Absorption, Distribution and Excretion
The bioavailability of the intramuscularly administered sustained-release formulation is estimated to be approximately 90%. This study investigated the pharmacological effects of subcutaneous and intramuscular injections of leuprolide acetate sustained-release microspheres in rats and dogs. Following injection, the microspheres provided similar linear drug release and maintained serum drug concentrations for 3 months. In rats, injections of the microspheres at a dose of 100 μg/kg/day and in dogs at a dose of 25.6 μg/kg/day resulted in sustained inhibition of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, as well as serum testosterone levels in both rats and dogs, for more than 16 weeks. Periodic challenge assays showed that a single injection of the microspheres significantly inhibited the function of the pituitary-gonadal system in rats for 15 weeks. Reproductive organ growth was also inhibited in a dose-dependent manner for more than 3 months. The study concludes that sustained-release leuprolide microspheres administered for 3 months provide a durable pharmacological effect. This article reports the effect of formulation adjuvants on the absorption of leuprorelin acetate via duodenal injection and oral administration in male castrated rats. Compared with the intravenously administered control group, the absorption rates after oral and duodenal administration were approximately 0.01% and 0.08%, respectively. The duodenal bioavailability of aqueous formulations and water-in-oil emulsions of the lipophilic salt of leuprorelin (decane sulfonic acid derivative) was approximately 0.2% and 1%, respectively. Assessment of the effect of formulations on oral absorption showed that the lipophilicity, surfactant, and excipient properties significantly affected the duodenal absorption of leuprorelin. The absolute bioavailability of this drug in typical emulsion systems was approximately 3-10%, representing an approximately 100-fold increase in gastrointestinal bioavailability compared to intravenous administration. The implications of these findings for the effect of formulation adjuvants on the oral absorption of leuprorelin and other peptide drugs following duodenal administration are discussed. This study compared the bioavailability of leuprolide acetate in rats and healthy men (19-39 years old) after inhalation and intranasal administration, and compared it with intravenous and subcutaneous administration. α-Cyclodextrin, edanoic acid, and solution volume all significantly improved the bioavailability of intranasal administration in rats. In vivo variability was 30-60%, with an absorption rate ranging from 8% to 46% compared to the intravenous control group. In humans, the bioavailability of subcutaneous administration was 94%, higher than that of intravenous administration. The mean intranasal bioavailability was 2.4%, with significant inter-individual variability. The peak plasma concentrations in the 1 mg and 3 mg dose groups were 0.24-1.6 ng/ml and 0.1-11 ng/ml, respectively. The mean peak plasma concentrations of the 1 mg aerosol and 2 mg suspension aerosol were… The bioavailability of the suspension aerosol was four times that of the solution aerosol. /Leuprolide Acetate/

Interactions
Objective: To evaluate the efficacy of etidronate sodium in combination with low-dose 19-nortestosterone-progestin norethindrone or high-dose norethindrone alone in preventing vasomotor instability and bone mineral density loss induced by GnRH agonist monotherapy. Methods: This randomized study included 11 patients who received intramuscular injections of the long-acting GnRH agonist leuprorelin acetate 3.75 mg every 4 weeks for 24 weeks. Six patients (Group I) received oral etidronate sodium 400 mg daily for 14 days over three 56-day cycles, followed by oral calcium carbonate 500 mg daily for 42 days. This regimen was supplemented with oral norethindrone 2.5 mg daily. Five patients (Group II) received oral norethindrone 10 mg/day. Two control groups were included in this study. Group III consisted of ten previously reported patients who received only the same gonadotropin-releasing hormone agonist treatment. Group IV consisted of 12 treatment-naïve patients with regular menstrual cycles. The study continuously assessed bone mineral density, vasomotor symptoms, circulating estrogen levels, and blood lipids. Results: Significant vasomotor instability (P < .01) and decreased bone mineral density (-4.8 ± 0.9%; P < .05) observed in Group III patients were avoided in Groups I and II, despite persistent hypoestrogenic status in both groups. Bone mineral density changes in Groups I and II were similar to those in the untreated control group (Group IV). A sustained decrease in high-density lipoprotein cholesterol (HDL-C) (P = .005) and an increase in the low-density lipoprotein/HDL ratio (P < .05) were observed only in Group II patients receiving high-dose norethindrone supplementation. Conclusion: These preliminary data suggest that adding cyclic etidronate sodium in combination with low-dose norethindrone to GnRH agonist therapy effectively alleviates the hypoestrogenic side effects induced by GnRH agonist monotherapy.

According to state or federal labeling requirements, leuprorelin acetate may cause developmental toxicity, female reproductive toxicity, and male reproductive toxicity. Leuprorelin acetate is an acetate formed by conjugating the nonapeptide leuprorelin with acetic acid. It is a long-acting gonadotropin-releasing hormone (GnRH) analog and a luteinizing hormone-releasing hormone (LH-Rh) agonist. It is a synthetic nonapeptide analog of gonadotropin-releasing hormone used in subcutaneous hydrogel implants to treat prostate cancer and suppress the secretion of sex hormones in children with central precocious puberty. It has antitumor effects and is also a gonadotropin-releasing hormone agonist. It contains leuprorelin. Leuprorelin acetate is the acetate of a synthetic nonapeptide analog of gonadotropin-releasing hormone. Leuprorelin binds to and activates the gonadotropin-releasing hormone (GnRH) receptor. Long-term continuous use of leuprorelin in men leads to desensitization of pituitary gonadotropin-releasing hormone (GnRH) receptors and inhibits the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland, thereby significantly reducing testosterone levels; long-term use in women leads to a decrease in estradiol levels. This drug can lower testosterone levels to castration levels and may inhibit the progression of androgen receptor-positive tumors. Leuprorelin is a potent synthetic long-acting gonadotropin-releasing hormone agonist that regulates the synthesis and release of pituitary gonadotropins, including luteinizing hormone and follicle-stimulating hormone. See also: leuprorelin (containing the active ingredient); leuprorelin acetate; norethindrone acetate (ingredient). Mechanism of Action: Similar to naturally occurring luteinizing hormone-releasing hormone, initial or intermittent use of leuprorelin stimulates the anterior pituitary gland to release luteinizing hormone and follicle-stimulating hormone. The anterior pituitary gland releases luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which can temporarily increase testosterone levels in men. However, continuous use of leuprorelin in prostate cancer treatment suppresses gonadotropin-releasing hormone (GnRH) secretion, leading to a decrease in testosterone levels and resulting in "medical castration." The initial stimulation by anterior pituitary gonadotropins is followed by long-term suppression. The anterior pituitary gland releases gonadotropins, which can temporarily increase estrogen and estradiol levels in women. However, continuous use of leuprorelin to treat endometriosis can cause estrogen levels to drop to postmenopausal levels. Due to suppressed ovarian function, both normal and ectopic endometrial tissues lose activity and atrophy, resulting in amenorrhea.

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Therapeutic Uses
Antitumor drug, hormone; female fertility drug
Leuprorelin is indicated for palliative treatment of advanced prostate cancer, especially as an alternative to orchiectomy or estrogen therapy. /US Product Label Includes/
Leuprorelin is indicated for the treatment of endometriosis, including pain relief and shrinking of endometriotic lesions. /US Product Label Includes/
Leuprorelin is approximately 30 times more potent than natural gonadotropin-releasing hormone and approximately 100 times more potent than gonadotropin-releasing hormone (Gonarelin).
For more complete data on the therapeutic uses of leuprorelin (15 in total), please visit the HSDB record page.
Drug Warnings

Patients sensitive to other synthetic gonadotropin-releasing hormone analogs may also be sensitive to leuprorelin.
Men: Suppression of testosterone production can lead to impaired fertility. While it is unclear whether fertility is restored upon discontinuation of leuprorelin, the fertility suppression effect is usually reversed upon discontinuation of similar analogs.
Leuprorelin is not recommended for use during pregnancy. Since the impact on fetal mortality is likely due to the hormonal effects of leuprorelin, it can be concluded that there is a risk of miscarriage when using leuprorelin during pregnancy.
It is currently unknown whether leuprorelin passes into breast milk. However, breastfeeding is generally not recommended while receiving leuprorelin treatment due to potential adverse effects on infants. For more complete data on leuprorelin (14 total), please visit the HSDB records page.

C61H88N16O14

1269.473

1268.666

74381-53-6

53714-56-0 (Parent)

657180

Fluffy solid

1720.5ºC at 760 mmHg

150-155ºC

994.3ºC

3.447

16

16

32

91

2420

9

O=C([C@]([H])(C([H])([H])C([H])([H])C([H])([H])/N=C(\N([H])[H])/N([H])[H])N([H])C([C@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([C@@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([C@]([H])(C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])O[H])N([H])C([C@]([H])(C([H])([H])O[H])N([H])C([C@]([H])(C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12)N([H])C([C@]([H])(C([H])([H])C1=C([H])N=C([H])N1[H])N([H])C([C@]1([H])C([H])([H])C([H])([H])C(N1[H])=O)=O)=O)=O)=O)=O)=O)=O)N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(N([H])C([H])([H])C([H])([H])[H])=O.O([H])C(C([H])([H])[H])=O

RGLRXNKKBLIBQS-XNHQSDQCSA-N

InChI=1S/C59H84N16O12.C2H4O2/c1-6-63-57(86)48-14-10-22-75(48)58(87)41(13-9-21-64-59(60)61)68-51(80)42(23-32(2)3)69-52(81)43(24-33(4)5)70-53(82)44(25-34-15-17-37(77)18-16-34)71-56(85)47(30-76)74-54(83)45(26-35-28-65-39-12-8-7-11-38(35)39)72-55(84)46(27-36-29-62-31-66-36)73-50(79)40-19-20-49(78)67-401-2(3)4/h7-8,11-12,15-18,28-29,31-33,40-48,65,76-77H,6,9-10,13-14,19-27,30H2,1-5H3,(H,62,66)(H,63,86)(H,67,78)(H,68,80)(H,69,81)(H,70,82)(H,71,85)(H,72,84)(H,73,79)(H,74,83)(H4,60,61,64)1H3,(H,3,4)/t40-,41-,42-,43+,44-,45-,46-,47-,48-/m0./s1

Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt acetate

Abbott-43818 A-43818 ELIGARD Lupron LEUP A43818 TAP144Abbott 43818Lupron Depot

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)