Pizotifen (BC-105) is a strong antagonist of the 5-HT2 receptor that has a high affinity for the binding region of the 5-HT1C [1]. Pizotifen is an anti-5-HT2A receptor antagonist that prevents platelet aggregation generated by ADP that is increased by serotonin [2].

Placental weight was considerably reduced after pethidine at 0.6 and 1.2 mg/kg and solely at the intermediate dose of pethidine; fetal weight was significantly lowered at all administered doses of benzotifen (BC-105). Later on, it was greatly alleviated. There was no difference observed between the treated and control groups in terms of implantation, viable pregnancies, stillbirths, resorptions, and external, skeletal, and visceral abnormalities. There was no discernible difference between the treatment group's and the negative control group's number of chromosomal abnormalities in the mice's bone marrow cells. Testing for micronuclei revealed no rise in micronucleus frequency as compared to controls. Following two increased dosages of bentifen maleate (BC-105) and pethidine, the mitotic index was reduced in comparison to the control group [3].

Absorption, Distribution and Excretion
The absorption half-life of pizotifen following oral administration is 0.5 to 0.8 hours in an adult male with nearly complete absorption rate of 80%. Maximum blood levels are reached 5 hours post-administration and the absolute bioavailability is 78%.
About one third of the total orally administered dose is excreted into the feces. Less than 1% of the total dose is excreted in the urine as the unchanged parent drug, and up to 55% of the dose is excreted as its metabolites.
The volume of distribution in an adult male is 833L for pizotifen and 70L for the N-glucuronide conjugate.

---

Metabolism / Metabolites
Pizotifen is extensively metabolized in the liver, where it primarily undergoes N-glucuronidation to form the main metabolite, N-glucuronide conjugate. N-glucuronide conjugate accounts for at least 50% of the plasma and 60-70% of the urinary-excreted radioactivity.

---

Biological Half-Life
The elimination half-life for pizotifen and N-glucuronide conjugate is about 23 hours.

Protein Binding
Plasma protein binding of pizotifen is > 90%.

[1]. 5-HT2 receptor antagonists and migraine therapy. J Neurol. 1991;238 Suppl 1:S45-52.

[2]. The antidepressant 5-HT2A receptor antagonists pizotifen and cyproheptadine inhibit serotonin-enhanced platelet function. PLoS One. 2014 Jan 23;9(1):e87026.

[3]. Teratological and cytogenetical evaluation of two antihistamines (pipethiadene and pizotifen maleate) in mice. Agents Actions. 1988 Apr;23(3-4):376-8.

Pizotifen is a benzocycloheptathiophene that is 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene 4-ylidene)-1-methylpiperidine which is joined from the 4 position to the 4 position of an N-methylpiperidine moiety by a double bond. It is a sedating antihistamine, with strong serotonin antagonist and weak antimuscarinic activity. It is generally used as the malate salt for the treatment of migraine and the prevention of headache attacks during cluster periods. It has a role as a serotonergic antagonist, a muscarinic antagonist and a histamine antagonist. It is functionally related to a piperidine. It is a conjugate base of a pizotifen(1+).
Pizotifen belongs to the class of antamines and is related to [cyproheptadine]. It is a potent serotonin and tryptamine antagonist that has been used for migraine prevention for many years. It exhibits weak anticholinergic, antihistamine, and antikinin actions in addition to sedative and appetite-stimulating properties. Some patients receiving pizotifen treatment developed tolerance with the prolonged use of the drug. Numerous studies have revealed the potential antidepressant effects of pizotifen, which are independent of its antimigraine action. While it is suggested that pizotifen may act similarly to the classic tricyclic antidepressants, its full mechanism of antidepressant action is not fully elucidated. Pizotifen hydrochloride is an active ingredient in Sandomigran, which is used for the prophylactic management of migraines. Sandomigran is available in a number of countries but is not approved by the FDA nor EMA.
Serotonin antagonist used against MIGRAINE DISORDERS and vascular headaches.

---

Drug Indication
Indicated for the prophylactic management of migraines.

---

Mechanism of Action
While the mechanism of action is not fully understood, it is proposed that pizotifen works by inhibiting the peripheral actions of serotonin and histamine in increasing the membrane permeability of cranial vessels and transudation of plasmakinin, while altering pain thresholds in migraines. By blocking 5-HT receptors, pizotifen attenuates the signalling of serotonin in causing cranial vasoconstriction, as well as serotonin-enhanced platelet function and aggregation. There is evidence that it also inhibits the peripheral actions of bradykinin. Pizotifen may inhibit serotonin reuptake by blood platelets, which affects the tonicity and decreases passive distension of extracranial arteries. The effects of pizotifen leading to appetite stimulation may be due to the drug acting at the metabolic level rather than a direct stimulation of the appetite centre.

C19H21NS

295.4417

295.139

15574-96-6

Pizotifen malate;5189-11-7

27400

White to off-white solid powder

1.2±0.1 g/cm3

436.7±45.0 °C at 760 mmHg

140-142°C

217.9±28.7 °C

0.0±1.0 mmHg at 25°C

1.631

6.13

0

2

0

21

406

0

FIADGNVRKBPQEU-UHFFFAOYSA-N

InChI=1S/C19H21NS/c1-20-11-8-15(9-12-20)19-16-5-3-2-4-14(16)6-7-18-17(19)10-13-21-18/h2-5,10,13H,6-9,11-12H2,1H3

1-methyl-4-(6-thiatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),4,10,12-pentaen-2-ylidene)piperidine

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)

DMSO : ~20 mg/mL (~67.70 mM)
H2O : < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2 mg/mL (6.77 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 20.0 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.

---

Solubility in Formulation 2: ≥ 2 mg/mL (6.77 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 20.0 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.

---

View More

Solubility in Formulation 3: ≥ 2 mg/mL (6.77 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 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

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