In human pancreatic ductal adenocarcinoma cells, biperiden (29.6 μg/ml, 72 hours) can dramatically induce apoptosis and limit proliferation at high doses [1].

Biperiden (ip, 10 mg/kg, daily, for 3 weeks) reduces tumor size by 83% in mice subcutaneously xenografted with Panc-1 human pancreatic ductal adenocarcinoma cells [1]. Biperiden (ip, 8 mg/kg, every 8 hours for 10 days) reduces spontaneous seizure frequency and extracellular hippocampal glutamate levels, while causing a long-term decrease in hippocampal excitability [2].

Cell Proliferation Assay[1]
Cell Types: Panc-1, Panc-2 and BxPC3 Human pancreatic ductal adenocarcinoma cells
Tested Concentrations: 29.6 μg/mL
Incubation Duration: 72 hrs (hours)
Experimental Results: Visibly diminished nuclear c-Rel translocation after 72 hrs (hours) Inhibits cell proliferation.

Animal/Disease Models: Using Panc-1 human pancreatic ductal adenocarcinoma cells subcutaneously (sc) (sc) transplanted into mice [1]
Doses: 10 mg/kg
Route of Administration: intraperitoneal (ip) injection; daily; 3 weeks
Experimental Results: tumor size diminished by 83%.

---

Animal/Disease Models: Male Wistar rat (200-250 g) [2]
Doses: 8 mg/kg
Route of Administration: intraperitoneal (ip) injection; once every 8 hrs (hrs (hours)); 10 days
Experimental Results: Late epileptic seizures were diminished by about three times without affecting mood Memory impairment.

Absorption, Distribution and Excretion
87% bioavailability
The serum concentration at 1 to 1.5 hours following a single, 4 mg oral dose was 4-5 ng/mL. Plasma levels (0.1-0.2 ng/mL) could be determined up to 48 hours after dosing. Six hours after an oral dose of 250 mg/kg in rats, 87% of the drug had been absorbed.
The subcellular distribution of biperiden (BP), trihexyphenidyl (TP) and (-)-quinuclidinyl benzylate (QNB) in brain, heart and lung following high dose (3.2 mg/kg) iv administration was investigated in rats. The subcellular distribution of BP or TP used clinically conformed with that of QNB, a typical potent central muscarinic antagonist. The concentration-time courses of the brain subcellular fractions for these drugs were of two types which decreased slowly and in parallel to the plasma concentration. The subcellular distribution in the brain and heart was dependent on the protein amount of each fraction. The percent post-nuclear fraction (P2) of the total concentration in the lung was characteristically about 3-5 times larger than that in the heart. It was elucidated that the distribution in the lung differs from that in the brain and heart, with high affinity which is not dependent on the protein amount in the P2 fraction containing lysosomes. On the other hand, at a low dose (650 ng/kg) of 3H-QNB, each fraction as a percentage of the total concentration in the brain increased in synaptic membrane and synaptic vesicles and decreased in nuclei and cytosol as compared with the high dose. These results show that although the tissue concentration-time courses of anticholinergic drugs appear to decrease simply in parallel to plasma concentration, the subcellular distribution exhibits a variety of patterns among various tissues.
The pharmacokinetics of biperiden were studied and compared with pharmacodynamics (pupil size, accommodation, self-rating mood scale) in 6 healthy volunteers. A single-blind cross-over design was employed with placebo and biperiden (4 mg as commercially available tablets). After a lag time of 0.5 hr, biperiden was rapidly absorbed with a half-life of 0.3 hr, plasma peak levels of 5 ng/mL being reached after 1.5 hr. Biperiden showed good tissue penetration (distribution half-life 0.6 hr; ratio of total to central distribution volume 9.6), the terminal half-life time of plasma concentration was 18 hr, and the oral clearance was 146 L/hr. The pharmacodynamic maximum lagged behind the plasma peak concentration by 1 (self-rating) to 4 hr (accommodation).

---

Metabolism / Metabolites
The metabolism of biperiden is not completely understood, but does involve hydroxylation.
The metabolism of biperiden is not completely understood, but does involve hydroxylation.

---

Biological Half-Life
A single-blind cross-over design was employed with placebo and biperiden (4 mg as commercially available tablets). After a lag time of 0.5 hr, biperiden was rapidly absorbed with a half-life of 0.3 hr, ... Biperiden showed good tissue penetration (distribution half-life 0.6 hr; ratio of total to central distribution volume 9.6), the terminal half-life time of plasma concentration was 18 hr, ... .

Toxicity Summary
Parkinsonism is thought to result from an imbalance between the excitatory (cholinergic) and inhibitory (dopaminergic) systems in the corpus striatum. The mechanism of action of centrally active anticholinergic drugs such as biperiden is considered to relate to competitive antagonism of acetylcholine at cholinergic receptors in the corpus striatum, which then restores the balance.

---

Hepatotoxicity
Biperiden has not been reported to cause serum aminotransferase elevations, but it has not been evaluated for effects on serum enzyme levels in a prospective manner. Despite its use for more than 50 years, there have been no reports of biperiden liver injury in the literature and it must be a very rare cause of liver injury, if it occurs at all.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Drug Class: Antiparkinson Agents
Other Drugs in the Subclass, Anticholinergic Agents: Benztropine, Trihexyphenidyl

---

Protein Binding
60%

---

Toxicity Data
LD₅₀=760 mg/kg (Orally in rats).

---

Interactions
In rats the pharmacokinetic interactions between the anticholinergic drug biperiden and [3(H)]quinuclidinyl benzylate ([3(H)]QNB) or [3(H)]N-methylscopolamine ([3(H)]NMS) is affected by the sequence in which the drugs are administered. Drug concentrations in various tissues were determined after intravenous administration of [3(H)]QNB or [3(H)]NMS (325 ng kg(-1)). Biperiden (6.4 mg kg(-1)) was administered either 5 min before, concomitantly with or 20 min after injection of [3(H)]QNB or [3(H)]NMS. When biperiden was administered concomitantly with or before [3(H)]QNB, distribution of [3(H)]QNB among the regions of the brain and other tissues was reduced; at 4 hr the ratio of the distribution of [3(H)]QNB for experimental animals to that for control animals ranged from 0.15 to 0.9. When biperiden was administered after [3(H)]QNB, the distribution of [3H]QNB in the brain and other tissues was significantly higher than for the other two treatments (P < 0.01). However, for [3(H)]NMS the sequence of administration had no effect on the distribution of the drug in the brain and other tissues except for the kidney. In-vitro, in crude synaptosomal membranes, the amount of [3(H)]QNB at 2 hr relative to the control concentration at equilibrium was 87% when biperiden was added before [3(H)]QNB and 56% when biperiden was added after [3(H)]QNB. In both instances the concentration of [3(H)]NMS reached equilibrium within 30 min. These findings suggest that the difference between the rate constant of association and dissociation at the possible site of action gives rise to the effect of the sequence of administration on the pharmacokinetic interaction.
Concomitant administration of biperiden with other drugs having anticholinergic effects (e.g., opiate agonists, phenothiazines and other antipsychotics, tricyclic antidepressants, quinidine, antihistamines) may increase the risk of adverse anticholinergic effects.
In order to find molecules affected by administration of an antipsychotic drug with an antimuscarinic drug, which is a common prescription used to prevent extrapyramidal adverse effects caused by the antipsychotic drugs, gene expression profiling in the frontal cortex was studied in mice. After 14 days of administration with 2 mg/kg haloperidol, a typical antipsychotic drug, and 2 mg/kg biperiden, a high-affinity antagonist for muscarinic receptors in the brain, approximately 500 mRNAs related to synaptic function were investigated. The levels of the mRNAs related to the ubiquitin-related systems were significantly reduced after the combined administration. However, the separate administration of either haloperidol or biperiden had little effect on the levels of the mRNAs. This result suggests that coadministration of haloperidol and biperiden specifically affects the ubiquitin-related system.

---

Non-Human Toxicity Values
LD50 Dog oral 340 mg/kg /Biperiden hydrochloride/
LD50 Dog iv 222 mg/kg /Biperiden lactate/
LD50 Rat ip 270 mg/kg /Biperiden lactate/
LD50 Rat oral 750 mg/kg
For more Non-Human Toxicity Values (Complete) data for BIPERIDEN (7 total), please visit the HSDB record page.

[1]. Biperiden and mepazine effectively inhibit MALT1 activity and tumor growth in pancreatic cancer. Int J Cancer. 2020 Mar 15;146(6):1618-1630.

[2]. Modification of the natural progression of epileptogenesis by means of biperiden in the pilocarpine model of epilepsy. Epilepsy Res. 2017 Dec;138:88-97. doi: 10.1016/j.eplepsyres.2017.10.019. Epub 2017 Oct 29.

[3]. Effects of two anticholinergic drugs, trospium chloride and biperiden, on motility and evoked potentials of the oesophagus. Aliment Pharmacol Ther. 1998 Oct;12(10).

[4]. Identification of novel functional inhibitors of acid sphingomyelinase. PLoS One. 2011;6(8).

[5]. Antiparkinson drugs used as prophylactics for nerve agents: studies of cognitive side effects in rats. Pharmacol Biochem Behav. 2008 Jun;89(4):633-8.

Biperiden is a member of the class of piperidines that is N-propylpiperidine in which the methyl hydrogens have been replaced by hydroxy, phenyl, and 5-norbornen-2-yl groups. A muscarinic antagonist affecting both the central and peripheral nervous systems, it is used in the treatment of all forms of Parkinson's disease. It has a role as a muscarinic antagonist, a parasympatholytic, an antiparkinson drug, an antidyskinesia agent and an antidote to sarin poisoning. It is a member of piperidines, a tertiary amino compound and a tertiary alcohol.
A muscarinic antagonist that has effects in both the central and peripheral nervous systems. It has been used in the treatment of arteriosclerotic, idiopathic, and postencephalitic parkinsonism. It has also been used to alleviate extrapyramidal symptoms induced by phenothiazine derivatives and reserpine.
Biperiden is an Anticholinergic. The mechanism of action of biperiden is as a Cholinergic Antagonist.
Biperiden is an oral anticholinergic agent used predominantly in the symptomatic therapy of Parkinson disease and movement disorders. Biperiden has not been associated with serum enzyme elevations during treatment and must be a very rare cause of clinically apparent acute liver injury, if it occurs at all.
A muscarinic antagonist that has effects in both the central and peripheral nervous systems. It has been used in the treatment of arteriosclerotic, idiopathic, and postencephalitic parkinsonism. It has also been used to alleviate extrapyramidal symptoms induced by phenothiazine derivatives and reserpine. [PubChem]
A muscarinic antagonist that has effects in both the central and peripheral nervous systems. It has been used in the treatment of arteriosclerotic, idiopathic, and postencephalitic parkinsonism. It has also been used to alleviate extrapyramidal symptoms induced by phenothiazine derivatives and reserpine.

---

Drug Indication
For use as an adjunct in the therapy of all forms of parkinsonism and control of extrapyramidal disorders secondary to neuroleptic drug therapy.

---

Mechanism of Action
Parkinsonism is thought to result from an imbalance between the excitatory (cholinergic) and inhibitory (dopaminergic) systems in the corpus striatum. The mechanism of action of centrally active anticholinergic drugs such as biperiden is considered to relate to competitive antagonism of acetylcholine at cholinergic receptors in the corpus striatum, which then restores the balance.
Akineton is a weak peripheral anticholinergic agent. It has, therefore, some antisecretory, antispasmodic and mydriatic effects. In addition, Akineton possesses nicotinolytic activity. Parkinsonism is thought to result from an imbalance between the excitatory (cholinergic) and inhibitory (dopaminergic) systems in the corpus striatum. The mechanism of action of centrally active anticholinergic drugs such as Akineton is considered to relate to competitive antagonism of acetylcholine at cholinergic receptors in the corpus striatum, which then restores the balance.
Like other antimuscarinic agents of the trihexyphenidyl group, biperiden has an atropine-like blocking action on parasympathetic-innervated peripheral structures, including smooth muscle. In addition to antispasmodic, antisecretory, and mydriatic effects, biperiden has an antinicotinic potency about 6 times that of atropine and 5 times that of trihexyphenidyl on a weight basis in experimental animals.

---

Therapeutic Uses
Biperiden is used for the adjunctive treatment of all forms of parkinsonian syndrome, in which it appears to be more effective in the postencephalitic and idiopathic than in the arteriosclerotic types. Biperiden usually relieves muscle rigidity, reduces sweating and salivation, and improves gait and, to a lesser extent, tremor. Biperiden also is used for the relief of parkinsonian signs and symptoms of antipsychotic agent-induced (e.g., phenothiazines) extrapyramidal reactions. Although it has been used as adjunctive therapy in the management of other disorders of the extrapyramidal system and of unrelated spastic conditions such as multiple sclerosis, cerebral palsy, and spinal cord injuries, the value of the drug in these conditions requires further investigation.
/EXPL THER/ To study the influence of antidotes on tabun-induced neurotoxicity, the rats were injected intramuscularly with organophosphate tabun. The efficacy of choice antidotal treatment consisting of acetylcholinesterase reactivator obidoxime and one of four anticholinergic drugs (atropine, benactyzine, biperiden, scopolamine) was compared. Testing of tabun-induced neurotoxicity progress was carried out using the method Functional observational battery. The experimental animals as well as controls were observed at 24 hours and 7 days following tabun or saline administration. The results were compared to the condition of animals without anticholinergic drug (oxime alone) and control rats that received physiological solution instead of tabun and treatment. Antidotal treatment involving centrally acting anticholinergic drugs (benactyzine, biperiden, scopolamine) showed significantly higher neuroprotective efficacy compared to antidotal treatment containing atropine.
/EXPL THER/ To study the influence of pharmacological pretreatment (PANPAL or pyridostigmine combined with biperiden) and antidotal treatment (the oxime HI-6 plus atropine) on soman-induced neurotoxicity, male albino rats were poisoned with a lethal dose of soman (54 (g/kg im; 100% of LD50 value) and observed at 24 hours and 7 days following soman challenge. The neurotoxicity of soman was evaluated using a Functional observational battery and an automatic measurement of motor activity. Pharmacological pretreatment as well as antidotal treatment were able to eliminate some of soman-induced neurotoxic effects observed at 24 hours following soman poisoning. The combination of pharmacological pretreatment (PANPAL or pyridostigmine combined with biperiden) and antidotal treatment was found to be more effective in the elimination of soman-induced neurotoxicity in rats at 24 hours following soman challenge in comparison with the administration of pharmacological pretreatment or antidotal treatment alone. To compare both pharmacological pretreatments, the combination of pyridostigmine with biperiden seems to be more efficacious to eliminate soman-induced signs of neurotoxicity than PANPAL. At 7 days following soman poisoning, the combination of pharmacological pretreatment involving pyridostigmine and biperiden with antidotal treatment was only able to completely eliminate soman-induced neurotoxic signs. Thus, our findings confirm that the combination of pharmacological pretreatment and antidotal treatment is able not only to protect the experimental animals from the lethal effects of soman, but also to eliminate most soman-induced signs of neurotoxicity in poisoned rats. The pharmacological pretreatment containing pyridostigmine and biperiden appears to be more efficacious to eliminate soman-induced neurotoxic sings than PANPAL.

---

Drug Warnings
Isolated instances of mental confusion, euphoria, agitation and disturbed behavior have been reported in susceptible patients. Also, the central anticholinergic syndrome can occur as an adverse reaction to properly prescribed anticholinergic medication, although it is more frequently due to overdosage. It may also result from concomitant administration of an anticholinergic agent and a drug that has secondary anticholinergic actions. Caution should be observed in patients with manifest glaucoma, though no prohibitive rise in intraocular pressure has been noted following either oral or parenteral administration. Patients with prostatism, epilepsy or cardiac arrhythmia should be given this drug with caution. Occasionally, drowsiness may occur, and patients who drive a car or operate any other potentially dangerous machinery should be warned of this possibility. As with other drugs action on the central nervous system, the consumption of alcohol should be avoided during Akineton therapy.
Biperiden should be used with caution or may be contraindicated in patients with conditions in which anticholinergic effects are undesirable. The usual precautions and contraindications associated with antimuscarinics should be observed with biperiden.
Adverse reactions to biperiden are mainly extensions of its anticholinergic effects. Dryness of the mouth and blurred vision are common and are dose related. GI disturbances may occur and can be alleviated by administering the drug with or after meals. Drowsiness, dizziness, and mental confusion occur less frequently. Transient psychotic reactions, euphoria or disorientation, agitation, disturbed behavior, urinary retention, and hematuria have been reported rarely. In some severe cases of parkinsonian syndrome, tremor may increase as spasticity is relieved. In addition, generalized choreiform movements have been reported in at least one patient with parkinsonian syndrome when biperiden was added to levodopa-carbidopa therapy. A reduction in rapid eye movement (REM) sleep, characterized by increased REM latency and decreased percentage of time spent in REM sleep, also has been reported.
It is not known whether biperiden is distributed into milk. Because many drugs are distributed into milk, biperiden should be used with caution in nursing women.
For more Drug Warnings (Complete) data for BIPERIDEN (8 total), please visit the HSDB record page.

---

Pharmacodynamics
Biperiden is a weak peripheral anticholinergic agent. It has, therefore, some antisecretory, antispasmodic and mydriatic effects. In addition, biperiden possesses nicotinolytic activity. The parenteral form of biperiden is an effective and reliable agent for the treatment of acute episodes of extrapyramidal disturbances sometimes seen during treatment with neuroleptic agents. Akathisia, akinesia, dyskinetic tremors, rigor, oculogyric crisis, spasmodic torticollis, and profuse sweating are markedly reduced or eliminated. With parenteral biperiden, these drug-induced disturbances are rapidly brought under control.

311.224

514-65-8

Biperiden hydrochloride;1235-82-1;Biperiden lactate;7085-45-2

2381

White to off-white solid powder

1.1±0.1 g/cm3

462.1±40.0 °C at 760 mmHg

114ºC

224.5±26.0 °C

0.0±1.2 mmHg at 25°C

1.583

4.01

1

2

5

23

422

0

OC([C@H]1C[C@@H]2C=C[C@H]1C2)(CCN3CCCCC3)C4=CC=CC=C4

YSXKPIUOCJLQIE-UHFFFAOYSA-N

InChI=1S/C21H29NO/c23-21(19-7-3-1-4-8-19,11-14-22-12-5-2-6-13-22)20-16-17-9-10-18(20)15-17/h1,3-4,7-10,17-18,20,23H,2,5-6,11-16H2

1-(2-bicyclo[2.2.1]hept-5-enyl)-1-phenyl-3-piperidin-1-ylpropan-1-ol

Biperiden KL-373 KL 373

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 : ~50 mg/mL (~160.53 mM)
H2O : ~1.82 mg/mL (~5.84 mM)

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.

---

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).

View More

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)

---

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).

View More

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

---

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.

---

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