Spironolactone Metabolism: Steady‐State Serum Levels of the Sulfur‐Containing Metabolites

Gardiner, Peter; Schrode, Kathy; Quinlan, David; Martin, Bernard; Boreham, D. R.; Rogers, Maurice S.; Stubbs, Katherine; Smith, Margaret M.; Karim, Aziz

doi:10.1002/j.1552-4604.1989.tb03339.x

Cited by 119 publications

(72 citation statements)

References 9 publications

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“…S1). Although the steady-state levels of SPR achieved in vivo are likely to be lower than the concentrations used in vitro in our study (24), the metabolite CAN has a much longer half-life in vivo (24) and may potentiate the activity of the parent compound. Nevertheless, because the mineralocorticoid antagonist activity of SPR does not seem to be related to its anti-EBV activity, SPR provides an ideal lead compound for developing antiherpesvirus drugs without SPR's known side effects.…”

Section: Discussionmentioning

confidence: 74%

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

Verma

Thompson

Swaminathan

2016

Proc. Natl. Acad. Sci. U.S.A.

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Clinically available drugs active against Epstein-Barr virus (EBV) and other human herpesviruses are limited to those targeting viral DNA replication. To identify compounds directed against other steps in the viral life cycle, we searched for drugs active against the EBV SM protein, which is essential for infectious virus production. SM has a highly gene-specific mode of action and preferentially enhances expression of several late lytic cycle EBV genes. Here we demonstrate that spironolactone, a mineralocorticoid receptor antagonist approved for clinical use, inhibits SM function and infectious EBV production. Expression of EBV viral capsid antigen is highly SM dependent, and spironolactone inhibits viral capsid antigen synthesis and capsid formation, blocking EBV virion production at a step subsequent to viral DNA replication. In addition, spironolactone inhibits expression of other SM-dependent genes necessary for infectious virion formation. We further demonstrate that molecules structurally related to spironolactone with similar antimineralocorticoid blocking activity do not inhibit EBV production. These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action directed against SM and homologous essential proteins in other herpesviruses. . EBV infects the majority of humans worldwide and establishes a persistent, lifelong latent infection in memory B cells. Occasional reactivation from latency occurs, and EBV enters a lytic phase of replication, during which a tightly regulated series of lytic genes is expressed, culminating in lysis of the host cell and release of infectious viral progeny. All herpesviruses share these abilities to establish asymptomatic latent infection and reactivate intermittently.All herpesviruses also express a regulatory protein early in lytic replication that is essential for efficient gene expression and infectious virion production. The EBV member of this family, which includes herpes simplex virus ICP27, cytomegalovirus (CMV) UL69, and Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57, is known as SM (2). SM acts posttranscriptionally to enhance accumulation of many lytic EBV transcripts. SM activity is highly gene-specific and preferentially enhances expression of several late lytic transcripts, including those encoding the major viral capsid antigen (VCA) and gp350, which is required for infection of B lymphocytes (3-5). SM and its homologs in other herpesviruses may also enhance transcription and translation of specific viral genes (6).Currently, all available antiherpesvirus drugs target viral DNA polymerases and are usually highly effective, but toxicity and development of resistance limits their use (7). To discover potential novel therapeutic compounds, we applied a cell-based screening assay to identify compounds that would specifically target SM function (8). Using this assay, spironolactone (SPR), a drug in clinical use for over 50 y, was identified as inhibiting SM function and EBV virion production. SPR is an aldosterone antagonis...

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Section: Discussionmentioning

confidence: 74%

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

Verma

Thompson

Swaminathan

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The high dose in this study is the most likely explanation for the difference in results between the present and the above-quoted study. Because of the importance of hyperkalemia as a clinically relevant side effect, we selected deliberately, on the basis of pilot experiments, a dose that, in combination with losartan, failed to cause hyperkalemia but was still high compared with the therapeutic range (9,26).…”

Section: Discussionmentioning

confidence: 99%

Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination

Piecha¹,

Koleganova²,

Gross³

et al. 2008

American Journal of Physiology-Renal Physiology

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Piecha G, Koleganova N, Gross M-L, Geldyyev A, Adamczak M, Ritz E. Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination. Am J Physiol Renal Physiol 295: F137-F144, 2008. First published April 23, 2008 doi:10.1152/ajprenal.00065.2008.-Angiotensin II accelerates and renin-angiotensin system blockade halts progression; blockade with high doses even reverses established glomerulosclerosis. Aldosterone also accelerates progression of glomerulosclerosis, partially independently of angiotensin II. The purpose of this study was to assess the relative ability of an angiotensin receptor type 1 (AT1) blocker, a mineralocorticoid receptor blocker, and their combination to reverse glomerulosclerosis. Sprague-Dawley rats were subjected to subtotal renal ablation (SNX) or sham operation. Eight weeks after surgery, they were either euthanized or allocated to treatment with vehicle, losartan, spironolactone, their combination, or unspecific antihypertensive treatment (dihydralazine) for 4 wk. Renal morphology was evaluated by stereology in tissues obtained using pressure-controlled perfusion fixation. Systolic blood pressure was significantly higher in SNX compared with sham-operated animals and decreased in all treatment groups. Compared with wk 8 after SNX, the glomerulosclerosis index (GSI) had increased further by week 12 in the vehicle-and dihydralazine-treated groups but was significantly lowered in the SNXϩlosartan as well as in the SNXϩlosartanϩspironolactone groups and had not progressed further in the SNXϩspironolactone group. The study confirms the partial regression of established glomerulosclerosis in subtotally nephrectomized rats after high-dose AT1 receptor blockade. Nonhyperkalemic doses of spironolactone prevented the increase but failed to decrease the GSI below the 8-wk level and preserved podocyte numbers. Combining the AT1 blocker with mineralocorticoid receptor blockade failed to further increase the regression of glomerulosclerosis. aldosterone escape; renin-angiotensin system GLOMERULOSCLEROSIS AND INTERSTITIAL fibrosis tend to progress over time even if the primary insult to the kidney is no longer operative (11). Blocking the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or angiotensin type 1 receptor (AT 1 ) blockers slows progression in various experimental models and in patients with chronic kidney disease (11). In humans the possibility to reverse established glomerular lesions was clearly demonstrated in diabetic nephropathy after isolated pancreatic transplantation (7). In the renal ablation model in the rat, reversal of glomerulosclerosis was seen after administration of high-dose ACE inhibitors or AT 1 blockers (2,8,16). In this model, aldosterone accelerated progression of glomerulosclerosis independently of ANG II (10, 13). This finding is clinically relevant because frequently, during prolonged treatment with ACE-inhibitors or AT 1 blockers, "aldosterone breakthrou...

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“…Spironolactone undergoes rapid extensive metabolism to three active metabolites with prolonged half-lives (13.8-16.5 h). 3 Eplerenone also undergoes extensive metabolism, but its metabolites are inactive and its elimination half-life is short (4-6 h). 4 The effects of aldosterone are mediated via 1 of 2 mechanisms.…”

Section: Pharmacologymentioning

confidence: 99%

A Comparison of the Aldosterone‐blocking Agents Eplerenone and Spironolactone

Struthers

Krum

Williams

2008

Clinical Cardiology

223

146

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Improved understanding of the adverse pharmacological properties of aldosterone has prompted investigation of the clinical benefits of blocking aldosterone at the receptor level. This article reviews the pharmacology, clinical efficacy, and tolerability of the two available blocking agents, spironolactone and eplerenone. A Medline search identified clinical studies assessing spironolactone and eplerenone. Priority was given to large, wellcontrolled, clinical trials and comparative studies. Pharmacological differences between spironolactone and eplerenone include lower affinity of eplerenone for progesterone, androgen, and glucocorticoid receptors; more consistently demonstrated nongenomic properties for eplerenone; and the presence of long-acting metabolites for spironolactone. Both agents effectively treat hypertension and heart failure but comparisons are complicated by the deficiency of head-to-head trials and differences between patient populations. There are differences in the tolerability profiles; spironolactone is associated with dose-dependent sexual side effects. Both agents produce dose-dependent increases in potassium concentrations, although the effect with spironolactone appears to be greater when both agents are administered at recommended doses. Choice of a specific agent should be based on individual patient issues, such as the nature of heart failure and patient concerns about adverse events.

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Spironolactone Metabolism: Steady‐State Serum Levels of the Sulfur‐Containing Metabolites

Cited by 119 publications

References 9 publications

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

Spironolactone blocks Epstein–Barr virus production by inhibiting EBV SM protein function

Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination

A Comparison of the Aldosterone‐blocking Agents Eplerenone and Spironolactone

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