title: 17α-alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism.
abstract: 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235, Apoptone) is an orally bioavailable synthetic analogue of 3β-androstanediol, that is active in rodent models of prostate and breast cancer, and is in Phase IIa clinical trials for the treatment of early- and late-stage prostate cancer. In preparation for clinical studies, nuclear hormone receptor and P450 interactions for HE3235 and major metabolites were characterized in vitro, and pharmacokinetics and metabolite profiles were studied in rodents, dogs, and monkeys. Four-week safety studies conducted in rats and dogs indicated a substantial margin of safety for clinical use, and no evidence of electrocardiographic or neurological effects, although anorexia, thrombocytopenia, and hypokalemia were identified as potentially dose-limiting toxicities at superpharmacological exposures. Pharmacokinetics and drug metabolism have been studied in prostate cancer patients.
authors.affiliation: Harbor BioSciences, Inc., 9171 Towne Centre Drive, Suite 181, San Diego, CA 92122, USA. cahlem@harborbiosciences.com
authors.forename: Clarence
authors.initials: C
authors.lastname: Ahlem
authors.forename: Michael
authors.initials: M
authors.lastname: Kennedy
authors.forename: Theodore
authors.initials: T
authors.lastname: Page
authors.forename: David
authors.initials: D
authors.lastname: Bell
authors.forename: Evelyn
authors.initials: E
authors.lastname: Delorme
authors.forename: Sonia
authors.initials: S
authors.lastname: Villegas
authors.forename: Chris
authors.initials: C
authors.lastname: Reading
authors.forename: Steven
authors.initials: S
authors.lastname: White
authors.forename: Dwight
authors.initials: D
authors.lastname: Stickney
authors.forename: James
authors.initials: J
authors.lastname: Frincke
mesh_terms: D000284:Administration, Oral; D000732:Androstanols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D000735:Androstenedione / Q000097:blood; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000097:blood; D004285:Dogs; D004334:Drug Administration Schedule; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D055432:Metabolomics; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D053719:Tandem Mass Spectrometry; D013739:Testosterone / Q000097:blood; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
chemical_list: C540077:17-ethynylandrostane-3,17-diol; D000732:Androstanols; D018931:Antineoplastic Agents, Hormonal; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D013739:Testosterone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D003577:Cytochrome P-450 Enzyme System
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