Pharmacological profile and effects of mitotane in adrenocortical carcinoma

Abstract

Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour tissues; it induces cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids, which are involved in the pathogenesis of ACC. However, high doses of mitotane are usually necessary to reach the therapeutic plasma concentration, which may result in several adverse effects. This suggests that important pharmacological processes, such as first pass metabolism, tissue accumulation and extensive time for drug elimination, are associated with mitotane administration. Few studies have reported the pharmacological aspects and therapeutic effects of mitotane. Therefore, the aim of this review was to summarize the chemistry, pharmacokinetics and pharmacodynamics, and therapeutic and toxic effects of mitotane. This review also discusses new perspectives of mitotane formulation that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects.

What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics

“…In this aspect, complete surgical resection with negative margins is an important prognostic factor [126]. If locally advanced or spread to distant sites, administration of the adrenolytic agent mitotane is usually recommended [128][129][130].…”

The Challenging Pharmacokinetics of Mitotane: An Old Drug in Need of New Packaging

“…In the pool of hydrophobic drugs, mitotane, being a drug of choice for adrenocortical carcinoma (ACC) [7,8], also suffers from intrinsic poor aqueous solubility and low bioavailability [9,10]. Recently, Corso et al published a review which has provided a systematic details about the poor pharmacokinetics and pharmacodynamics of mitotane [11]. Contrarily, our article focuses more on the biopharmaceutics of mitotane with a special emphasis on development of new formulations and dosage forms.…”

Estrogen-Like Effect of Mitotane Explained by Its Agonist Activity on Estrogen Receptor-α

“…Sixty years after the introduction of mitotane in the medical treatment of ACC, the whole spectrum of its pharmacological activities remains elusive. The main effect of mitotane in ACC is the induction of tumor cell death by apoptosis and/or necroptosis [ 39 ] and the on-target result of toxic disruption of adrenocortical steroidogenesis induced by mitotane remains the reduction of glucocorticoid excess, and other endocrine effects are considered off-target results. Among these, endocrine effects attributable to enhanced estrogen activity have been only partially studied, and the main conclusion of previous studies is that mitotane has an estrogenic effect that is ER-α dependent and mediated by mitotane-dependent increased hepatic SHBG synthesis [ 15 ].…”

“…The study of crystal structures of complexes with agonist and antagonist molecules identified the helix 12 (H12, residues 532–552) as the most important structural element of each LBD monomer, acting as a molecular switch between the active and inactive conformation of the receptor with “flip-flop” mechanism [ 24 , 25 , 26 , 40 ]. After ligand interaction, the H12 helix undergoes a conformational change, assuming either an active conformation, where it is packed against helixes H3, H5/6, and H11 to close the binding site and create a surface essential for coactivators binding, or an inactive conformation, where it is displaced from the binding site and located in a groove formed by H3 and H5 [ 24 , 37 , 39 ]. As a consequence, the conformation of helix H12 can be used to assess the ability of a ligand to act as an agonist or antagonist in molecular dynamics simulations [ 40 ].…”

“…These results supported the rationale to antagonize these side effects with drugs such as the SERM tamoxifen or the SERD fulvestrant, added to the mitotane therapy. This point, however, needs to be carefully addressed since, although fulvestrant did not report significant drug–drug interaction [ 41 ], the chronic administration of this combination may result in a drug–drug metabolic interaction between tamoxifen and mitotane, due to the CYP3A4-mediated tamoxifen metabolism [ 42 ] and the well-known CYP3A4 inducer effect of mitotane [ 39 ]. From a pharmacological point of view, however, the interaction may be more complex than described above.…”