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Radiotracer Localization by Receptor-Ligand Interactions
Published in Lelio G. Colombetti, Principles of Radiopharmacology, 1979
Raymond E. Gibson, William C. Eckelman, Waclaw J. Rzeszotarski, Victor Jiang, J. Krijn Mazaitis, Chang Paik, Toru Komai, Richard C. Reba
The interactions of inhibitors with enzymes or uptake/transport mechanisms can be treated as the interactions of ligands with receptors (provided the inhibitors are not partial substrates). A wider variety of structures are available to inhibitors than for analogues of naturally occurring metabolites and need not bear any resemblance to the natural metabolite. For example, 1-naphthylvinylpyridine is a potent inhibitor of the enzyme choline acetyltransferase,65 but is structurally dissimilar to either choline or acetyl-CoA. Similarly, aminoglutethimide, metyrapol, and amphenone B are inhibitors of cholesterol metabolism in the adrenal glands,66 but have little in common with the structure of cholesterol.
New and emerging drug therapies for Cushing’s disease
Published in Expert Opinion on Pharmacotherapy, 2018
Sylvère Störmann, Jochen Schopohl
Another drug derived from amphenone B is mitotane, a drug approved for and primarily used in advanced or inoperable adrenocortical carcinoma. Fundamentally, it is cytotoxic to the adrenal gland, but is also an inhibitor of the cholesterol side-chain cleavage enzyme. To a lesser extent, it also inhibits 11β- and 18-hydroxylase and 3β-hydroxysteroid dehydrogenase [35]. In the long term, it leads to permanent adrenal atrophy equivalent to a chemical adrenalectomy. Its main cytotoxic effect is mediated by an apoptotic process activated by the disruption of mitochondria, and is restricted to the zona reticularis and the zona fasciculata [155,156]. Clinically, the use of mitotane causes a significant reduction in adrenal cortisol and androgen synthesis. Onset of action is slow and due the lipophilic nature of the drug it has a very long half-life so that it may have effects lasting months after discontinuation. Mitotane has a wide range of side effects including nausea, vomiting, and neurotoxicity. Its use in CD is limited to select cases, but only after careful consideration. In the largest series to date, 67 patients with CD were treated with mitotane, of which 72% achieved UFC normalization after 5–8 months [157]. However, after discontinuation of mitotane among patients considered in remission, recurrence occurred in as much as 71%.