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| Title: A possible explanation for the peripheral selectivity of a
novel non-steroidal pure antiandrogen, Casodex (ICI 176,334). |
| Title Abreviation: Br J Cancer |
Date of Pub: 1989 Nov |
| Author: Freeman SN; Mainwaring WI; Furr BJ; |
| Issue/Part/Supplement: 5 |
Volume Issue: 60 |
Pagination: 664-8 |
| MESH Headings: Androgen Antagonists (ME/*PD/PK); Anilides
(ME/*PD/PK); Animal; Flutamide (PD); LH (BL); Male; Rats; Rats, Inbred Strains; Receptors,
Androgen (ME); Support, Non-U.S. Gov't; Testosterone (BL); Tissue Distribution; -RN-; |
| Journal Title Code: AV4 |
Publication Type: JOURNAL ARTICLE |
| Date of Entry: 891215N |
Entry Month: 9002 |
| Country: ENGLAND |
Index Priority: 1 |
| Language: Eng |
Unique Identifier: 90028052 |
| Unique Identifier: 90028052 |
ISSN: 0007-0920 |
| Abstract: The in vivo antiandrogenicity of Casodex has been
confirmed and characterised. Androgen receptor (AR) binding assays of rat ventral prostate
gland cytosols revealed a relative binding affinity (RBA) for the AR of 0.267 and a k1 of
1.25 x 10(-7) M for Casodex. In addition, the peripheral selectivity of Casodex relative
to other non-steroidal antiandrogens was confirmed in that daily treatment of
non-castrated rats with Casodex (25 mg kg-1) did not elicit any changes in serum LH and
testosterone concentrations relative to vehicle-treated controls, whereas elevated serum
LH and testosterone were observed in rats treated with flutamide (25 mg kg-1). The
peripheral selectivity of Casodex in the intact male rat was related to the distribution
of radiolabelled antiandrogen following intravenous injection. All tissues with the
exception of the hypothalamus and cerebral cortex (CC) sequestered radioactivity such that
the tissue:serum ratio (TSR) for the drug was greater than unity. In the testis, the TSR
was less than unity 1 h after injection but approached unity 5 h after injection and was
greater than unity 10 h after injection. This may be explained by the presence of a
blood-testis barrier for the drug, resulting in delayed equilibration between the blood
and testis tissue. By comparison, an order of magnitude lower amounts of radioactivity in
the hypothalamus and CC were maintained for the 10 h period after injection. These data,
together with known physicochemical properties of Casodex suggest that a blood-brain
barrier exists for the drug which results in exclusion of this antiandrogen from central
sites of androgen negative feedback and that this accounts for its peripherally selective
antihormonal profile. |
| Abstract By: Author |
| Address: Department of Biochemistry, University of Leeds, UK. |
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