Absorption, Distribution and Excretion
Trihexyphenidyl is absorbed from the gastrointestinal tract. Trihexyphenidyl reaches a Cmax of 7.2 ng/mL, with a Tmax of 1.3 hours, and an AUC of 201 ng\*h/mL.
Data regarding the route of elimination of trihexyphenidyl are not readily available. However, it is likely eliminated predominantly in the urine.
Using a sensitive radioreceptor assay for anticholinergic drugs, trihexyphenidyl /was assayed/ in human serum and ... its pharmacokinetics following short-term and long-term administration to patients with dystonia /was studied/. Previously untreated patients had a biphasic semilogarithmic plot of serum concentration-time consisting of an initial rapid distribution phase and a later slower elimination phase. Patients on long-term treatment showed only the slower elimination phase. Elimination followed first-order kinetics and was rapid, with a half-life of 3.7 + or - 0.4 (SEM) hours. There was no relationship between half-life and peak serum level, age, duration of therapy, or etiology or severity of dystonia. Although acute anticholinergic side effects paralleled the rise and fall of serum anticholinergic levels, the response of dystonia did not.
Trihexyphenidyl is rapidly absorbed from the GI tract. Following oral administration of trihexyphenidyl hydrochloride tablets, the onset of action occurs within 1 hour, peak effects last 2-3 hours, and the duration of action is 6-12 hours. The metabolic fate of trihexyphenidyl has not been determined; the drug is excreted in the urine, probably as unchanged drug. /Trihexylphenidyl hydrochloride/
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.
Twenty-four male subjects were randomized to receive two oral dosage forms of trihexyphenidyl HCl (alpha-cyclohexyl-alpha-phenyl-1-piperidinepropanol HCl). The dosage regimens were (1) a 5-mg immediate release (IR) tablet given twice daily at time zero and 12 hr later, and (2) two 5-mg sustained-release (SR) capsule formulations given daily. The number of adverse experiences following the SR formulation were approximately 50% of those for the IR formulation, the peak concentration (Cmax) after the SR formulation was significantly lower (p less than 0.05) than that after the first dose of the IR formulation, and the time to reach Cmax (tmax) was significantly longer after the SR formulation (p less than 0.05). The SR formulation maintained serum concentrations above 50, 60, and 70% of Cmax values for average time periods of 11.7, 9.4, and 5.9 hr, respectively, compared with values of 1.8, 1.2, and 0.9 hr after the IR formulation; the differences were all significant (p less than 0.05). The mean elimination half-life (t1/2) was similar (p greater than 0.05) after the SR (10.1 hr) and IR (8.7 hr) formulations. The statistical power of the study was 98.1% to detect a 20% difference in the area under the curve from time zero to time infinity (AUC0----infinity) between formulations. Although the AUC0----infinity after the SR formulation was statistically smaller (p less than 0.05) than after the IR tablet, the difference was less than 20%. Therefore, the SR formulation was bioequivalent to the IR tablet formulation of trihexyphenidyl. /Trihexylphenidyl hydrochloride/

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Metabolism / Metabolites
Data regarding the metabolism of trihexyphenidyl are not readily available. However, it is likely not heavily metabolized.
Benzhexol and three of its metabolites excreted in urine in man have been investigated by glc.--mass spectrometry. Three isomeric hydroxylated metabolites were identified as the 1-(hydroxycyclohexyl)-1-phenyl-3-piperidinopropan-1-ols. 3. The amounts of benzhexol and its identified metabolites have been semiquantitatively determined after a single oral dose in two healthy adults. Approx. 56% of the dose was excreted as the hydroxylated metabolites. The levels of benzhexol excreted were too low to be measured by the techniques used.
Half Life: 3.3-4.1 hours

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Biological Half-Life
The mean elimination half life of trihexyphenidyl is 3.2 ± 0.3 hours.
Twenty-four male subjects were randomized to receive two oral dosage forms of trihexyphenidyl HCl (alpha-cyclohexyl-alpha-phenyl-1-piperidinepropanol HCl). The dosage regimens were (1) a 5-mg immediate release (IR) tablet given twice daily at time zero and 12 hr later, and (2) two 5-mg sustained-release (SR) capsule formulations given daily. ... The mean elimination half-life (t1/2) was similar (p greater than 0.05) after the SR (10.1 hr) and IR (8.7 hr) formulations. /Trihexylphenidyl hydrochloride/
Using a sensitive radioreceptor assay for anticholinergic drugs, trihexyphenidyl /was assayed/ in human serum and ... its pharmacokinetics following short-term and long-term administration to patients with dystonia /was studied/. ... Elimination followed first-order kinetics and was rapid, with a half-life of 3.7 + or - 0.4 (SEM) hours. There was no relationship between half-life and peak serum level, age, duration of therapy, or etiology or severity of dystonia. ...

Toxicity Summary
Trihexyphenidyl is a selective M1 muscarinic acetylcholine receptor antagonist. It is able to discriminate between the M1 (cortical or neuronal) and the peripheral muscarinic subtypes (cardiac and glandular). Trihexyphenidyl partially blocks cholinergic activity in the CNS, which is responsible for the symptoms of Parkinson's disease. It is also thought to increase the availability of dopamine, a brain chemical that is critical in the initiation and smooth control of voluntary muscle movement.

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Hepatotoxicity
Trihexyphenidyl 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. Trihexyphenidyl was cited as the cause of two cases of acute liver injury resulting in death in the Japanese literature, but few details were given and there have been no other reports of such injury in the literature in the subsequent 40 years. Thus, trihexyphenidyl must be a very rare cause of liver injury, if it occurs at all.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal doses of trihexyphenidyl up to 4 mg daily together with haloperidol or risperidone did not produce any adverse effects in breastfed infants. Long-term use of trihexyphenidyl might reduce milk production or milk letdown, but a single dose is not likely to interfere with breastfeeding. The prolactin elevating effect of concurrent antipsychotic agents might counteract any prolactin lowering effect of trihexyphenidyl. During long-term use, observe for signs of decreased lactation (e.g., infant insatiety and poor weight gain).
◉ Effects in Breastfed Infants
One woman with schizophrenia took trihexyphenidyl and haloperidol during 3 pregnancies and postpartum. The trihexyphenidyl dose was 4 mg daily in all 3 pregnancies. She breastfed (extent not stated) all 3 children for 6 to 8 months using the same doses. Development was age-appropriate in all children aged 16 months at 8 years of age at the time of assessment.
A woman diagnosed with undifferentiated schizophrenia took risperidone 4 to 5 mg and trihexyphenidyl 2 mg daily throughout 5 pregnancies. She breastfed each infant for 20 to 24 months. No adverse developmental consequences were noted in any of the children. At the time of publication, the oldest three children, aged 26, 23 and 22 years, had completed their education and were employed, while the youngest two were 15 and 19 years old and were doing well academically in their education.
◉ Effects on Lactation and Breastmilk
Anticholinergics can inhibit lactation in animals, apparently by inhibiting growth hormone and oxytocin secretion. Anticholinergic drugs can also reduce serum prolactin in nonnursing women. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
One woman with schizophrenia took trihexyphenidyl and haloperidol during 3 pregnancies and postpartum. She was able to breastfeed (extent not stated) all 3 children for 6 to 8 months.
A woman diagnosed with undifferentiated schizophrenia took risperidone 4 to 5 mg and trihexyphenidyl 2 mg daily throughout 5 pregnancies. She successfully breastfed each infant for 20 to 24 months.

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Protein Binding
Data regarding the extent of trihexyphenidyl protein binding in plasma are not readily available. Trihexyphenidyl is 36.13-41.92% bound to albumin under controlled conditions in a dialysis bag.

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Interactions
When trihexyphenidyl hydrochloride is used concomitantly with levodopa, the usual dose of each may need to be reduced. Careful adjustment is necessary, depending on side effects and degree of symptoms control. /Trihexylphenidyl hydrochloride/
...CENTRALLY ACTING ANTICHOLINERGIC AGENTS THAT MAY EXACERBATE TARDIVE DYSKINESIA /CAUSED BY CHLORPROMAZINE/ INCL...TRIHEXYPHENIDYL.
Trihexyphenidyl, applied in doses of 30 and 50 mg/kg (ip), did not influence the electroconvulsive threshold per se but when combined with valproate, strongly enhanced its anticonvulsant activity against maximal electroshock-induced seizures /in mice/ lowering the ED50 from 206 to 103 and 46 mg/kg, respectively. The chimney test and retention testing in mice revealed that administration of ... trihexyphenidyl at 30 mg/kg (ip) together with valproate in doses of 130 or 103 mg/kg (ip), respectively, resulted in motor impairment and caused impairment of long-term memory, similar to the effects of valproate alone, when applied at its ED50 against maximal electroshock. ... trihexyphenidyl /did not/ alter the total level of valproate in plasma. ...

[1]. Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine. Br J Pharmacol. 1986 Sep;89(1):83-90.

[2]. Trihexyphenidyl. 2022 Feb 27. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.

Therapeutic Uses
Anti-Dyskinesia Agents; Antiparkinson Agents; Muscarinic Antagonists; Parasympatholytics
Trihexyphenidyl hydrochloride is used for the adjunctive treatment of all forms of parkinsonian syndrome including the postencephalitic, arteriosclerotic, and idiopathic types. Trihexyphenidyl is also used for the relief of parkinsonian signs and symptoms of antipsychotic agent-induced (e.g., butyrophenones, phenothiazines, thioxanthenes) extrapyramidal effects. /Trihexylphenidyl hydrochloride/
Clinical results from preliminary trials with trihexyphenidyl in the treatment of other dyskinesias, Huntington's chorea, spasmodic torticollis, and associated disorders have been equivocal.
Trihexyphenidyl may also be effective in diminishing the frequency and duration of oculogyric crises, in decreasing salivation, in reducing spastic contractions and involuntary movements characteristic of dyskinesia, and in relieving mental inertia and depression characteristic of all forms of parkinsonian syndrome. As with other antiparkinsonian drugs, tolerance to trihexyphenidyl may develop during prolonged use. The maximum therapeutic response attainable with trihexyphenidyl is in the range of 20-30% symptomatic improvement in 50-75% of patients. Frequently, the maximum response requires empiric combination of trihexyphenidyl with other antimuscarinic drugs or with antihistaminic or dopaminergic agents. Some clinicians believe trihexyphenidyl to be of little value, but the majority have found it a useful adjunct in the multidimensional therapeutic approach to parkinsonian syndrome. Trihexyphenidyl is effective as adjunctive therapy for parkinsonian syndrome in patients receiving levodopa.
/EXPL THER/ The influence of two anticholinergic drugs (atropine, trihexyphenidyle) on the effectiveness of antidotal treatment to eliminate soman-induced lethal effects and convulsions was studied in rats. The oxime HI-6 when combined with centrally acting anticholinergic drug trihexyphenidyle seems to be more efficacious in the elimination of acute toxic effects of soman than its combination with atropine. The findings support the hypothesis that the choice of the anticholinergic drug is important for the effectiveness of antidotal mixture in the case of antidotal treatment of soman-induced acute poisoning.

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Drug Warnings
Adverse reactions to trihexyphenidyl are mainly extensions of its anticholinergic effects. Adverse effects of trihexyphenidyl, which are experienced by 30-50% of patients receiving the drug, may include dryness of the mouth, dizziness, blurred vision, nausea, and nervousness. Other adverse effects typical of those produced by antimuscarinic drugs include constipation, tachycardia, mydriasis, urinary hesitancy or retention, drowsiness, increased intraocular tension, weakness, vomiting, and headache. CNS stimulation, usually manifested by restlessness, agitation, confusion, delirium, and hallucination or euphoria may occur with high dosage, or in persons with a history of hypersensitivity to other drugs, or in patients with arteriosclerosis. Isolated instances of rashes, dilatation of the colon, paralytic ileus, and suppurative parotitis secondary to dryness of the mouth have been reported. Angle-closure glaucoma has reportedly occurred in patients receiving prolonged therapy with trihexyphenidyl. Rarely, psychiatric disturbances such as delusion, amnesia, depersonalization, a sense of unreality, and one possible case of paranoia have been reported with trihexyphenidyl. The incidence and severity of adverse effects are generally dose related and adverse effects may occasionally be obviated by reduction in dosage. If a severe reaction occurs, the drug should be discontinued for several days and then readministered at a lower dosage.
Trihexyphenidyl 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 trihexyphenidyl.
Tardive dyskinesia may appear in some patients on long-term therapy with antipsychotic drugs or may occur after therapy with these drugs has been discontinued. Antiparkinsonism agents do not alleviate the symptoms of tardive dyskinesia and, in some instances, may aggravate them. However, parkinsonism and tardive dyskinesia often coexist in patients receiving chronic neuroleptic treatment, and anticholinergic therapy with trihexyphenidyl HCl may relieve some of these parkinsonism symptoms. /Trihexyphenidyl hydrochloride/
Since the use of trihexyphenidyl hydrochloride may, in some cases, continue indefinitely and since it has atropine-like properties, patients should be subjected to constant and careful long-term observation to avoid allergic and other untoward reactions. Inasmuch as trihexyphenidyl hydrochloride possesses some parasympatholytic activity, it should be used with caution in patients with glaucoma, obstructive disease of the gastrointestinal or genitourinary tracts, and in elderly males with possible prostatic hypertrophy. Geriatric patients, particularly over the age of 60, frequently develop increased sensitivity to the actions of drugs of this type, and hence, require strict dosage regulation. Incipient glaucoma may be precipitated by parasympatholytic drugs such as trihexyphenidyl hydrochloride. /Trihexyphenidyl hydrochloride/
For more Drug Warnings (Complete) data for TRIHEXYPHENIDYL (10 total), please visit the HSDB record page.

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Pharmacodynamics
Trihexyphenidyl is an antimuscarinic indicated as an adjunct in the treatment of parkinsonism or as a treatment for drug-induced extrapyramidal symptoms. It has a long duration of action as it does not need to be given every day. It has a wide therapeutic window, with acute toxicity being non fatal in doses as high as 300 mg. Patients should have their iridocorneal angle examined before and intraocular pressure monitored during therapy. Patients should be counselled regarding the risk of anhidrosis and hyperthermia.

C20H31NO

301.474

301.241

144-11-6

Trihexyphenidyl hydrochloride;52-49-3

5572

Typically exists as solid at room temperature

1.04g/cm3

447.9ºC at 760 mmHg

258.5ºC

211ºC

8.34E-09mmHg at 25°C

1.546

4.268

1

2

5

22

314

0

C1=CC=C(C=C1)C(CCN2CCCCC2)(C3CCCCC3)O

HWHLPVGTWGOCJO-UHFFFAOYSA-N

InChI=1S/C20H31NO/c22-20(18-10-4-1-5-11-18,19-12-6-2-7-13-19)14-17-21-15-8-3-9-16-21/h1,4-5,10-11,19,22H,2-3,6-9,12-17H2

1-cyclohexyl-1-phenyl-3-piperidin-1-ylpropan-1-ol

Apo-TrihexBenzhexol Trihex Benzhexol free base TrihexyphenidylArtane Parkin Pacitane

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.)