Spironolactone metabolism in target tissues. Characteristics of deacetylation in kidney, liver, adrenal cortex, and testes.

Prior investigations demonstrated that many of the actions of spironolactone (SL) required deacetylation of the parent compound as the first step in the formation of biologically active metabolites. Studies were done to characterize the process of deacetylation in several target tissues. The reaction was catalyzed by microsomal and cytosolic fractions of livers, kidneys, adrenal glands, and testes. Microsomal activity was greatest in liver and kidney and far exceeded cytosolic metabolism in those tissues. In adrenal glands and testes, by contrast, deacetylation was greater in cytosolic than microsomal fractions. The metabolism-mediated destruction of adrenal microsomal cytochromes P-450 by SL was enhanced by coincubation of microsomes with cytosol, illustrating the potential importance of combined microsomal and cytosolic metabolism in the actions of SL. The deacetylation of SL was decreased by various esterase inhibitors; the organophosphate compounds were the most potent inhibitors. The effectiveness of the esterase inhibitors varied from tissue to tissue, as well as from microsomes to cytosol within each tissue. The results indicate that SL deacetylation is catalyzed by microsomal and cytosolic esterases in various target tissues; several isozymes appear to be involved. These and prior observations suggest that tissue metabolism of SL is of major importance in the actions of the drug.