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ONCOVET M (mitotane)

Target species: Canines and Felines

 

Strength:
ONCOVET® M: Mitotane 200 mg. 
ONCOVET® M: Mitotane 500 mg. 


Presentations:
ONCOVET® M, 200 mg and 500 mg blue tablets in individual cases with a non-toxic homopolymer polypropylene container, screen-printed, with a blue RP-28 cap containing 10, 20 and 30 tablets and a leaflet, in the following presentations:


ONCOVET® M - Mitotane 200 mg - 1 bottle of 10 tablets per bottle and case.
ONCOVET® M - Mitotane 200 mg - 1 bottle of 20 tablets per bottle and case.
ONCOVET® M - Mitotane 200 mg - 1 bottle of 30 tablets per bottle and case.
ONCOVET® M - Mitotane 500 mg - 1 bottle of 10 tablets per bottle and case.
ONCOVET® M - Mitotane 500 mg - 1 bottle of 20 tablets per bottle and case.
ONCOVET® M - Mitotane 500 mg - 1 bottle of 30 tablets per bottle and case.


Administration: Oral.

 

Indications of use: Treatment for unresectable and/or metastatic adrenocortical carcinoma. Pituitary dependent hyperadrenocorticism. Adrenal gland-dependent hyperadrenocorticism.

ONCOVET® M contains as an active ingredient a chlorinated hydrocarbon (mitotane) which is an adrenocorticolytic compound, although the exact mechanisms of action are unknown, it is known to cause necrosis of the zona fasciculata and reticulata, which are the adrenocortical areas that secrete cortisol, aldosterone and sex hormones. Despite being a cytotoxic agent, mitotane can also inhibit adrenocortical function without causing cell destruction. The major metabolites of mitotane are covalently bound to adrenal mitochondrial proteins, following their metabolism in adrenocortical tissue to a reactive acyl chloride intermediate. This drug is highly specific to the adrenal glands. However, in normal dogs, mitotane caused fatty degeneration and centrilobular atrophy of the liver, and hepatotoxicity secondary to mitotane therapy (hyperadrenocorticism) occurred. Mitotane usually causes minimal degeneration of the zona glomerulosa (site of aldosterone biosynthesis); however, this region can be damaged by prolonged therapy.

 

Mitotane inhibits corticosteroid production and alters adrenal metabolism of endogenous and exogenous steroids. Mitotane inhibits the normal 11-beta-hydroxylation of 11-deoxycortisol (compound S) and 11-deoxycorticosterone (DOC) in the adrenal cortex, thereby blocking the conversion of compound S to cortisol (hydrocortisone) and DOC to corticosterone. The drug can also inhibit 18-hydroxylase activity in the adrenal cortex and thus decrease aldosterone production by blocking the conversion of corticosterone to 18-hydroxycorticosterone (the immediate precursor of aldosterone). Mitotane decreases the rate of cortisol secretion; plasma cortisol concentration; urinary excretion of free cortisol, 17-hydroxycorticosteroids (17-OHCS), 17-ketosteroids (17-KS), and 17 ketogenic steroids; and the adrenocortical response to tetracosactide stimulation. It has been suggested that the drug may have a partial suppressive effect on pituitary corticotropin-secreting cells. Mitotane appears to increase adrenal metabolism of cortisol to 6-beta-hydroxycortisol, resulting in measurable decreased urinary excretion of 17-OHCS; this occurs even in the presence of an unchanged cortisol secretion rate or plasma cortisol concentration. Although urinary excretion of aldosterone metabolites may decrease, serum aldosterone concentrations may remain in the normal range. Therefore, it has been suggested that mitotane may also alter adrenal metabolism of aldosterone. Mitotane decreases the extra-adrenal conversion of androgens to androsterone and etiocholanolone; this results in decreased urinary excretion of 17-KS. The drug also inhibits the extra-adrenal conversion of 3-beta-hydroxysteroids to 3-alpha-hydroxypregnane derivatives. In a recent study, he discovered that one of its mechanisms of action is the inhibition of sterol-O-acyl-transferase 1 (SOAT1), an enzyme that catalyzes the conversion of free cholesterol to cholesterol esters. Inhibition of this conversion increases the amount of free cholesterol in the cell, which can lead to stress on the endoplasmic reticulum and subsequently to cell apoptosis. Mitotane also inhibits the growth of human renal carcinoma cells, astrocytoma cells, and fibroblasts in vitro.

 

Pharmacokinetics (Absorption, fate and elimination): Mitotane is well absorbed after oral administration with a bioavailability of 40% which has a medium solubility, high permeability, hepatic and renal metabolism. The maximum concentration is achieved within 6 hours after administration. Administration of mitotane with food is recommended as it has a relevant effect on bioavailability. The half-life of mitotane is between 18 - 160 days. In dogs and cats, peak plasma concentrations occur approximately 4 hours after dosing with an elimination half-life after a single dose of 1-2 hours. A variable amount of the metabolites (1% - 17%) are excreted in the bile and the remainder is apparently stored in the tissues.
It is extensively metabolized, primarily by cytochrome P450 (CYP) 3A4, and can competitively inhibit the metabolism of drugs that are CYP3A4 substrates. Its metabolism is mainly hepatic through CYP3A4. In the dog, CYP 3A12 is a known substrate. 6% of mitotane is bound to plasma proteins. Other cytochrome P450 enzymes, such as CYP21A2, CYP11A1 (inh), CYP11B1 (inh), CYP17A and CYP2C19, play a minor role in its metabolism, as well as in humans it inhibits the action of HSD3B1, HSD3B2 genes in H295R cell lines. The main circulating active metabolite is mitotane acyl hydrochloride, the generation of this metabolite is mainly mediated by a mitochondrial cytochrome P450. The addition of water causes the generation of the acetic acid derivative, or, p'DDA, which is widely excreted in the urine and has recently been shown to be inactive, without antitumor properties in adrenal cells, and not capable of activating stress. oxidative stress and apoptosis in H295R cells, nor do they cause downregulation of genes involved in steroidogenesis.

 

Exclusive use in Veterinary Medicine.
Sale with Archived Veterinary Prescription (Cat. II).
Its fractional sale is prohibited.
Use in Canines and Felines.
Made in Argentina.
Expiration: 2 years from the moment of its elaboration.
Keep out of the reach of children and pets.
Used containers must be discarded according to current local legislation.
Store at temperatures between 15 and 30ºC

9 de Julio 3875, Lanús, Buenos Aires, Argentina

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