Pharmacokinetics and pharmacodynamics of lisinopril in advanced renal failure

Abstract

To prevent drug accumulation and adverse effects the dose of hydrophilic angiotensin-converting enzyme (ACE) inhibitors, e. g. lisinopril, must be reduced in patients with renal failure. To obtain a rational basis for dose recommendations, we undertook a prospective clinical trial. After 15 days of lisinopril treatment pharmacokinetic and pharmacodynamic parameters were determined in patients with advanced renal failure (n=8; endogenous creatinine clearance [CL_CR]: 18 ml·min⁻¹·1.73m⁻²) and in healthy subjects with normal renal function (n=16; CL_CR: 107 ml·min⁻¹·1.73m⁻²). The volunteers received 10 mg lisinopril once daily, the daily dose in patients (1.1–2.2 mg) was adjusted to the individual CL_CR according to the method of Dettli [13].

After 15 days of lisinopril treatment the mean maximal serum concentration (C _max) in patients was lower than in volunteers (30.7 vs 40.7 ng·ml⁻¹, while the mean area under the concentration-time curve (AUC _{0–24 h}) was higher (525 vs 473 ng·h⁻¹·ml⁻¹). ACE activity on day 15 was almost completely inhibited in both groups. Plasma renin activity, angiotensin I and angiotensin II levels documented marked inhibition of converting enzyme in volunteers and patients. Furthermore, average mean arterial blood pressure in patients decreased by 5 mmHg and proteinuria from 3.9–2.7 g per 24 h after 15 days of treatment with the reduced dose of lisinopril.

Adjustment of the dose of lisinopril prevents significant accumulation of the drug in patients with advanced renal failure during chronic therapy. Mean serum levels did not exceed this in subjects with normal renal function receiving a standard dose. Despite substantial dose reduction, blood pressure and proteinuria decreases were observed.