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1 Lisinopril and enalapril were administered as 2.5 mg single doses and as eight single
daily 2.5 mg doses to separate groups of six patients with chronic renal failure. Patients
were receiving regular haemodialysis.
2 In the absence of haemodialysis, the decline in plasma concentrations of lisinopril and
enalaprilat was extremely slow and plasma concentrations were generally high.
3 Haemodialysis had large effects on plasma concentrations of lisinopril and enalaprilat.
A 4 h period reduced plasma concentrations of both drugs by around one-half and often by
significantly more than this. Even 1 or 2 h of haemodialysis had significant effects.
4 Haemodialysis plasma clearance was similar for both drugs with mean values of the
order of 40 ml min-'. Clearance did not markedly differ when measured after 1, 2 or 4 h of
haemodialysis or after single or multiple doses of lisinopril or enalapril.
5 The design of dosage regimens of both lisinopril and enalapril for patients with severe
renal impairment or chronic renal failure should take into consideration the use and effects
of haemodialysis.
dialysis.
Methods
Subjects
Observations were made in two separate groups
each comprising six patients with end-stage
chronic renal failure, who were receiving regular
maintenance haemodialysis. All gave informed
consent and the study was approved by the
Hospital Ethics Committee. Table 1 contains
details of the patients studied.
Study procedures
The studies were divided into four periods; baseline, acute pharmacokinetics, chronic treatment,
chronic pharmacokinetics.
781
782
J. G. Kelly et al.
Table 1 Details of subjects
Subject
Sex
Age
(years)
TCu
JC
PDOY
TCa
LO'B
PR
M
M
F
F
F
M
57
36
30
43
47
59
JL
M
M
M
F
M
F
54
19
50
38
21
43
TW
P DON
LB
TB
TMF
Lisinopril
Weight Height
(kg)
(cm)
168
165
155
63
158
64
158
165
69
Enalapril
170
63
65
167
70
169
67
168
64
167
163
48.5
64
61
58
Creatinine clearance
(ml min')
4.5
6.0
2.8
4.0
2.5
1.7
5.4
0
3.6
2.0
5.2
3.8
CLD = QP
CA-CV
CA
Lisinopril group
Venous plasma concentrations of lisinopril following the first and final doses are shown in Figure
1. Following the first dose, plasma concentrations
increased steadily to reach a maximum observed
mean concentration at 24 h of 25.9 5.5 ng ml -1.
The mean peak concentration was 29.7 6.9 ng
783
103
102
E
cs
-5
C,o
._
._
X(10
c lo
80
100
Time (h)
Figure 1 Plasma concentrations of lisinopril (ng ml-1) following the first (A) and final (0) doses. Note
the effects of haemodialysis at 44-48 h.
180
J. G. Kelly et al.
784
haemodialysis
Subject
TCu
JC
PD
TCa
LO'R
PR
Mean
s.d.
s.e. mean
Time (days)
3
12
3.9
4.0
6.2
1.9
1.5
4.9
3.9
4.9
250
26
52
85
56
28
82.8
84.7
34.6
300
60
63
173
135
30
126.8
100.1
40.9
120
76
63
195
130
41
104.2
55.9
22.8
First dose
Last dose
Time (h)
2
39.9 7.5
55.4 11.7
46.6 6.0
40.2 11.6
47.7 5.6
34.4 3.7
Enalapril group
Figure 2 shows mean venous plasma concentrations of enalaprilat following the first and final
doses of enalapril. Concentrations of enalaprilat
103 1
CD
-W
._Q
a)
CL
E(I
CU
Time (h)
Figure 2 Plasma concentrations of enalaprilat (ng ml-1) following the first (A) and final (o) doses of
enalapril. Note the effects of haemodialysis at 44-48 h.
785
Subject
JL
TW
P DON
LB
TB
TMF
Mean
s.d.
s.e. mean
6.2
2.7
2.1
23.0
4.2
5.1
7.2
7.9
7.2
Time (days)
3
5
84.0
100.0
49.0
20.0
72.0
78.0
67.2
28.5
11.6
144.0
134.0
47.0
184.0
158.0
96.0
127.2
48.8
19.9
170.0
161.0
77.0
171.0
252.0
101.0
155.3
61.5
25.1
First dose
Last dose
Time (h)
2
49.4 6.1
28.9 7.5
35.7 5.4
38.8 6.7
42.0 13.0
38.8 12.4
drug administration.
Mean plasma concentrations of enalapril
reached a peak of 24.7 8.3 ng ml-' following
the first dose and initially declined rapidly to 8.2
3.3 ng ml-1 at 8 h. In one subject, enalapril
was still measurable at 44 h, in a further two it
was measurable at 20 h and in the remainder was
not measurable after 8 h. Following the final
dose, the maximum mean enalapril concentration
was 51.2 ng ml-1 at 6 h but was not present in
measurable quantities at 20 h. It was not possible
to draw any conclusions about haemodialysis
plasma clearance of enalapril.
Discussion
The elimination rate of both lisinopril and enalaprilat is markedly reduced in renal failure.
Also, times-to-peak of both substances appear
to be long, often observed at 24 h. This is
consistent with our earlier findings (Kelly et al.,
1986, 1987) of times-to-peak which increase with
progressive renal impairment. It is of interest
that times-to-peak appear to be similarly influenced by renal failure for both lisinopril and
enalaprilat, even though enalaprilat is formed by
esterolytic cleavage of enalapril. There is no
obvious explanation for this finding at present.
In the absence of haemodialysis, it is apparent
that the elimination rate of both lisinopril and
enalaprilat would be extremely slow. Inspection
of Figures 1 and 2 suggests that without haemodialysis, it would require several days for plasma
concentrations of either drug to fall by one-half.
However haemodialysis had dramatic effects
on plasma concentrations of both lisinopril and
enalaprilat. A 1 h period of haemodialysis is
capable of reducing significantly plasma concentrations of either drug. At the end of a 4 h
period of haemodialysis, administered following
a single 2.5 mg dose of either lisinopril or enalaprilat, venous plasma concentrations of lisinopril and enalaprilat were on average, only 49.7%
786
J. G. Kelly et al.
References
Hitchens, M., Hand, E. L. & Mulcahy, W. S. (1981).
Radio-immunoassay for angiotensin converting
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Kelly, J. G., Doyle, G., Donohue, J., Laher, M.,
Vandenburg, M. J., Currie, W. J. C. & Cooper,
W. D. (1986). Pharmacokinetics of enalapril in
normal subjects and patients with renal impairment.
Br. J. clin. Pharmac., 21, 63-69.
Kelly, J. G., Doyle, G., Donohue, J., Laher, M.,
Long, C., Glover, D. G. & Cooper, W. D. (1987).
Acute and chronic dose pharmacokinetics of lisinopril: effects of renal impairment. Br. J. clin.
Pharmac., 23, 629-630.
Lowenthal, D. T., Irvin, J. D., Merrill, D., Saris, S.,
Ulm, E., Goldstein, S., Hichens, M. M., Klein, L.,
Till, A. & Harris, K. (1985). The effect of renal
function on enalapril kinetics. Clin. Pharmac. Ther.,
38, 661-666.