Definition
Mitotane is currently marketed as Lysodren. Designated chemically as 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane, it is best known by its trivial name, o,p-DDD and is an isomer of the insecticide para (p’) p’DDD. The chemical structure is:
Classification
• oral chemotherapeutic agent
• adrenolytic drug
Indications
• adrenal cortical carcinoma of both functional and non-functional types
• other causes of Cushing’s syndrome
Pharmacokinetics
Absorption
• oral administration
• after oral administration, 60% is excreted in stool, usually unchanged, and 40% concentrates in liver, brain, adipose and adrenal tissues
Distribution
clinically relevant concentrations are 14-20 mg/l, the binding to plasma proteins is approximately 6%
Metabolism
Mitotane is hydroxylated at the ß-carbon and quickly transformed by dehydrochlorination into an acyl-chloride. The acyl-chloride either covalently binds to bionucleophiles in the target cells or, by losing water, is transformed to the acetic acid derivative o,p’-DDA (1,1 –[o,p’- dichlorodiphenyl] acetic acid) for renal excretion. The initial hydroxylation step is carried out in the mitochondria and is catalyzed through a P-450 enzyme. The metabolic reaction is dependent on oxygen and nicotinamide adenine dinucleotide phosphate, and is inhibited by ketoconazole but not by aminoglutethimide, metyrapone, or other steroids. This has led to the suggestion that mitotane is metabolized by a novel, nonsteroidogenic CYP that is active in xenobiotic metabolism in the adrenal cortex
Interactions
Mitotane can decreases effect of
• Anisindione
• Acenocoumarol
• Dicumarol
• Warfarin
Instead Spironolactone antagonizes the effect of mitotane. Mitotane increases the clearance of exogenoisly administered steroids. Mitotane effects on other drugs are not well documented. For example, full doses of adriamycin, etoposide and vincristine- chemotherapy agents metabolized principally by CYP3A4- have been administered with mitotane without evidence of additional toxicities
Elimination:
elimination half-lives are from 18 to 159 days
Mechanism of Action
Its biochemical mechanism of action is unknown, although data are available to suggest that the drug modifies the peripheral metabolism of steroids as well as directly suppressing the adrenal cortex. Mitotane can best be described as an adrenal cytotoxic agent, although it can cause adrenal inhibition, apparently without cellular destruction. The administration of Mitotane alters the extra-adrenal metabolism of cortisol in man; leading to a reduction in measurable 17-hydroxy corticosteroids, even though plasma levels of corticosteroids do not fall. The drug apparently causes increased formation of 6-B-hydroxyl cortisol
Toxicity
Although mitotane can effectively manage hormone excess, its toxicity profile limits tolerability. The main types of adverse reactions consist of the following:
1. Gastrointestinal disturbances, which consist of anorexia, nausea or vomiting, and in some cases diarrhea, occur in about 80% of the patients.
2. Central nervous system side effects occur in 40% of the patients. These consist primarily of depression as manifested by lethargy and somnolence (25%), and dizziness or vertigo (15%).
3. Skin toxicity has been observed in about 15% of the cases. These skin changes consist primarily of transient skin rashes. Infrequently occurring side effects involve the eye (visual blurring, diplopia, lens opacity, toxic retinopathy); the genitourinary system (hematuria, hemorrhagic cystitis, and albuminuria); cardiovascular system (hypertension, orthostatic hypotension, and flushing); and some miscellaneous effects including generalized aching, hyperpyrexia, and lowered protein bound iodine (PBI).
Resistance
Adrenocortical carcinoma (ACC) is commonly recognized as a chemoresistant disease. Normal Adrenocortical tissue produces high levels of the multi-drug resistance protein MDR1. High MDR1 expression is retained in ACC. In vitro studies have shown that mitotane is able to target MDR1. This may be mechanism by which combination chemotherapy regimens containing mitotane have seemed to be more active than those not containing mitotane.
