Absorption, Distribution and Excretion
Bioavailablity after intramuscular injection of the depot formulation is estimated to be about 90%.
The pharmacological effects of leuprolide acetate depot microspheres were studied in rats and dogs following subcutaneous and intramuscular injection. After injection the microspheres provided similar linear drug release and sustained serum drug levels for 3 months. Persistent suppression of serum luteinizing hormone, follicle stimulating hormone in rats, and testosterone in rats and dogs for over 16 wk was achieved with microspheres at a dose of 100 ug/kg/day in rats and 25.6 ug/kg/day in dogs. Responses upon periodic challenge tests revealed that a single injection of microspheres dramatically suppressed the function of the pituitary-gonadal system for 15 wks in rats. The growth of genital organs was also suppressed dose-dependently for over 3 months. It was concluded that persistent pharmacological effects are obtained with an injection of leuprolide 3-month depot microspheres.
The effect of formulation adjuvants on the absorption of leuprolide acetate after intraduodenal injection and oral administration to male castrate rats is reported. Absorption was low, approximately 0.01% and 0.08% by oral and intraduodenal administration, respectively, compared with intravenous controls. An aqueous formulation and a water-in-oil emulsion of a lipophilic salt, a decane sulfonic acid derivative of leuprolide gave intraduodenal bioavailabilities of approximately 0.2% and 1% respectively. Evaluation of formulation effects on the oral absorption of the drug showed that lipophilicity, surfactant, and vehicle properties significantly affected intraduodenal absorption of leuprolide. Absolute bioavailability of the drug in typical emulsion systems ranged from approximately 3-10% and represented an improvement of about 100-fold in gastrointestinal bioavailability of this peptide. The implications of these findings relative to the effect of formulation adjuvants on oral absorption of leuprolide and other peptides following intraduodenal administration are discussed.
The bioavailability of leuprolide acetate was studied in rats and in healthy males (ages 19-39 yr) after inhalation and intranasal administration, compared with intravenous and subcutaneous injection. Intranasal bioavailability in rats was significantly increased by alpha-cyclodextrin, eidetic acid, and solution volume. Intra-animal variability was 30-60% and absorption ranged from 8 to 46% compared with intravenous controls. In humans, the subcutaneous injection was 94% bioavailable compared with intravenous. Intranasal bioavailability averaged 2.4%, with significant intersubject variability. Plasma peak concentrations for one and 3 mg dosages were 0.24-1.6 and 0.1-11 ng/ml, respectively. Mean plasma peak concentrations of one mg aerosol and 2 mg suspension aerosols, respectively. Bioavailability of suspension aerosols was fourfold greater than that of the solution aerosol. /Leuprolide acetate/

Interactions
OBJECTIVE: To assess the efficacy of combining sodium etidronate with low doses of the 19-nor-testosterone progestin norethindrone or using high doses of norethindrone alone as prophylaxis against the vasomotor instability and bone density loss induced by GnRH agonists alone. METHODS: Eleven patients enrolled in this randomized study received the long-acting GnRH agonist leuprolide acetate 3.75 mg intramuscularly every 4 weeks for 24 weeks. Six patients (group I) self-administered sodium etidronate 400 mg/day orally for 14 days followed by calcium carbonate 500 mg/day orally for the next 42 days during three 56-day cycles. This regimen was supplemented by norethindrone 2.5 mg/day orally. Five patients (group II) self-administered norethindrone 10 mg/day orally. Two sets of controls were used. Group III consisted of ten previously reported patients who received the same GnRH agonist only. Group IV comprised 12 regularly cycling untreated controls. Bone mineral density, vasomotor symptoms, circulating estrogens, and lipids were assessed serially. RESULTS: The significant vasomotor instability (P < .Ol) and bone mineral density loss (-4.8 +/- 0.9%; P < .05) experienced by patients in group III was prevented in those ln groups I and II despite maintenance of a persistent hypoestrogenlc state. Bone density changes ln groups I and II were similar to those in untreated controls (group IV). Persistent decreases in high-density lipoprotein (HDL) cholesterol (P = .005) and increases in the low-density lipoprotein-to-HDL ratio (P < .05) were noted only in group II patients receiving supplemental high-dose norethindrone. CONCLUSION: These preliminary data suggest that the addition of cyclic sodium etidronate in combination with low-dose norethindrone to GnRH agonists is an effective means of ameliorating the hypoestrogenic side effects induced by GnRH agonist alone.

Leuprolide Acetate can cause developmental toxicity, female reproductive toxicity and male reproductive toxicity according to state or federal government labeling requirements.
Leuprolide acetate is an acetate salt obtained by combining the nonapeptide leuprolide with acetic acid. A long lasting GnRH analog, LH-Rh agonist. It is a synthetic nonapeptide analogue of gonadotropin-releasing hormone, and is used as a subcutaneous hydrogel implant for the treatment of prostate cancer and for the suppression of gonadal sex hormone production in children with central precocious puberty. It has a role as an antineoplastic agent and a gonadotropin releasing hormone agonist. It contains a leuprolide.
Leuprolide Acetate is the acetate salt of a synthetic nonapeptide analogue of gonadotropin-releasing hormone. Leuprolide binds to and activates gonadotropin-releasing hormone (GnRH) receptors. Continuous, prolonged administration of leuprolide in males results in pituitary GnRH receptor desensitization and inhibition of pituitary secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH), leading to a significant decline in testosterone production; in females, prolonged administration results in a decrease in estradiol production. This agent reduces testosterone production to castration levels and may inhibit androgen receptor-positive tumor progression.
A potent synthetic long-acting agonist of GONADOTROPIN-RELEASING HORMONE that regulates the synthesis and release of pituitary gonadotropins, LUTEINIZING HORMONE and FOLLICLE STIMULATING HORMONE.
See also: Leuprolide (has active moiety); Leuprolide acetate; norethindrone acetate (component of).

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Mechanism of Action
Like naturally occurring luteinizing hormone-releasing hormone, initial or intermittent administration of leuprolide stimulates release of luteinizing hormone and follicle-stimulating hormone from the anterior pituitary.
Luteinizing hormone and follicle-stimulating hormone release from the anterior pituitary transiently increases testosterone concentration in males. However, continuous administration of leuprolide in the treatment of prostatic carcinoma suppresses secretion of gonadotropin-releasing hormone, with a resultant fall in testosterone concentrations and a "medical castration".
Initial stimulation of gonadotropins form the anterior pituitary is followed by prolonged suppression. Gonadotropin release from the anterior pituitary transiently increases estrone and estradiol concentrations in females. However, continuous administration of leuprolide in the treatment of endometriosis produces a fall in estrogens to postmenopausal levels. As a consequence of suppression of ovarian function, both normal and ectopic endometrial tissues become inactive and atrophic. As a result, amenorrhea occurs.

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Therapeutic Uses
Antineoplastic Agents, Hormonal; Fertility Agents, Female
Leuprolide is indicated for the palliative treatment of advanced prostatic cancer, especially as an alternative to orchiectomy or estrogen administration. /Included in US product labeling/
Leuprolide is indicated for management of endometriosis, including pain relief and reduction of endometriotic lesions. /Included in US product labeling/
Leuprolide is about 30 times more active than natural gonadotropin-releasing hormone ... and 100 times more active than gonadorelin.
For more Therapeutic Uses (Complete) data for LEUPROLIDE (15 total), please visit the HSDB record page.

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Drug Warnings
Patients sensitive to other synthetic gonadotropin-releasing hormone analogs may also be sensitive to leuprolide.
In males: Suppression of testosterone secretion results in impairment of fertility. Although it is not known whether fertility is restored after leuprolide is withdrawn, reversal of fertility suppression does occur after withdrawal of similar analogs.
Leuprolide is not recommended during pregnancy. Because the effects on fetal mortality would logically result from the hormonal effects of leuprolide, it can be concluded that there is a risk of spontaneous abortion if leuprolide is administered during pregnancy.
It is not known whether leuprolide passes into breast milk. However, because of potential adverse effects in the infant, breast-feeding is usually not recommended during treatment with leuprolide.
For more Drug Warnings (Complete) data for LEUPROLIDE (14 total), please visit the HSDB record 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.)