In the treatment of androgen-mediated skin disorders spironolactone provides a valuable therapeutic option. This article reviews the use of spironolactone as an antiandrogen in dermatologic therapy. The endocrinologic effects, pharmacology, dermatologic uses, and side effects are discussed, and guidelines for its use are provided.

Spironolactone in dermatologic therapy

Substrate specificities and functions of the p450 cytochromes

Mineralocorticoid receptor ligands: Biochemical, pharmacological, and clinical aspects

Water-soluble derivatives of beta-cyclodextrin have been considered for solubilization of spironolactone in the formulation of a safe liquid preparation for premature infants. The oral absorption of spironolactone was studied in rats to evaluate the need to adjust spironolactone dosage in prospective clinical studies. Spironolactone was administered in solutions of sulphobutyl ether beta-cyclodextrin (SBE7) or dimethyl-beta-cyclodextrin (DM-beta-CyD) and also as spironolactone-containing powder papers (reference preparation). Spironolactone in SBE7 solution was administered intravenously to assess the extent of intestinal absorption from the different formulations. Spironolactone and the metabolites 7alpha-thiospirolactone, 7alpha-thiomethylspirolactone and canrenone were determined in rat serum after intravenous administration of spironolactone. Half-lives for spironolactone, 7alpha-thiomethylspirolactone and canrenone were 0.72 +/- 0.17, 1.5 +/- 0.3 and 2.2 +/- 0.3 h, respectively. Although, according to Cmax values, 7alpha-thiomethylspirolactone was the major serum metabolite in rats, higher AUC (area under the serum concentration-time curve) values were obtained for canrenone. After oral administration of spironolactone the bioavailabilities evaluated from the AUC values of 7alpha-thiomethylspirolactone were 27.5 +/- 9.3%, 81.3 +/- 28.8% and 82.8 +/- 28.6% for powder papers, DM-beta-CyD and SBE7 solutions, respectively. The oral absorption of spironolactone by rats was better after administration of spironolactone in SBE7 and DM-beta-CyD solutions than after administration as powder papers. Both cyclodextrin formulations enhanced spironolactone bioavailability to a similar extent despite some deacetylation of spironolactone in the presence of SBE7. A reduction of spironolactone dosage would be recommended during clinical studies with premature infants. These results indicate that SBE7 could be a safe and suitable excipient for the solubilization of spironolactone in paediatric formulations.

Water-soluble beta-cyclodextrins in paediatric oral solutions of spironolactone: preclinical evaluation of spironolactone bioavailability from solutions of beta-cyclodextrin derivatives in rats.

https://www.kidney-international.org/article/S0085-2538(15)56998-6/pdf

Cellular and molecular aspects of the renal effects of diuretic agents

Regional differences in microsomal lipid peroxidation and antioxidant levels in the guinea pig adrenal cortex.

Conversion of spironolactone to 7α-thiomethylspironolactone by hepatic and renal microsomes

Species differences in adrenal spironolactone metabolism: relationship to cytochrome P-450 destruction

Studies were carried out to evaluate the effects of cadmium in vitro on microsomal steroid metabolism in the inner (zona reticularis) and outer (zona fasciculata and zona glomerulosa) zones of the guinea pig adrenal cortex. Microsomes from the inner zone have greater 21-hydroxylase than 17 alpha-hydroxylase activity, resulting in the conversion of progesterone primarily to 11-deoxycorticosterone and of 17 alpha-hydroxyprogesterone principally to its 21-hydroxylated metabolite, 11-deoxycortisol. Microsomes from the outer zones, by contrast, have far greater 17 alpha-hydroxylase and C17,20-lyase activities than 21-hydroxylase activity. As a result, progesterone is converted primarily to its 17-hydroxylated metabolite, 17 alpha-hydroxyprogesterone; and 17 alpha-hydroxyprogesterone is converted principally to delta 4-androstenedione, with only small amounts of 21-hydroxylated metabolites being produced. Addition of cadmium to incubations with inner zone microsomes causes concentration-dependent decreases in 21-hydroxylation and increases in 17 alpha-hydroxylase and C17,20-lyase activities, resulting in a pattern of steroid metabolism similar to that in normal outer zone microsomes. Cadmium similarly decreases 21-hydroxylation by outer zone microsomes but has no effect on the formation of 17-hydroxylated metabolites or on androgen (delta 4-androstenedione) production. In neither inner nor outer zone microsomes did cadmium affect cytochrome P-450 concentrations, steroid interactions with cytochrome(s) P-450, or NADPH-cytochrome P-450 reductase activities. The results indicate that cadmium produces both quantitative and qualitative changes in adrenal microsomal steroid metabolism and that the nature of the changes differs in the inner and outer adrenocortical zones. In inner zone microsomes, there appears to be a reciprocal relationship between 21-hydroxylase and 17 alpha-hydroxylase/C17,20-lyase activities which may influence the physiological function(s) of that zone.

Effects of cadmium in vitro on microsomal steroid metabolism in the inner and outer zones of the guinea pig adrenal cortex

The use of anabolic steroids in an attempt to enhance athletic performance has become a widespread practice in both amateur and professional sports in recent years. The rationale for such use (or abuse) of these agents is based upon the growth-promoting and musculature-developing, or anabolic, effects of the naturally occurring steroid hormones known as androgens. These are the hormones that play an important part in the sexual development of males, that is, the production of various masculine traits. The physiologically most important of the naturally occurring androgens is the hormone testosterone, which is produced principally by the testes. The anabolic steroids used by athletes are various synthetic derivatives of testosterone, substances with longer durations of action and/or greater potencies than the physiological androgens. Some of these compounds have been synthesized with the goal of enhancing the anabolic effects of testosterone relative to its masculinizing actions. Since these synthetic preparations are not native or endogenous to the body, they are classified as exogenous substances or drugs.

Howard D. Colby

Papers

Regional differences in microsomal lipid peroxidation and antioxidant levels in the guinea pig adrenal cortex.

Conversion of spironolactone to 7α-thiomethylspironolactone by hepatic and renal microsomes

Species differences in adrenal spironolactone metabolism: relationship to cytochrome P-450 destruction

Effects of cadmium in vitro on microsomal steroid metabolism in the inner and outer zones of the guinea pig adrenal cortex

Fate of Anabolic Steroids in the Body