indication

For palliative treatment of advanced breast cancer in postmenopausal women.

pharmacology

Testolactone is a synthetic anti-neoplastic agent that is structurally distinct from the androgen steroid nucleus in possessing a six-membered lactone ring in place of the usual five-membered carbocyclic D-ring. Despite some similarity to testosterone, testolactone has no in vivo androgenic effect. No other hormonal effects have been reported in clinical studies in patients receiving testolactone.

mechanism of action

Although the precise mechanism by which testolactone produces its clinical antineoplastic effects has not been established, its principal action is reported to be inhibition of steroid aromatase activity and consequent reduction in estrone synthesis from adrenal androstenedione, the major source of estrogen in postmenopausal women. Based on in vitro studies, the aromatase inhibition may be noncompetitive and irreversible. This phenomenon may account for the persistence of testolactone's effect on estrogen synthesis after drug withdrawal.

toxicity

Oral LD₅₀s in mouse and dog are 1630 mg/kg and 593-926 mg/kg, respectively.

biotransformation

Hepatic. Metabolized to several derivatives in the liver, all of which preserve the lactone D-ring.

absorption

Testolactone is well absorbed from the gastrointestinal tract.

route of elimination

No clinical effects in humans of testolactone on adrenal function have been reported; however, one study noted an increase in urinary excretion of 17-ketosteroids in most of the patients treated with 150 mg/day orally. It is metabolized to several derivatives in the liver, all of which preserve the lactone D-ring. These metabolites, as well as some unmetabolized drug, are excreted in the urine.

drug interactions

Acenocoumarol: The androgen, Testolactone, may incrase the anticoagulant effect of the Vitamin K antagonist, Acenocoumarol. Monitor for changes in the therapeutic effect of Acenocoumarol if Testolactone is initiated, discontinued or dose changed.

Cyclosporine: The androgen, Testolactone, may increase the hepatotoxicity of Cyclosporine. Testolatone may also elevate serum concentrations of Cyclosporine. Consider alternate therapy or monitor for signs of renal and hepatic toxicity.

Warfarin: Testolactone may increase the serum concentration and anticoagulant effect of warfarin. Monitor for changes in prothrombin time and therapeutic effects of warfarin if testolactone is initiated, discontinued or dose changed.