FP receptor; prostaglandin analog

A significant reduction in IOP was observed in the bimatoprost-treated eye of wild-type mice at 2 hours, with a mean difference and 95% confidence interval (CI) of the difference in means of -1.33 mm Hg (-0.81 to -1.84). Bimatoprost did not lead to a significant reduction in IOP in either the heterozygous knockout -0.36 mm Hg (-0.82 to +0.09) or homozygous FP-knockout mice 0.25 mm Hg (-0.38 to +0.89). The lack of an IOP response in the FP-knockout mice was not a consequence of blood-aqueous barrier breakdown, as there was no significant difference in aqueous humor protein concentration between treated and fellow eyes. Tissue and aqueous humor concentrations of bimatoprost, latanoprost, and their C-1 free acids indicate that latanoprost, but not bimatoprost, is hydrolyzed in the mouse eye after topical administration. Conclusions: An intact FP receptor gene is critical to the IOP response to bimatoprost in the mouse eye.[6]

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Both control and treated rabbit eyes matched regarding eyelash length before treatment (9.80±0.388mm vs 9.88±0.24mm) (P=0.108). There was a significant increase in eyelash length between control (9.75±0.33 mm) and treated rabbit eyes (11.60±0.46 mm) (P=0.369). Light and electron microscopy revealed, bimatoprost treated eyes had thick epidermis. The dermis contained two hairs growing out of the same hair follicle. Heavily keratinized Henle’s layer, the cortical cells (Cx) have prominent nucleolus and cytoplasm is studded with melanin granules. Conclusion: Bimatoprost-induced eyelash changes were not restricted to increased eyelash length, thickness, and pigmentation but also showed increased number of eyelashes within the same hair follicle which were stronger and could resist pulling from the skin without any evidence of inflammatory cells within the specimens. These changes occurred as early as 1 month of treatment, giving rise to thoughts about the possibility of using bimatoprost eye drops as a prophylaxis against madarosis associated with chemotherapy if it is started 1 month before chemotherapy and continued afterwards, making eyelashes stronger and resistant to falling out.[7]

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Bimatoprost is a powerful prostaglandin FP receptor agonist and the ethyl amide derivative of 17-phenyl trinor PGF2α. When bimatoprost is administered, [Ca2+] experiences an instantaneous, strong spike that quickly returns to baseline levels. At the FP prostanoid receptors in rats, mice, and humans, bimatoprost exhibits direct agonist activities. [5]

Bimatoprost (17-phenyl-prostaglandin F(2alpha) ethyl amide) has been reported not to exert its actions via prostaglandin receptors. Here, bimatoprost displaced [3H]prostaglandin F(2alpha) from FP receptors (K(i)=6310+/-1650 nM). Bimatoprost rapidly mobilized intracellular Ca(2+) ([Ca(2+)](i)) via cloned human FP receptors expressed in human embryonic kidney cells (EC(50)=2940+/-1663 nM) and via native FP receptors in 3T3 mouse fibroblasts (EC(50)=2200+/-670 nM). Furthermore, AL-8810 ((5Z, 13E)-(9S,11S,15R)-9,15-dihydroxy-11-fluoro-15-(2-indanyl)-16,17,18,19,20-pentanor-5,13-prostadienoic acid), an FP receptor antagonist, blocked the bimatoprost-induced [Ca(2+)](i) mobilization[2].

Bimatoprost is a synthetic analog of prostaglandin F(2 alpha) ethanolamide (prostamide F(2 alpha)), and shares a pharmacological profile consistent with that of the prostamides. Like prostaglandin F(2 alpha) carboxylic acid, bimatoprost potently lowers intraocular pressure in dogs, primates and humans. In order to distinguish its mechanism of action from prostaglandin F(2 alpha), fluorescence confocal microscopy was used to examine the effects of bimatoprost, prostaglandin F(2 alpha) and 17-phenyl prostaglandin F(2 alpha) on calcium signaling in resident cells of digested cat iris sphincter, a tissue which exhibits contractile responses to both agonists. Constant superfusion conditions obviated effective conversion of bimatoprost. Serial challenge with 100 nM bimatoprost and prostaglandin F(2 alpha) consistently evoked responses in different cells within the same tissue preparation, whereas prostaglandin F(2 alpha) and 17-phenyl prostaglandin F(2 alpha) elicited signaling responses in the same cells. Bimatoprost-sensitive cells were consistently re-stimulated with bimatoprost only, and prostaglandin F(2 alpha) sensitive cells could only be re-stimulated with prostaglandin F(2 alpha). The selective stimulation of different cells in the same cat iris sphincter preparation by bimatoprost and prostaglandin F(2 alpha), along with the complete absence of observed instances in which the same cells respond to both agonists, strongly suggests the involvement of distinct receptors for prostaglandin F(2 alpha) and bimatoprost. Further, prostaglandin F(2 alpha) but not bimatoprost potently stimulated calcium signaling in isolated human embryonic kidney cells stably transfected with the feline- and human-prostaglandin F(2 alpha) FP-receptor and in human dermal fibroblast cells, and only prostaglandin F(2 alpha) competed with radioligand binding in HEK-feFP cells. These studies provide further evidence for the existence of a bimatoprost-sensitive receptor that is distinct from any of the known prostaglandin receptor types[4].

The IOP response to a single 1.2-microg (4 microL) dose of bimatoprost was measured in the treated and untreated fellow eyes of homozygote (FP+/+, n = 9) and heterozygote (FP+/-, n = 10) FP-knockout mice, as well as in wild-type C57BL/6 mice (FP+/+, n = 20). Serial IOP measurements were also performed after topical bimatoprost in a separate generation of homozygous FP-knockout mice and wild-type littermate control animals (n = 4 per group). Aqueous humor protein concentrations were measured to establish the state of the blood-aqueous barrier. Tissue, aqueous humor and vitreous concentrations of bimatoprost, latanoprost, and their C-1 free acids were determined by liquid chromatography and tandem mass spectrometry.[6]

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The study included 15 clinically healthy male rabbits. All rabbits were treated with bimatoprost 0.03% daily for 4 weeks with one drop of the topical eye drops applied to the conjunctival fornix of the right eyes; left eyes were used as controls. Eyelash lengths were measured before and after treatment. The eyelid of each animal was dissected for light and electron microscopic analysis.[7]

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Treatment with Bimatoprost Bimatoprost belongs to a newer subset of PGs; prostamides which are created from anandamide that is derived from arachidonic acid.11,12 Anandamide is converted to prostamide G2 and H2 by cyclooxygenase (COX). Bimatoprost is a synthetic prostamide with a molecular formula of C25H37NO4. The unique substitution of ethyl amide instead of isopropyl ester at the C-1 carbon of the alpha chain gives different properties to bimatoprost than other PGF2α analogs (latanoprost, travoprost, and unoprostone).13 All rabbits were treated with bimatoprost 0.03% daily for 4 weeks with one drop of the topical eye drops applied to the conjunctival fornix of animals' right eye. Left eyes were used as a control group with instillation of vehicle eye drops.[7]

Absorption, Distribution and Excretion
This drug is absorbed systemically when administered to the eye. A study was performed on 15 healthy volunteers and bimatoprost ophthalmic solution 0.03% was administered once daily for 14 days. The mean Cmax was approximately 0.08 ng/mL and AUC0-24hr was approximately 0.09 on days 7 and 14 of the study. By 10 minutes, peak blood concentration was achieved. Bimatoprost was not detectable at 1.5 hours after administration in most subjects. The maximum blood concentration in a study of 6 healthy volunteers was determined to be 12.2 ng/mL. Steady state was reached in the first week of dosing. One drug label mentions that onset of decreased intraocular pressure occurs approximately 4 hours after the first administration and the peak effect occurs in the range of 8-12 hours. Bimatoprost effects may last up to 24 hours.
One pharmacokinetic study of bimatoprost in 6 healthy volunteers determined that 67% of the administered dose was found to be excreted in the urine while 25% of the dose was recovered in the feces.
The volume of distribution at steady state is 0.67 L/kg.. It penetrates the human cornea and sclera.
The clearance was measured to be 1.5 L/hr/kg in healthy subjects receiving IV administration of bimatoprost dosed at 3.12 ug/kg.

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Metabolism / Metabolites
Bimatoprost is hydrolyzed to its active form, bimatoprost acid, in the eye. Bimatoprost undergoes oxidation, N-deethylation, and glucuronidation after it is systemically absorbed, and this leads to the production of various metabolites. In vitro studies show that CYP3A4 is an enzyme that participates in the metabolism of bimatoprost. Despite this, many enzymes and pathways metabolize bimatoprost, therefore, no significant drug-drug interactions are likely to occur. Glucuronidated metabolites comprise most of the excreted drug product in the blood, urine, and feces in rats.

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Biological Half-Life
The elimination half-life of bimatoprost is approximately 45 minutes.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of bimatoprost during breastfeeding. Because of its short half-life it is not likely to reach the bloodstream of the infant or cause any adverse effects in breastfed infants. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue. With the implant, plasma levels are usually undetectable, so the amount in milk is likely to be negligible.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Bimatoprost is about 88%-90% bound to plasma proteins.

[1]. Surv Ophthalmol . 2001 May:45 Suppl 4:S347-51.

[2]. Eur J Pharmacol . 2001 Dec 7;432(2-3):211-3.

[3]. J Biol Chem . 2003 Jul 18;278(29):27267-77.

[4]. Exp Eye Res . 2005 Jan;80(1):135-45

[5]. J Pharmacol Exp Ther . 2003 Jan;304(1):238-45.

[6]. Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4571-7.
[7]. Clin Ophthalmol. 2019; 13: 2421–2426.

Bimatoprost is a monocarboxylic acid amide. It has a role as an antiglaucoma drug and an antihypertensive agent.
Bimatoprost, also known as Latisse or Lumigan, belongs to a group of drugs called prostamides, which are synthetic structural analogs of prostaglandin. Bimatoprost, marketed by Allergan, is administered in both the ophthalmic solution and implant form. It has the ability to reduce ocular hypotension, proving effective in conditions such as ocular hypertension and glaucoma. Bimatoprost is also used to treat eyelash hypotrichosis, or sparse eyelash growth. It was initially approved by the FDA in 2001 for ocular hypertension and later approved for hypothrichosis in 2008, as eyelash growth became a desirable adverse effect for patients using this drug.
Bimatoprost is a Prostaglandin Analog.
Bimatoprost is a synthetic prostamide and structural prostaglandin analogue with ocular hypotensive activity. Bimatoprost mimics the effects of the endogenous prostamides and reduces intraocular pressure by increasing outflow of aqueous humor through both the pressure-sensitive outflow pathway (the trabecular meshwork), and the pressure-insensitive outflow pathway (the uveoscleral routes). It is not clear whether bimatoprost lowers intraocular pressure by stimulating F-Prostanoid receptors or by acting on specific prostamide receptors.
A cloprostenol-derived amide that is used as an ANTIHYPERTENSIVE AGENT in the treatment of OPEN-ANGLE GLAUCOMA and OCULAR HYPERTENSION.

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Drug Indication
Bimatoprost is used for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. These patients must be intolerant to other intraocular pressure lowering medications or inadequately responsive to other treatments. Bimatoprost is also indicated to treat eyelash hypotrichosis.
Reduction of elevated intraocular pressure in chronic open-angle glaucoma and ocular hypertension (as monotherapy or as adjunctive therapy to beta-blockers). ,
Treatment of glaucoma, Treatment of non-scarring hair loss
Treatment of androgenic alopecia

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Mechanism of Action
Bimatoprost imitates the effects of prostamides, specifically prostaglandin F2α. Bimatoprost mildly stimulates aqueous humor outflow, relieving elevated intraocular pressure and decreasing the risk of optic nerve damage. It is thought that bimatoprost reduces intraocular pressure (IOP) in humans by causing an increase in outflow of the aqueous humor via the trabecular meshwork and uveoscleral pathways. It achieves the above effects by decreasing tonographic resistance to aqueous humor outflow. Bimatoprost does not affect aqueous humor production.

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Pharmacodynamics
High intraocular pressure is a major risk factor for glaucoma-related visual field loss. A linear relationship exists between intraocular pressure and the risk of damaging the optic nerve, which can lead to considerable visual impairment. Therefore, conditions such as ocular hypertension and glaucoma can cause dangerous elevations of intraocular pressure. Bimatoprost rapidly decreases intraocular pressure and reduces the risk for visual field loss from ocular hypertension due to various causes. Other effects of this drug may include gradual changes in eyelid pigmentation, changes in iris pigmentation, changes in eyelash pigmentation, growth and thickness. Patients should be informed of these possible effects, especially if this drug is only administered to one eye, which may noticeably change in appearance with bimatoprost treatment.

C25H37NO4

415.57

415.272

C, 72.26; H, 8.97; N, 3.37; O, 15.40

155206-00-1

5,6-trans-Bimatoprost; 1163135-95-2; Bimatoprost-d5; Bimatoprost methyl ester; 38315-47-8; N-Desethyl Bimatoprost; 155205-89-3; Bimatoprost-d4

5311027

White to off-white solid powder

1.1±0.1 g/cm3

629.8±55.0 °C at 760 mmHg

66-68°C

334.7±31.5 °C

0.0±1.9 mmHg at 25°C

1.591

1.98

4

4

12

30

541

5

O([H])[C@]1([H])C([H])([H])[C@]([H])([C@@]([H])(/C(/[H])=C(\[H])/C([H])(C([H])([H])C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])O[H])[C@]1([H])C([H])([H])/C(/[H])=C(/[H])\C([H])([H])C([H])([H])C([H])([H])C(N([H])C([H])([H])C([H])([H])[H])=O)O[H]

AQOKCDNYWBIDND-FTOWTWDKSA-N

InChI=1S/C25H37NO4/c1-2-26-25(30)13-9-4-3-8-12-21-22(24(29)18-23(21)28)17-16-20(27)15-14-19-10-6-5-7-11-19/h3,5-8,10-11,16-17,20-24,27-29H,2,4,9,12-15,18H2,1H3,(H,26,30)/b8-3-,17-16+/t20-,21+,22+,23-,24+/m0/s1

(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxy-5-phenylpent-1-enyl]cyclopentyl]-N-ethylhept-5-enamide

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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