Goserelin

Goserelin

Systematic (IUPAC) name
N-(21-((1H-indol-3-yl)methyl)-1,1-diamino-12-(tert-butoxymethyl)-6-(2-(2-carbamoylhydrazinecarbonyl)cyclopentanecarbonyl)-15-(4-hydroxybenzyl)-18-(hydroxymethyl)-25-(1H-imidazol-5-yl)-9-isobutyl-8,11,14,17,20,23-hexaoxo-2,7,10,13,16,19,22-heptaazapentacos-1-en-24-yl)-5-oxopyrrolidine-2-carboxamide
Clinical data
Trade names	Zoladex
AHFS/Drugs.com	monograph
MedlinePlus	a601002
Pregnancy category	D (3.6mg) / X (10.8mg) (USA)
Routes of administration	implant
Legal status	℞ (Prescription only)
Pharmacokinetic data
Protein binding	27.3%
Biological half-life	4-5 hours
Excretion	hepatic
Identifiers
CAS Number	65807-02-5
ATC code	L02AE03 (WHO)
PubChem	CID 5311128
IUPHAR/BPS	3879
DrugBank	DB00014
ChemSpider	4470656
UNII	0F65R8P09N
KEGG	D04405
ChEBI	CHEBI:5523
ChEMBL	CHEMBL1201247
Synonyms	D-Ser(But)^6Azgly^10LHRH
Chemical data
Formula	C59H84N18O14
Molar mass	1269.410 g/mol
SMILES CC(C)C[C@H](NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@H](CC1=CC=C(O)C=C1)NC(=O)[C@H](CO)NC(=O)[C@H](CC1=CNC2=CC=CC=C12)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@H]1C(=O)NNC(N)=O
InChI InChI=1S/C59H84N18O14/c1-31(2)22-40(49(82)68-39(12-8-20-64-57(60)61)56(89)77-21-9-13-46(77)55(88)75-76-58(62)90)69-54(87)45(29-91-59(3,4)5)74-50(83)41(23-32-14-16-35(79)17-15-32)70-53(86)44(28-78)73-51(84)42(24-33-26-65-37-11-7-6-10-36(33)37)71-52(85)43(25-34-27-63-30-66-34)72-48(81)38-18-19-47(80)67-38/h6-7,10-11,14-17,26-27,30-31,38-46,65,78-79H,8-9,12-13,18-25,28-29H2,1-5H3,(H,63,66)(H,67,80)(H,68,82)(H,69,87)(H,70,86)(H,71,85)(H,72,81)(H,73,84)(H,74,83)(H,75,88)(H4,60,61,64)(H3,62,76,90)/t38-,39-,40-,41-,42-,43-,44-,45+,46-/m0/s1 Key:BLCLNMBMMGCOAS-URPVMXJPSA-N=
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Goserelin acetate (trade name Zoladex, by AstraZeneca^[1]) is a drug used to suppress production of the sex hormones (testosterone and estrogen), particularly in the treatment of breast and prostate cancer. It is an injectable gonadotropin releasing hormone superagonist (GnRH agonist), also known as a luteinizing hormone releasing hormone (LHRH) agonist.

Structurally, it is a decapeptide. It is the natural LHRH/GnRH decapeptide with two substitutions to inhibit rapid degradation.

Goserelin acetate stimulates the production of the sex hormones testosterone and estrogen in a non-pulsatile (non-physiological) manner. This causes the disruption of the endogenous hormonal feedback systems, resulting in the down-regulation of testosterone and estrogen production.

Zoladex was approved by the U.S. Food and Drug Administration in 1989^[2] for treatment of prostate cancer.

Pharmacokinetics

Goserelin is a synthetic analogue of a naturally occurring luteinizing-hormone releasing hormone (LHRH). Bioavailability is almost complete. Goserelin is poorly protein bound and has a serum elimination half-life of two to four hours in patients with normal renal function. The half-life increases with patients with impaired renal function. There is no significant change in pharmacokinetics in subjects with liver failure. After administration, peak serum concentrations are reached in about two hours. It rapidly binds to the LHRH receptor cells in the pituitary gland thus leading to an initial increase in production of luteinizing hormone and thus leading to an initial increase in the production of corresponding sex hormones. This initial flare may be treated by co-prescribing/co-administering an androgen receptor antagonist such as bicalutamide (Casodex). Eventually, after a period of about 14–21 days, production of LH is greatly reduced due to receptor downregulation, and sex hormones are generally reduced to castrate levels.^[3]

Indications

10.8mg implant syringe

Goserelin acetate is used to treat hormone-sensitive cancers of the breast (in pre- and peri-menopausal women) and prostate, and some benign gynaecological disorders (endometriosis, uterine fibroids and endometrial thinning). In addition, goserelin is used in assisted reproduction and in the treatment of precocious puberty. It may also be used in the treatment of male-to-female transsexuals^[4] and is favoured above other anti-androgens in some countries, such as the UK. It is available as a 1-month depot and a long-acting 3-month depot.

Side effects

Goserelin acetate may cause a temporary increase in bone pain and symptoms of prostatic cancer during the first few weeks of treatment. This is known as the tumour flare effect, and is the result of an initial increase in luteinizing hormone production, before the receptors are desensitised and hormonal production is inhibited. The symptoms will disappear, with hormonal inhibition. It is therefore advisable to co-treat with an antiandrogen during the first 2–3 weeks of goserelin treatment, particularly in patients with pre-existing bone symptoms.

Goserelin may cause bone pain, hot flushes, headache, stomach upset, depression, difficulty urinating (isolated cases), weight gain, swelling and tenderness of breasts (infrequent), decreased erections and reduced sexual desire. Bone pain can be managed symptomatically, and erectile dysfunction can be treated by Levitra (Vardenafil) or other similar oral therapies, although they will not treat the reduced sexual desire.

References

1. AstraZeneca official Zoladex site
2. FDA Approval for Zoladex 3.6 mg
3. Kotake, Toshihiko; Michiyuki Usami; et al. (August 1999). "Goserelin Acetate with or without Antiandrogen or Estrogen in the Treatment of Patients with Advanced Prostate Cancer: a Multicenter, Randomized, Controlled Trial in Japan". Japanese Journal of Clin. Oncol. 29 (11): 562–570. doi:10.1093/jjco/29.11.562. ISSN 1465-3621. PMID 10678560. Retrieved 2007-02-26.
4. Dittrich R, Binder H, Cupisti S, Hoffmann I, Beckmann MW, Mueller A. Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist. Exp Clin Endocrinol Diabetes 2005;113:586–92.

External links

• One man's experience of prostate cancer treatment using goserelin - BBC News