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| Clinical data | |
|---|---|
| Trade names | Lysodren |
| Other names | 1,1-(Dichlorodiphenyl)-2,2-dichloroethane; o,p'-DDD |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a608050 |
| License data | |
| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | 40% |
| Protein binding | 6% |
| Eliminationhalf-life | 18–159 days |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.152 |
| Chemical and physical data | |
| Formula | C14H10Cl4 |
| Molar mass | 320.03 g·mol−1 |
| 3D model (JSmol) | |
| Chirality | Racemic mixture |
| Melting point | 76 to 78 °C (169 to 172 °F) |
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Mitotane, sold under the brand nameLysodren, is asteroidogenesis inhibitor andcytostaticantineoplastic medication which is used in the treatment ofadrenocortical carcinoma andCushing's syndrome.[3][4][5][6] It is aderivative of the earlyinsecticideDDT and anisomer ofp,p'-DDDTooltip dichlorodiphenyldichloroethane (4,4'-dichlorodiphenyldichloroethane) and is also known as2,4'-(dichlorodiphenyl)-2,2-dichloroethane (o,p'-DDD).[7]
Mitotane has been produced byBristol Myers Squibb but it is marketed as anorphan drug for adrenocortical carcinoma due to the small number of patients in need of it. Its main use is in those patients who have persistent disease despite surgical resection, those who are not surgical candidates, or those who have metastatic disease. In a 2007 retrospective study of 177 patients from 1985 to 2005 showed a significant increase in the recurrence-free interval after radical surgery followed by mitotane when compared to surgery alone.[8] The drug is also sometimes used in the treatment ofCushing's syndrome.[5]
Therapy with mitotane is initiated using an escalating regimen. The extent or intensity of the therapy is gradually increased. This depends on how well the individual patient tolerates the drug and the extent to which it affects the patient's performance status (according to the ECOG/Karnofsky Performance Status). Monitoring of the mitotane concentration in the blood is recommended. The general target value is ≥ 14 mg/L.[9]
Mitotane therapy is initiated using an escalating regimen. In all patients receiving mitotane therapy, glucocorticoid replacement is recommended, except for patients with persistent cortisol excess. In these cases, at least twice the standard replacement dose is generally required. This is due to the increased steroid excretion and the rise in cortisol-binding globulin. Mitotane-induced side effects must be monitored regularly and treated appropriately, avoiding over-, under-, or inappropriate treatment. Furthermore, initiating supportive therapy is advisable to improve mitotane tolerance. Ideally, this should be done before severe toxicity develops. Mitotane causes significant drug interactions due to strong induction of CYP3A4. Therefore, it is crucial to check all concomitant medications for CYP3A4 interactions and replace them with an alternative if necessary and available. Other healthcare providers should be advised not to initiate any other drug therapies without prior consultation.[9]
The use of mitotane is unfortunately limited byside effects,[10] which, as reported by Schteingart et al., includeanorexia andnausea (88%),diarrhea (38%),vomiting (23%), decreasedmemory and ability to concentrate (50%),rash (23%),gynecomastia (50%),arthralgia (19%), andleukopenia (7%).[11]
Mitotane is an inhibitor of theadrenal cortex. It acts as aninhibitor ofcholesterol side-chain cleavage enzyme (P450scc, CYP11A1), and also of11β-hydroxylase (CYP11B1),18-hydroxylase (aldosterone synthase, CYP11B2), and3β-hydroxysteroid dehydrogenase (3β-HSD) to a lesser extent.[3][10] In addition, mitotane has direct and selectivecytotoxic effects on the adrenal cortex, via an unknown mechanism, and thereby induces permanentadrenal atrophy similarly to DDD.[12][13] Mitotane has also been reported to interact withtubulin and inhibit its polymerization.[14]
Analogues of mitotane includeaminoglutethimide,amphenone B, andmetyrapone.
Mitotane was introduced in 1960 for the treatment ofadrenocortical carcinoma.[5]
Mitotane is thegeneric name of the medication and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andJANTooltip Japanese Accepted Name.[6][15]
Mitotane is sold under the brand name Lysodren.[6]
Mitotane is also used to treatCushing's disease (pituitary-dependentCushing's syndrome) indogs. The medication is used in the controlled destruction of adrenal tissue, leading to a decrease in cortisol production.[16]
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