Difference in metabolic profile of potassium canrenoate and spironolactone in the rat: Mutagenic metabolites unique to potassium canrenoate

Abstract

The metabolic fates of potassium canrenoate (PC) and spironolactone (SP) were compared for the rat in vivo and in vitro. Approximately 18% of an in vivo dose of SP was metabolized to canrenone (CAN) and related compounds in the rat. In vitro, 20-30% of SP was dethioacetylated to CAN and its metabolites by rat liver 9000 g supernatant (S9). Thus, the major route of SP metabolism is via pathways that retain the sulfur moiety in the molecule. PC was metabolized by rat hepatic S9 to 6 alpha, 7 alpha- and 6 beta, 7 beta-epoxy-CAN. The beta-epoxide was further metabolized to its 3 alpha- and 3 beta-hydroxy derivatives as well as its glutathione (GSH) conjugate. Both 3 alpha- and 3 beta-hydroxy-6 beta, 7 beta-epoxy-CAN were shown to be direct acting mutagens in the mouse lymphoma assay, whereas 6 alpha, 7 alpha- and 6 beta, 7 beta-epoxy-CAN were not. These mutagenic metabolites, their precursor epoxides and their GSH conjugates were not formed from SP under identical conditions. The above findings appear to be due to inhibition of metabolism of CAN formed from SP by SP and/or its S-containing metabolites, since the in vitro metabolism of PC by rat hepatic microsomes was appreciably reduced in the presence of SP. The hypothesized mechanism(s) for this inhibition is that SP and its S-containing metabolites specifically inhibit an isozyme of hepatic cytochrome P-450 or SP is a preferred substrate over PC/CAN for the metabolizing enzymes. Absence of the CAN epoxide pathway in the metabolism of SP provides a possible explanation for the observed differences in the toxicological profiles of the two compounds.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

“…This led to a thorough reinvestigation of the metabolism of spironolactone and canrenoate, and Searle scientists resolved the phenomenon of the different toxicological findings: potassium canrenoate is metabolized to different epoxy-canrenone derivatives, which were found to be direct mutagens in the mouse lymphoma assay. Importantly, these mutagenic metabolites or their precursor epoxides were not formed from spironolactone (Cook et al 1988, Oppermann et al 1988). Therefore, the occurrence of myelocytic leukemia in long-term studies with canrenoate in rats can be explained by the formation of these mutagenic metabolites, whereas the generation of benign adenomas by very high doses of spironolactone is most probably related to endocrine pharmacological effects (Mayer et al 1988).…”

Aldosteron und Aldosteronrezeptorantagonisten in der Herzinsuffizienztherapie

“…Es gibt tierexperimentellen Anhalt für die Kanzerogenität von Canrenon/Canrenoat, nicht aber für tumorauslösende Effekte von Spironolacton. Dies wird auf die Hemmung einiger Abbauschritte von Canrenon zu Epoxiden durch Spironolacton und seine schwefelhaltigen Metabolite zurückgeführt [69,70]. Für Canrenoat besteht aus diesen Gründen eine Anwendungsbeschrän-kung, die den Gebrauch auf das kürzeste notwendige Zeitintervall limitiert.…”

Potassium Canrenoate, an Aldosterone Receptor Antagonist, Reduces Isoprenaline-Induced Cardiac Fibrosis in the Rat

“…Indeed, potassium canrenoate is genotoxic (Martelli et al, 2002) and induces DNA damage in different tissues, including the liver, thyroid, brain, and mammary gland (Cook et al, 1988). Studies in primary cultures of rat hepatocytes demonstrate that potassium canrenoate induces DNA fragmentation and DNA repair (Martelli et al, 1999).…”