Pharmacokinetic Profiles of Single and Repeat Doses of Lisinopril and Enalapril in Congestive

Heart Failure Dennis Johnston, MD, FRCP, and Donal Duffin, MB, MRCP

T his study was undertaken to determine whether the presence of congestive heart failure (CHF) would alter absorption, first-

pass metabolism, and drug elimination and result in different pharmacokinetic profiles for lisinopril and enalapril.

Lisinopril is pharmacologically active after oral administration and does not require hepatic activa- tion. Bioavailability is low and the time to peak concentration is prolonged, mainly due to poor absorption. The drug undergoes renal elimination and has a duration effect of > 24 hours.’ Enalapril is a prodrug that requires conversion in the liver to its active form, enalaprilat. Enalaprilat is then excreted by the kidney and has a duration effect of about 24 hours.2

Medication was administered on day 1 and days 3-8; no drug was given on day 2 to allow for plasma concentration measurement after the first dose.

Blood samples were taken after the first dose to determine levels of serum lisinopril, enalapril, and enalaprilat predose, hourly for 12 hours and at 24, 32, and 48 hours. Hepatic blood flow was measured before the first and last dose, using indocyanine green clearance.3 Blood pressures and heart rate were measured at baseline and 2,4,6,8,12, and 24 hours after dosing. Serum and urine concentra- tions of lisinopril, enalapril, enalaprilat, and angio- tensin II were measured by radioimmunoassay.

Six patients received lisinopril (mean age 70 years; weight 71.8 kg) and 7 received enalapril (mean age 69 years; weight 73.7 kg). One patient

METHODS ioo- This was an open, randomized, parallel-group - SINGLE -----MULTIPLE

study in 13 patients (2 18 years) with CHF (New York Heart Association class III-IV) on back- g lo d*’ ground therapy of diuretics and/or digoxin. Male and female patients were included in the study and

g S 1.0

the diagnosis of CHF was established when at least

1;

2 of the following features were present: increased jugulovenous pressure, peripheral edema, tender

0.1 I I I I I I I I I I 0 5 IO 15 20 25 30 35 40 45 50

hepatomegaly, or radiologic signs of pulmonary TIME AFTER DOSE (h)

edema. Exclusion criteria were recent myocardial infarc-

FIGURE 1. Mean serum concentratio~~~ of ibinopdi (ng/mL)

tion or stroke, aortic stenosis, primary right heart after singis and muttipie dosing in heart failure patients.

failure, systolic blood pressure <90 mm Hg, ar- rhythmias other than atria1 fibrillation, severe liver

100 or renal disease, malabsorption syndromes, and I 1 -SINGLE -----MULTIPLE

known sensitivity to angiotensin-converting en- zyme inhibitors or indocyanine green.

Patients received either 2.5 mg lisinopril or 2.5 mg enalapril as single daily doses for 7 days.

z 2

10

i * ---_ --.. -- --__ s -.------- l

2

8

From the Department of Therapeutics and Pharmacology, The Queen’s University of Belfast and Belfast City Hospital, Northern Ireland.

Address for reprints: Dennis Johnston, MD, FRCP, Depart- ment of Therapeutics and Pharmacology, The Whitla Medical Building, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland.

01; I I I I I , I 1 I 1 I (

0 5 10 15 20 25 30 35 40 45 50 55 60

TIME AFTER DOSE (h)

FIGURE 2. Mean serum concentrations of enaiaprii (ngl ml) after singie and multiple dosiq$ in heart faiiure pa- tients.

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TABLE I Serum Pharmacokinetic Parameters for Lisinopril, Enalapril, and Enalaprilat in Patients with Congestive Heart Failure

Cm,, (ng/mL) T,,, (hr)* AUC (ng/mL)

Single Multiple Accumulation Single Multiple Single Multiple Accumulation Effective Treatment Dose Dose Ratio Dose Dose Dose dose Dose Half-Life

Lisinopril 11.5 -+ 2.5 19.2 f 2.9 1.6 r 0.3 9 6 192.3 t 20.6 309.4 rt 50.4 1.6 r 0.2 16.4 t 4.0

Enalaprilat 10.3 t 1.8 14.8 +- 2.6 1.5 f 0.2 8 6 218.3 -t- 47.5 280.0 r 62.7 1.3 rt 0.2 14.7 rt: 3.0

Enalapril 29.0 -t- 4.4 24.7 2 4.0 - 1 1 86.9 f 18.7 69.1 f 21.7 - -

*Median. AUC = area under the plasma concentratw-time curve.

100

1 -SINGLE -----MULTIPLE

0.11 , , , , , , , , , ,

0 5 10 15 20 25 30 35 40 45 50

TIME AFTER DOSE(h)

FIGURE 3. Mean serum concentrations of enaiapriiat (ng/ ml) after single and muitipie dosing in heart failure pa- tients.

100

1 - ELDERLY NON-HYPER

-t- STUDY PATIENTS

0.1 14 I I I I I I I I I

0 5 10 15 20 25 30 35 40 45 50

TIME AFTER DOSE (h)

TABLE ii Urine Pharmacokinetic Parameters for Lisinopril,

Enalapril, and Enalaprilat in Patients with Congestive Heart Failure*

Urinary Recovery (%) Clearance (ml/min)

Enalaprilat 17.4 f 2.5 28.8 -c 2.7 33.1 r 6.7 55.0 -f- 11.4

100 1

- ELDERLY NON-HYPER

- STUDY PATIENTS

0.1 1 I , I I I I I I I 0 5 10 15 20 25 30 35 40 45 50

TIME AFTER DOSE(h) J

FiGURE 4. Comparison of normalized mean concentrations FIGURE 6. Comparison of normalized mean concentrations of ilsinoprii (ng/mL) after a Angle dose in heart failure (STUDY) patients and elderly nonhypertenshfe (NON-W

of enaiaprilat (ng/mL) after a singie dose In heart faliure

PER) paGents. (STUDY) patients and elderly nonhypertende (NON-RY- PER) patients.

100

1 --a-- NORMALNON-HYPER

- STUDY PATIENTS

0.11 , , I , , , I I I I 1 0 5 10 15 20 25 30 35 40 45 50 55 60

TIME AFTER DOSE (h) I

withdrew from lisinopril because of acute deterio- ration in renal function.

RESULTS The data show that serum concentrations of

lisinopril in heart failure patients were similar to those found in healthy subjects after single and multiple dosing (Table I). Mean maximum serum concentrations after 10 mg oral lisinopril in healthy subjects were about 40 ng/mL after 6-8 hours.46 Assuming a linear relation betwe+en dose and peak

FIGURE 5. Comparison of normalized mean concentrations of enaiaprii @g/ml) after a single dose In heart failure

plasma concentrations, these would represent a

(SNDY) patients and normal nonhypertenshre (NON-RY- value of about 10 ng/mL for 2.5 mg, approximately PER) patients. the value seen in this study. Values calculated at 24

152c THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70 OCTOBER 8, 1992

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