135 98 127 141 147 144 136 103 122 128.5 15.8
152 128 124 147 99 133 106 151 127 118 104 125 126.1 17.8
154 125 120 134 97 129 124 147 134 132 109 124 127.4 15.1
144 98 108 160 96 100 139 110 130 132 111 113 120 20.5
135 98 117 161 103 107 158 124 129 114 104 107 121.4 20.9
92 125 141 100 102 126 119 127 109 106 106 113.9 14.7
140 96 116 154 100 103 140 117 129 119 107 109 119.1 18.1
288 201 305 245 195 264 257 136 220 230 190 225 229.7 46.4
273 166 260 294 193 258 334 242 161 187 165 168 225.1 59.1
267 185 234 274 178 349 270 157 172 172 171 157 215.5 61.9
275 183 261 275 189 290 284 176 183 195 175 183 222.4 48.9
NOTE. To convert creatinine clearnace to mL/s, multiply by 0.01667.
eating a small component of tubular secretion of creatinine (Fig 3). In contrast, large deviations from unity were observed for the ratio of free enalaprilat to their respective inulin clearances (Fig 3). These results clearly indicate a major tu-
bular component of enalaprilat excretion. Mean fractional clearances were 1.72 and 1.85 for enalaprilat to creatinine and enalaprilat to inulin ratios, respectively. Both were significantly different from 1.0 (P < 0.05).
124
MUJAIS ET AL
2.75
..
2.25
1.75
1.25
0.75
• • •• • ••• ••
DOD
BB§ DO
Creatinine Inulin
Enalaprilat Inulin
Fig 3. Ratios of the clearance of creatinine and free enalaprilat to that of inulin show a modest tubular secretion of creatinine and a large tubular secretion of enalaprilat. .
Hemodynamic Effects The hemodynamic effects of enalaprilat in these normal subjects were minimal, with a small decline of blood pressure from the prestudy period (Fig 4). DISCUSSION
Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin or creatinine, and suggest that the elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion. Considering the chemical nature of enalaprilat, the secretory pathway is likely to reside in the proximal tubule and could be shared by a multitude of organic and inorganic substances with acidic residues. This pathway is known to be nonspecific and to facilitate the secretion of many substances. This shared property has been conclusively determined for captopril, IO enalaprilat, and other converting enzyme inhibitors. 8 ,9 This excretory mode implies that elimination of this class of drugs may be interfered with by substances that share the proximal tubular secretory pathway, such as furosemide, penicillins, and cephalosporins. Furthermore, inhibition of proximal tubular secretion by probenicid may
diminish elimination of other converting enzyme inhibitors as it does with captopril. IO Since the completion of this study, Noormohamed et al 16 have reported that probenicid reduces the renal clearance of both enalapril and enalaprilat. Although pharmacokinetic studies of interference between drugs excreted through this pathway and many converting enzyme inhibitors are not available, caution is advised when drugs from these categories are coadministered. The renal route is the major elimination pathway for enalaprilat. Following oral administration of 10 mg of enalapril to normal subjects, 61 % of the dose was recovered in the urine, of which 18% was enalapril and 43% was enalaprilat. Fecal excretion represented unabsorbed drug or biliary secretion. 17 ,18 The renal clearance found in the present study was somewhat greater than the 9 L/h (150 mL/min) reported by Todd and Heel, 17 probably due to the fact that total plasma enalaprilat was used to calculate enalaprilat clearance in those earlier studies, whereas unbound plasma enalaprilat was used in the present study. Had those studies used unbound plasma enalaprilat, they would have observed a clearance of approximately 207 mL/min (assuming 37.9% protein binding), which is comparable to the clearance observed in the present study. The secretory pathway for enalaprilat is interesting not only from a pharmacokinetic standpoint, but also because it allows access of the inhibitor to its target enzyme, which is localized predominantly in the proximal tubule. 19 Thus, both luminal and basolateral converting enzymes Blood Pressure (mmHg)
125
p
Renal Handling of Enalaprilat Salim K. Mujais, MD, Antonio Quintanilla, MD, Mohammed Zahid, MD, Kevin Koch, PhD, Wayne Shaw, BS, and Thomas Gibson, MD • Most converting enzyme inhibitors share a predominantly renal dual elimination pathway consisting of glomerular filtration and tubular secretion. Since enalaprilat has two functional acidic groups, it is likely that it may be secreted via the proximal tubule organic acid system and, thus, its clearances would exceed that of glomerular filtration rate markers. We therefore examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances to explore the contribution of tubular secretion to the renal elimination of the drug. Twelve healthy male subjects with an age range of 24 to 58 years (mean ± SE, 33.1 ± 2.8) were studied. They had representative height (178.6 ± 1.99 cm) and weight (73.3 ± 2.1 kg) and had normal renal function as judged by blood urea nitrogen (BUN) (6 ± 0.3 mmol/L [17 ± 0.8 mg/dL]), plasma creatinine (88 ± 3 p.mol/ L [1.0 ± 0.03 mg/dL]), and creatinine clearance determined by a prestudy 24-hour urine collection (123.2 ± 6.2 mL/ min). Results are as follows: mean creatinine clearance, 2.12 mL/s (127 mL/min); mean inulin clearance, 119.1 ml/min mean creatinine clearance/inulin clearance, 1.07 mean enalaprilat protein binding, 37.9% unbound enalaprilat clearance, 222.4 ml/min; and the mean fractional enalaprilat clearances were: enalaprilat clearance/creatinine clearance, 1.72 (P < 0.05, difference from 1.0); enalaprilat clearance/inulin clearance, 1.85 (P < 0.05, difference from 1.0). Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin and creatinine, suggesting that elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion. © 1992 by the National Kidney Foundation, Inc. INDEX WORDS: Enalaprilat; converting enzyme inhibitors; renal clearance; tubular secretion.
C
ONVERTING ENZYME inhibitors are becoming a mainstay of therapy for hypertension I and congestive heart failure. 2 In addition, experimental studies in animals 3-6 and preliminary clinical trials? suggest a potential role for this class of agents in reducing the progression of chronic renal disease, notably the inexorable deterioration of diabetic nephropathy.? This widening use of the drugs could entail their coadministration with agents that may interfere with their phamacokinetics, and their use in patients who may have renal insufficiency. Consequently, a detailed understanding of the renal handling of these agents becomes imperative for rational dosing. Most converting enzyme inhibitors share a predominantly renal elimination pathway8,9 consisting of glomerular filtration and tubular secretion,8,IO the latter probably occurring through the organic acid secretory pathway of the proximal tubule. Since enalaprilat has acidic functional groups, II it is likely that it may be secreted via the proximal organic acid system, and thus its clearance would exceed the glomerular filtration rate. In addition, coadministration of similarly transported drugs, such as the penicillins, cephalosporins, furosemide, and other compounds, could reduce the clearance of enalaprilat and set the stage for potential drug-drug interactions at the level of the kidney. Therefore, to
explore the contribution of tubular secretion to the renal elimination of the drug, we examined the renal clearance of enalaprilat in normal volunteers and compared it with simultaneously measured inulin and creatinine clearances. METHODS
Subjects Twelve healthy male subjects with an age range of24 to 58 years (mean ± SE, 33.1 ± 2.8 y) were studied. They had representative height (178.6 ± 1.99 cm) and weight (73.3 ± 2.1 kg), and had normal renal function as judged by blood urea nitrogen (BUN) (6 ± 0.3 mmo1jL [17 ± 0.8 mgJdL]), plasma creatinine (88 ± 3 p.mo1jL [1.0 ± 0.03 mgJdL]), and creatinine clearance determined in a prestudy 24-hour urine collection (2.05 ± 0.10 mL/s [123 ± 6 mL/min]).
Inulin and Enalaprilat Administration Subjects were studied in the morning after an overnight fast. Two indwelling intravenous catheters were placed, one in each arm, and water diuresis was induced by giving an oral water load (20 mL/kg) followed by replacement of all urine losses with an equal volume of water. Simultaneous adminFrom the Department ofMedicine, Northwestern University, and Veterans Administration Lakeside Medical Center, Chicago, IL; and Merck, Sharp and Dohme Research Laboratories, West Point, PA. Address reprint requests to Salim K. Mujais, MD, Section of Nephrology, VA Lakeside Medical Center, 333 H. Huron St, Chicago, IL 60611. © 1992 by the National Kidney Foundation, Inc. 0272-6386/92/1902-0002$3.00/0
American Journal of Kidney Diseases, Vol XIX, No 2 (February), 1992: pp 121-125
121
122
MUJAIS ET AL
istration of inulin and enalaprilat was performed as loading boli, followed by maintenance infusions piggy-backed into one of the indwelling catheters. Inulin was administered as a priming dose (50 mgJkg), followed by a sustaining infusion calculated to maintain a stable plasma concentration. A loading dose of enalaprilat of 1.5 mg was administered, followed immediately by a sustaining infusion (5 mL/min) of 0.475 JtgJkgJmin diluted in 5% dextrose in water. After a 45-minute equilibration period, the subjects were asked to void spontaneously. This was followed by three consecutive 3D-minute urine collection periods. Blood was drawn (from the catheter in the arm contralateral to the sustaining infusions) at the end of the equilibration period and subsequently at 15-minute intervals until the end of the third collection period. Sitting blood pressure (standard sphygmomanometer) and heart rate were monitored before and at 15-minute intervals after the start of enalaprilat administration.
Analytical Methods Clearances were calculated using standard formulas relating the amount recovered in urine and the corresponding area under the curve for the timed collection plasma concentrations. For the clearance of enalaprilat, the free plasma concentration was used in the calculation. Inulin concentration was determined by the method of Schreiner with minor modifications,12 and creatinine by a modification of the method of Jaffe. 13 Enalaprilat was determined by radioimmunoassay. 14 Total drug was measured in serum diluted fivefold with normal serum. This dilution placed the samples in the most accurate portion of the assay curve. Standards were diluted similarly with normal serum. Free drug was measured in an ultrafiltrate obtained by the Centrifree Micropartition System (Amicon). The ultrafiltrate was diluted fivefold with assay buffer for the radioimmunoassay.
Statistical Analysis Equivalence results of the ratio for enalaprilat to creatinine and enalaprilat to inulin were analyzed using the posterior Enalaprilat level (ng/m!) total
200
150 free
100
40
60
• •
•
100
120
80
......
%free
140
Time (min)
Fig 1. Profile of plasma enalaprilat levels during the clearance study. Levels of total and free enalaprilat increased progressively and in parallel.
Renal Cle arances (mVmio)
250
*
*
200 150 100 50
o Period 1
Period 2
Period 3
Fig 2. Clearances of • creatinine, 0 inulin, and 0 tree enalaprilat tor the three clearance periods. At every interval, the clearance of free enalaprilat s ignificantly exceeded the corresponding clearances of inulin and creatinine .•p < 0.05 v inulin and creatinine.
probability method of Rodda and DavisY Changes from baseline in heart rate and blood pressure were assessed using a paired t test. All tests were two-sided.
RESULTS
Plasma Levels of Enalaprilat Plasma levels and protein binding of enalaprilat were monitored at 15-minute intervals for the duration of the urinary collections (Fig 1). A slow, progressive, and parallel increase of total and free plasma enalaprilat was observed. The percent free enalaprilat (mean, 62.1 %) was constant at all plasma concentrations. Renal Clearances Renal clearances of inulin, creatinine, and enalaprilat for each of the collection periods are provided in Table 1 and illustrated in Fig 2. Values obtained in the three collection periods were remarkably similar for each subject. The coefficient of variation for inulin clearance was 4.2% ± 0.57%, for creatinine clearance 5.0% ± 0.72%, and for enalaprilat clearance 11.2% ± 1.70%. The clearance of creatinine determined in the collection periods was similar to that determined on a previous 24-hour collection for each subject (2.12 ± 0.25 v 2.05 ± 0.10 mLls [127 ± 15 v 123 ± 6 mL/min]). The creatinine to inulin clearance ratio exceeded unity in nine of the 12 cases, indi-
CLEARANCE OF ENALAPRILA T
123
Table 1. Renal Clearances by Collection Period for Each Subject
Subject
Creatinine clearances (mL/min) 1 2 3 4 5 6 7 8 9 10 11 12 Mean
SO
Inulin clearances (mL/min) 1 2 3 4 5 6 7 8 9 10 11 12 Mean
SO
Unbound enalaprilat renal clearances (mL/min) 1 2 3 4 5 6 7 8 9 10 11 12 Mean
SO
1st Interval (0-30 min)
2nd Interval (30-60 min)
3rd Interval (60-90 min)
Cumulative (0-90 min)
165 121 116 121 96 128 128 143 130 140 120 124 127.6 16.8
143 126 120 135 98 127 141 147 144 136 103 122 128.5 15.8
152 128 124 147 99 133 106 151 127 118 104 125 126.1 17.8
154 125 120 134 97 129 124 147 134 132 109 124 127.4 15.1
144 98 108 160 96 100 139 110 130 132 111 113 120 20.5
135 98 117 161 103 107 158 124 129 114 104 107 121.4 20.9
92 125 141 100 102 126 119 127 109 106 106 113.9 14.7
140 96 116 154 100 103 140 117 129 119 107 109 119.1 18.1
288 201 305 245 195 264 257 136 220 230 190 225 229.7 46.4
273 166 260 294 193 258 334 242 161 187 165 168 225.1 59.1
267 185 234 274 178 349 270 157 172 172 171 157 215.5 61.9
275 183 261 275 189 290 284 176 183 195 175 183 222.4 48.9
NOTE. To convert creatinine clearnace to mL/s, multiply by 0.01667.
eating a small component of tubular secretion of creatinine (Fig 3). In contrast, large deviations from unity were observed for the ratio of free enalaprilat to their respective inulin clearances (Fig 3). These results clearly indicate a major tu-
bular component of enalaprilat excretion. Mean fractional clearances were 1.72 and 1.85 for enalaprilat to creatinine and enalaprilat to inulin ratios, respectively. Both were significantly different from 1.0 (P < 0.05).
124
MUJAIS ET AL
2.75
..
2.25
1.75
1.25
0.75
• • •• • ••• ••
DOD
BB§ DO
Creatinine Inulin
Enalaprilat Inulin
Fig 3. Ratios of the clearance of creatinine and free enalaprilat to that of inulin show a modest tubular secretion of creatinine and a large tubular secretion of enalaprilat. .
Hemodynamic Effects The hemodynamic effects of enalaprilat in these normal subjects were minimal, with a small decline of blood pressure from the prestudy period (Fig 4). DISCUSSION
Our results demonstrate that the clearance of free enalaprilat exceeds that of inulin or creatinine, and suggest that the elimination of the drug proceeds through two complementary pathways, namely glomerular filtration and tubular secretion. Considering the chemical nature of enalaprilat, the secretory pathway is likely to reside in the proximal tubule and could be shared by a multitude of organic and inorganic substances with acidic residues. This pathway is known to be nonspecific and to facilitate the secretion of many substances. This shared property has been conclusively determined for captopril, IO enalaprilat, and other converting enzyme inhibitors. 8 ,9 This excretory mode implies that elimination of this class of drugs may be interfered with by substances that share the proximal tubular secretory pathway, such as furosemide, penicillins, and cephalosporins. Furthermore, inhibition of proximal tubular secretion by probenicid may
diminish elimination of other converting enzyme inhibitors as it does with captopril. IO Since the completion of this study, Noormohamed et al 16 have reported that probenicid reduces the renal clearance of both enalapril and enalaprilat. Although pharmacokinetic studies of interference between drugs excreted through this pathway and many converting enzyme inhibitors are not available, caution is advised when drugs from these categories are coadministered. The renal route is the major elimination pathway for enalaprilat. Following oral administration of 10 mg of enalapril to normal subjects, 61 % of the dose was recovered in the urine, of which 18% was enalapril and 43% was enalaprilat. Fecal excretion represented unabsorbed drug or biliary secretion. 17 ,18 The renal clearance found in the present study was somewhat greater than the 9 L/h (150 mL/min) reported by Todd and Heel, 17 probably due to the fact that total plasma enalaprilat was used to calculate enalaprilat clearance in those earlier studies, whereas unbound plasma enalaprilat was used in the present study. Had those studies used unbound plasma enalaprilat, they would have observed a clearance of approximately 207 mL/min (assuming 37.9% protein binding), which is comparable to the clearance observed in the present study. The secretory pathway for enalaprilat is interesting not only from a pharmacokinetic standpoint, but also because it allows access of the inhibitor to its target enzyme, which is localized predominantly in the proximal tubule. 19 Thus, both luminal and basolateral converting enzymes Blood Pressure (mmHg)
125
p
