DB00666 - Nafarelin
| Identification | |
|---|---|
| Name | Nafarelin |
| Accession Number | DB00666 (APRD01129) |
| Type | small molecule |
| Description | A potent synthetic agonist of gonadotropin-releasing hormone with 3-(2-naphthyl)-D-alanine substitution at residue 6. Nafarelin has been used in the treatments of central precocious puberty and endometriosis. [PubChem] |
| Structure |
|
| Categories (*) | |
| Molecular Weight | 1322.4713 |
| Groups | approved |
| Monoisotopic Weight | 1321.635625827 |
| Pharmacology | |
| Indication | For treatment of central precocious puberty (true precocious puberty, GnRH-dependent precocious precocity, complete isosexual precocity) in children of both sexes and for the treatment of endometriosis. |
| Mechanism of action | Like GnRH, initial or intermittent administration of nafarelin stimulates release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, which in turn transiently increases production of estradiol in females and testosterone in both sexes. However, with continuous daily administration, nafarelin continuously occupies the GnRH receptor, leading to a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. This causes a significant and sustained decline in the production of LH and FSH. A decline in gonadotropin production and release causes a dramatic reversible decrease in synthesis of estradiol, progesterone, and testosterone by the ovaries or testes. Like normal endometrium, endometriotic implants contain estrogen receptors. Estrogen stimulates the growth of endometrium. Use of nafarelin induces anovulation and amenorrhea and decreases serum concentrations of estradiol to the postmenopausal range, which induces atrophy of endometriotic implants. However, nafarelin does not abolish the underlying pathophysiology of endometriosis. In children with central precocious puberty receiving nafarelin, serum LH, testosterone, and estradiol concentrations return to prepubertal levels. This results in the supression of secondary sexual characteristics and decrased rate of linear growth and skeletal maturation. Following disconinuation of nafarelin, the effects of the drug is reversed, meaning FSH and LH concentrations usually return to pretreatment levels. |
| Absorption | Rapidly absorbed into the systemic circulation after intranasal administration. Bioavailability from a 400 µg dose averaged 2.8% (range 1.2 to 5.6%). Not absorbed after oral administration. |
| Protein binding | Approximately 80%. |
| Biotransformation | Enzymatic hydrolysis. |
| Route of elimination | Not Available |
| Toxicity | In experimental animals, a single subcutaneous administration of up to 60 times the recommended human dose (on a µg/kg basis, not adjusted for bioavailability) had no adverse effects. At present, there is no clinical evidence of adverse effects following overdosage of GnRH analogs. |
| Affected organisms |
|
| Interactions | |
| Drug Interactions | Not Available |
| Food Interactions | Not Available |
Targets
| Gonadotropin-releasing hormone receptor | |
|---|---|
| Name | Gonadotropin-releasing hormone receptor |
| Gene Name | GNRHR |
| Pharmacological action | yes |
| Actions | agonist |
| References |
|
| DTHybrid score | 1.3256 |
| Gonadotropin-releasing hormone II receptor | |
| Name | Gonadotropin-releasing hormone II receptor |
| Gene Name | GNRHR2 |
| Pharmacological action | yes |
| Actions | agonist |
| References |
|
| DTHybrid score | Not Available |
Predictions
| Id | Partner name | Gene Name | Score |
|---|---|---|---|
| 148 | Lutropin-choriogonadotropic hormone receptor | LHCGR | 0.2629 |
| 3811 | Cytochrome P450 19A1 | CYP19A1 | 0.0487 |
| 1649 | Small inducible cytokine A2 | CCL2 | 0.0242 |
| 756 | Sex hormone-binding globulin | SHBG | 0.017 |
| 614 | Progesterone receptor | PGR | 0.0157 |
| 146 | Androgen receptor | AR | 0.0135 |
| 136 | Estrogen receptor | ESR1 | 0.0125 |
| 4512 | Cytochrome P450 3A4 | CYP3A4 | 0.0079 |