Mitotane

Mitotane (Lysodren) produces selective atrophy of the zona fasciculata and zona reticularis, which results in a decrease in the secretion of 17-hydroxycorticosteroids. Direct inhibition of cholesterol side-chain cleavage and 11p/18-hydroxylase activities has also been demonstrated. Mitotane is capable of inducing remission of Cushing's disease, but only after several weeks of therapy and at the price of severe gastrointestinal distress. Moreover, more than half of patients relapse following cessation of therapy. Other side effects include lethargy, mental confusion, skin rashes, and altered hepatic function. Being a lipid-soluble substance, mitotane remains stored in body tissues for extended periods. This may account for the marked patient-to-patient variability in its therapeutic and/or toxic effects.

Mitotane is the drug of choice for the treatment of primary adrenal carcinoma when surgery or radiation therapy is not feasible (see Chapter 56). Its effectiveness in curtailing adrenal activity is due to an action on adrenocortical mitochondria to impair cytochrome P450 steps in steroid biosynthesis. Mitotane requires metabolic transformation to exert its therapeutic action, and the differential ability of tumors to metabolize the drug may determine its clinical effectiveness. It is advised to measure serum mitotane levels and urinary free cortisol excretion to ensure adequate therapeutic concentrations. Mitotane increases circulating cholesterol by inhibiting cytochrome P450-mediated reactions and therefore contributes to the cardiovascular events that are a significant cause of mortality in untreated Cushing's syndrome.

Mitotane, being closely related to the organochlo-rine insecticides, shares its inductive effects on the liver microsomal drug-metabolizing enzyme system, and its use may therefore alter the requirement for concomi-tantly administered drugs that are also metabolized by this pathway.

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