Administration spironolactone at a dosage of 400 mg/day to healthy male volunteers for 5 days resulted in a significant rise in plasma progesterone and 17alpha-hydroxyprogesterone which persisted throughout the study. A transient increase in plasma FSH and LH concentration was observed after the second but not the third or fifth days of drug administration. There was no change in plasma concentration of testosterone, 17beta-estradiol, or prolactin. These findings are consistent with a previously-reported spironolactone-induced destruction of the microsomal enzyme cytochrome P-450, an enzyme necessary for 17-hydroxylase and desmolase activity. The results do not explain the decrease of libido, the impotence, and the gynecomastia frequently associated with spironolactone therapy in males.

17-Ketosteroids↗

PubMed1975

Pre- and postnatal enzyme capacity for drug metabolite production.

Most lipid-soluble foreign compounds including drugs, insecticides and many environmental pollutants are metabolized in animals by cytochrome P-450 enzymes in the endoplasmic reticulum of liver. These enzymes are virtually absent in fetuses of laboratory animals, but their activities increase to adult levels within 3-8 weeks after birth. In human fetuses, the enzymes appear during the first half of pregnancy, and their activities during gestation reach about one third of those found in adults. The species differences in fetal activities apparently parallel the differences in the development of liver endoplasmic reticulum. In laboratory animals, the rough-surfaced reticulum does not develop until 4 days before birth adn the smooth-surfaced retuculum develops only after birth. In man, however, the rough-surfaced form appears at about 7 to 9 weeks of gestation, whereas the smooth-surfaced form appears at about the 3rd month of pregnancy. Despite the early development of these enzymes in humans, they probably play only a minor role in limiting the accumulation of most foreign compounds in human fetuses. Nevertheless, they may play an important role in drug-induced toxicities, particularly those that are mediated through the formation of chemically reactive metabolites.

Animals↗

PubMed1975

Metabolism, tissue distribution and covalent binding of tripelennamine and its N-nitroso derivative in the rat.

Benzyl-14C-labeled tripelennamine and its N-nitroso derivative (NDT) were administered (20 mg/kg; 50 muc/kg i.p.) separately to control and phenobarbital-pretreated rats. Tissue distribution and covalent binding of the two compounds in liver, lung, kidney, fat and muscle tissues, as well as in the plasma, were determined at 4 and 24 hours after the administration. No specific localization of the test compounds to any tissue or to the plasma was observed. The in vivo covalent binding of both the compounds to the proteins of the tissues and plasma was low; the highest binding occurred in the liver (approximately 25 pmol/mg of protein). Within 24 hours about 78% of the injected tripelennamine and its metabolites was excreted into the urine whereas only about 35% of the radioactivity of NDT was eliminated. Pretreatment with phenobarbital accelerated the elimination of both substances. The metabolites of the drug and NDT were isolated from urine, hydrolyzed by glucuronidase-sulfatase and identified as their trimethylsilyl derivatives by gas chromatography-mass spectrometry. Tripelennamine was found to be extensively metabolized by N-demethylation and aromatic hydroxylation pathways. By contrast most of the NDT was eliminated as NDT and hydroxylated metabolites; very little was excreted as N-demethylated metabolites. The hydroxylated metabolites identified were p-hydroxybenzyl, p-hydroxybenzyl-5-hydroxypyridyl and m,p-dihydroxybenzyl derivatives of the drug, its N-demethylated analog and NDT. The catechol formation with NDT was found to be 4 times that observed with tripelennamine.

Animals↗

PubMed1974