Absence of a pharmacokinetic interaction between enalapril and frusemide.

Hecken, A. M. Van; Verbesselt, René; Buntinx, Agnes; Cirillo, Vincent J.; Schepper, P. J. De

doi:10.1111/j.1365-2125.1987.tb03013.x

Cited by 14 publications

(3 citation statements)

References 10 publications

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“…Following single oral doses of enalapril lOmg and frusemide 80mg, the kinetics of the 2 drugs and their metabolites did not significantly affect each other (van Hecken et al 1987). The blood pressures of the 12 healthy subjects studied were not significantly reduced by frusemide alone, but they were decreased by enalapril alone and by coadministration of enalapril plus frusemide.…”

Section: Diureticsmentioning

confidence: 83%

Angiotensin-Converting Enzyme Inhibitors

Belz

Kirch

Kleinbloesem

1988

Clinical Pharmacokinetics

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The inter-relationship between the pharmacokinetic and pharmacodynamic behaviour of ACE inhibitors is reviewed. First, some of the methods which have been used to assess the pharmacodynamics of ACE inhibitors in humans are presented. They include humoral assays (e.g. ACE activity in plasma, renin activity, etc.), haemodynamic changes (blood pressure, total peripheral resistance, etc.) and agonist challenges (angiotensin I infusions). Subsequently a pharmacokinetic-dynamic model is described, based on biochemical processes obtained after ACE inhibition, which seems to be useful for the interpretation of the complex processes. The various correlations between plasma drug concentration on the one hand and plasma ACE activity, angiotensin II concentration in plasma or blood pressure on the other, are discussed on the basis of this model. From the model obtained it becomes obvious that under many circumstances the release of the inhibitor from ACE binding is the step which in fact determines the pharmacodynamically relevant elimination rate of the drug at low concentrations, whereas at high concentrations the elimination of the drug is mainly dependent on kidney (and/or liver) elimination rate. The dynamic-kinetic correlations are then presented for some ACE inhibitors in various disease states: arterial hypertension, heart failure, old age, renal failure, liver disease. In a final section the kinetic and dynamic relevance of interactions of ACE inhibitors with food and other drugs is described (e.g. prostaglandin inhibitors, diuretics, digoxin and cimetidine). Despite the great body of literature which deals with the kinetic and/or dynamic properties of ACE inhibitors, precise knowledge of the relationship between their kinetic and dynamic behaviour is rather limited and there is a clear need for further studies to elucidate this complex topic, thereby improving therapeutic possibilities with these useful new compounds.

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Section: Diureticsmentioning

confidence: 83%

Angiotensin-Converting Enzyme Inhibitors

Belz

Kirch

Kleinbloesem

1988

Clinical Pharmacokinetics

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“…For example, the IC 50 of the high-affinity OAT3 substrate furosemide is 7.3 µM [ 26 ] and observed therapeutic plasma concentrations are around 3.6 µM (total concentration) [ 27 ]. After co-administration of furosemide with enalapril at therapeutic dosages of both drugs (enalapril 10 mg and furosemide 80 mg), only a non-significant increase in both the enalaprilat C max (increase from 34.9 to 38.2 ng/mL) and area under the curve (AUC) (increase from 369 to 384 ng/mL/h) were observed [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Completing the Enalaprilat Excretion Pathway—Renal Handling by the Proximal Tubule

et al. 2020

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Background: Enalapril is often used in the treatment of cardiovascular diseases. Clinical data suggest that the urinary excretion of enalaprilat, the active metabolite of enalapril, is mediated by renal transporters. We aimed to identify enalaprilat specificity for renal proximal tubular transporters. Methods: Baculovirus-transduced HEK293 cells overexpressing proximal tubular transporters were used to study enalaprilat cellular uptake. Uptake into cells overexpressing the basolateral transporters OCT2, OAT1, OAT2, or OAT3 and apical transporters OAT4, PEPT1, PEPT2, OCTN1, OCTN2, MATE1, MATE2k, and URAT1 was compared with mock-transduced control cells. Transport by renal efflux transporters MRP2, MPR4, P-gp, and BCRP was tested using a vesicular assay. Enalaprilat concentrations were measured using LC-MS/MS. Results: Uptake of enalaprilat into cells expressing OAT3 as well as OAT4 was significantly higher compared to control cells. The enalaprilat affinity for OAT3 was 640 (95% CI: 520–770) µM. For OAT4, no reliable affinity constant could be determined using concentrations up to 3 mM. No transport was observed for other transporters. Conclusion: The affinity of enalaprilat for OAT3 and OAT4 was notably low compared to other substrates. Taking this affinity and clinically relevant plasma concentrations of enalaprilat and other OAT3 substrates into account, we believe that drug–drug interactions on a transporter level do not have a therapeutic consequence and will not require dose adjustments of enalaprilat itself or other OAT3 substrates.

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“…In healthy volunteers, it has been reported that single doses of enalapril 10mg and furosemide 80mg may not significantly affect the pharmacokinetics of each other when taken concomitantly (Van Hecken et al 1987). In their study, each of 12 volunteers received at 3 occasions, separated by a 2-week washout period, a single morning dose of either enalapril 10mg, furosemide 80mg, or both.…”

Section: Thiazide and Loop Diureticsmentioning

confidence: 96%

Pharmacokinetic Drug Interactions with ACE Inhibitors

Shionoiri

1993

Clinical Pharmacokinetics

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Angiotensin converting enzyme (ACE) inhibitors which have active moieties excreted mainly in urine require adjustment of either the dose or the interval between doses in patients with moderate to severe renal dysfunction or severe congestive heart failure. Those agents such as temocapril (CS 622) and fosinopril, excreted both in urine and bile, may not require such adjustment. Renal clearance of ACE inhibitors may be reduced and some accumulation may occur in elderly patients with mild renal dysfunction or congestive heart failure. The bioavailability of ACE inhibitors is reduced by concomitant food or antacids which may slow gastric emptying and raise gastric pH. Pharmacokinetic interactions with ACE inhibitors are unlikely in patients receiving thiazide or loop diuretics. When ACE inhibitors are given hyperkalaemia may occur in patients with renal insufficiency, those taking potassium supplements or potassium-sparing diuretics, and in diabetic patients with mild renal impairment. While no pharmacokinetic interaction precludes use of this combination, the pharmacokinetics of some ACE inhibitors are subject to greater variability when patients also receive beta-blockers. Calcium antagonists and ACE inhibitors have additive anti-hypertensive effects and pharmacokinetic interactions between these agents are unlikely. One report exists of a significant effect of coadministered hydralazine on the pharmacokinetics and urinary excretion of lisinopril. Data on interactions between ACE inhibitors and digitalis are contradictory. There is no evidence that the concomitant use of ACE inhibitors and digoxin is associated with an increased risk of digitalis toxicity. ACE inhibitors are mainly excreted by glomerular filtration and renal tubular secretion. Possible interactions between ACE inhibitors and probenecid have been noted, with renal and total body clearance of ACE inhibitors being potentially reduced in the presence of probenecid. Probenecid pretreatment may enhance the pharmacodynamic response of ACE inhibitors. Few but contradictory data exist on the effects of H2-blockers on ACE inhibitor pharmacokinetics and little information is available on interactions between ACE inhibitors and hypoglycaemic drugs. Some case reports link ACE inhibitors with the induction of lithium toxicity. Coadministration of lithium should be undertaken with caution, and frequent monitoring of lithium concentrations is recommended with all ACE inhibitors. Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the haemodynamic actions of ACE inhibitors. NSAIDs reduce renal excretion of ACE inhibitors, with a corresponding increase in circulating drug concentrations. There is little information available on the pharmacokinetic interaction with ACE inhibitors and cyclosporin, but caution should be employed when they are used together.(ABSTRACT TRUNCATED AT 400 WORDS)

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Absence of a pharmacokinetic interaction between enalapril and frusemide.

Abstract: Single doses of enalapril maleate 10 mg and frusemide 80 mg do not significantly affect the pharmacokinetics of each other when taken concomitantly. Their concomitant use may be associated with more adverse effects than with the individual entities.

Cited by 14 publications

References 10 publications

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-Converting Enzyme Inhibitors

Completing the Enalaprilat Excretion Pathway—Renal Handling by the Proximal Tubule

Pharmacokinetic Drug Interactions with ACE Inhibitors

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