Preferential biliary elimination of FPL 63547, a novel inhibitor of angiotensin‐converting enzyme, in the rat

Carr, Richard D.; Cooper, Anne; Hutchinson, R.; Mann, Jacinta; O'Connor, S. E.; Robinson, David; Wells, E. Buist

doi:10.1111/j.1476-5381.1990.tb12057.x

Cited by 10 publications

(3 citation statements)

References 13 publications

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“…This has led to recognition (Lancet, 1988) that newer agents of this class should demonstrate biological properties which distinguish them from the first generation ACE inhibitors. In the accompanying paper (Carr et al, 1990) we describe the marked preference of FPL 63547 for the biliary route of elimination, which is a novel feature of this compound.…”

Section: Methodsmentioning

confidence: 98%

“…The accompanying paper (Carr et al, 1990) describes the unusual elimination profile of FPL 63547, a feature which distinguishes it from other members of this class of drugs.…”

Section: Haemodynamic Effects In Anaesthetized Dogsmentioning

confidence: 99%

“…In summary, FPL 63547, a novel thiadiazoline, is a potent and long-acting ACE inhibitor which by virtue of vasodilator and antihypertensive properties should prove useful in the treatment of chronic heart failure and hypertension. The accompanying paper (Carr et al, 1990) describes the unusual elimination profile of FPL 63547, a feature which distinguishes it from other members of this class of drugs.…”

Section: Antihypertensive Effects In Spontaneously Hypertensive Ratsmentioning

confidence: 99%

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Pharmacological properties of FPL 63547, a novel inhibitor of angiotensin‐converting enzyme

Carr¹,

Higgs²,

Killingback³

et al. 1990

British J Pharmacology

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FPL 63547, in its active diacid form, was a potent inhibitor of rabbit lung angiotensin converting enzyme (ACE) in vitro (IC50 0.51 nm). In conscious normotensive dogs, FPL 63547 (10–300 μg kg−1 i.v.) produced prolonged, dose‐related inhibition of plasma ACE activity and angiotensin I pressor responses, without affecting basal blood pressure, heart rate or pressor responses to angiotensin II. In anaesthetized dogs, FPL 63547 diacid (3–300 μg kg−1 i.v. cumulatively) produced dose‐related increases in cardiac output accompanied by falls in total peripheral resistance indicative of vasodilatation. Mild stimulation of cardiac rate and contractility was also observed. Enalapril diacid had a similar profile. FPL 63547 was a highly effective antihypertensive agent after oral administration to spontaneously hypertensive rats (SHR) pretreated with a diuretic. It lowered systolic blood pressure (SBP) on acute administration over the range 3 × 10−7–10−5 mol kg−1 p.o. (⋍ 0.13–4.5 mg kg−1 p.o.). FPL 63547 was more potent than other ACE inhibitors tested, threshold active doses for lisinopril, enalapril and captopril being 10−6, 10−6 and 3 × 10−5 mol kg−1 p.o., respectively. The antihypertensive effects of FPL 63547, unlike those of enalapril and captopril, were of long duration. The antihypertensive efficacy of FPL 63547 was also observed following chronic oral administration. A dose of 0.5 mg kg−1 day−1 once daily for 23 days produced a sustained reduction of SBP. By the end of the treatment period, SBP was significantly lowered both pre‐ and post‐dose, i.e. effective 24 h control had been achieved. The profile of FPL 63547 is consistent with it being a potent, selective and long‐acting ACE inhibitor. As an antihypertensive agent in SHR it compared favourably with other members of this class with respect to potency and duration of action.

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Section: Methodsmentioning

confidence: 98%

“…The accompanying paper (Carr et al, 1990) describes the unusual elimination profile of FPL 63547, a feature which distinguishes it from other members of this class of drugs.…”

Section: Haemodynamic Effects In Anaesthetized Dogsmentioning

confidence: 99%

Section: Antihypertensive Effects In Spontaneously Hypertensive Ratsmentioning

confidence: 99%

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Pharmacological properties of FPL 63547, a novel inhibitor of angiotensin‐converting enzyme

Carr¹,

Higgs²,

Killingback³

et al. 1990

British J Pharmacology

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Pharmacokinetics and haemodynamic effects of a single oral dose of the novel ACE inhibitor spirapril in patients with chronic liver disease

Krähenbühl

Grass²,

Surve³

et al. 1993

Eur J Clin Pharmacol

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The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensin-converting enzyme (ACE) inhibitor, have been investigated in patients with liver cirrhosis (n = 10), in patients with chronic, non-cirrhotic liver disease (n = 8) and in a control group of healthy subjects (n = 16). The absorption and elimination of spirapril did not differ between patients with liver disease and control subjects. In contrast, the bioavailability of spiraprilat, the metabolite responsible for the pharmacological action of spirapril, was significantly reduced in patients (AUC 820 micrograms.h.l-1, 923 micrograms.h.l-1 and 1300 micrograms.h.l-1 in patients with cirrhosis, patients with non-cirrhotic liver disease and in healthy subjects, respectively. Compared to healthy subjects, cirrhotic patients had a reduced rate constant of spiraprilat formation (1.10 h-1 in patients vs. 2.00 h-1 in control subjects) while the elimination half-life of spiraprilat was not different. The effect of spirapril on diastolic blood pressure was decreased in patients with chronic liver disease as compared to the controls. Thus, the pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis. However, the bioavailability of spiraprilat and hypotensive effect of spirapril were reduced in patients.

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Single Dose Pharmacokinetics of Temocapril (CS-622), a Novel Angiotensin Converting Enzyme (ACE) Inhibitor, in Partially Nephrectomised Rats

et al. 1994

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SummaryThe single dose pharmacokinetics of temocapril, a prodrug type angiotensin converting enzyme (ACE) inhibitor with a thiazepin ring, were studied in nephrectomised rats and compared with those of enaJapril. The nephrectomised rats had much higher serum levels of creatinine (1.1 mg/dl) and blood urea nitrogen (73.5 mg/dl) than the control rats (0.6 and 18.6 mg/dl, respectively). Concentrations of RS-5139 and enalaprilat, the active metabolites of temocapril and enalapril, respectively, in the plasma, bile and urine were measured by the ACE inhibition assay or a gas chromatography-mass spectrometry system (GCIMS). There was no significant difference in the maximum plasma concentrations (C max ) of RS-5139 between the nephrectomised (243.3 Ilg/L) and control rats (342.8Ilg/L). On the other hand, the Cmax of enalaprilat in nephrectomised rats was significantly higher (399.3IlgIL) than in the control group (158.6Ilg/L; p < 0.05). Biliary excretion of RS-5139 was up to 79.2 and 8l.8% in the control and nephrectomised groups, respectively, whereas the corresponding values for enalaprilat were only 7.7 and 12.2%. Urinary excretion of RS-5139 was only 4.7 and 3.8% in the control and nephrectomised rats, respectively, whereas the corresponding values for enalaprilat were 48.9 and 54.1 %. These results show that a single dose of temocapril is preferentially excreted in bile and its elimination was unaffected by impaired renal function.

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Preferential biliary elimination of FPL 63547, a novel inhibitor of angiotensin‐converting enzyme, in the rat

Cited by 10 publications

References 13 publications

Pharmacological properties of FPL 63547, a novel inhibitor of angiotensin‐converting enzyme

Pharmacological properties of FPL 63547, a novel inhibitor of angiotensin‐converting enzyme

Pharmacokinetics and haemodynamic effects of a single oral dose of the novel ACE inhibitor spirapril in patients with chronic liver disease

Single Dose Pharmacokinetics of Temocapril (CS-622), a Novel Angiotensin Converting Enzyme (ACE) Inhibitor, in Partially Nephrectomised Rats

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