Clomipramine suppresses both norepinephrine and 5-HT reuptake, with clomipramine suppressing 5-HT reuptake more significantly than norepinephrine reuptake [1]. Clomipramine, an antidepressant, has no effect on AChE in the striatum of the rat brain, but it inhibits AChE in venom and human serum BChE in a concentration-dependent way [2]. Under cytotoxic stress, clomipramine causes disruptions to autophagic flow and significantly reduces the ability of tumorigenic cells to survive [3]. In primary neuronal cultures, clomipramine decreases autophagy. Neuronal autophagy pathway in primary cultured cells is negatively regulated by clomipramine (1 and 5 µM) [3].

Mice exposed to 5–20 mg/kg of clomipramine intraperitoneally develop significant hyperglycemia. Because clomipramine blocks 5-HT2B and/or 5-HT2C receptors, it causes hyperglycemia in mice by encouraging the release of adrenaline. Clomipramine decreased immobility in mice during the forced swim test, which is used as a behavioral model for antidepressants. Additionally, clomipramine prevents mice used as animal models for obsessive-compulsive disorder from burying marbles [1]. In mouse tissues, clomipramine (20 mg/kg) decreases autophagic flow [3].

Western Blot Analysis[3]
Cell Types: Primary Cortical Neurons
Tested Concentrations: 1 and 5 µM
Incubation Duration: 12, 24 and 48 hrs (hours)
Experimental Results: Enhanced LC3-I to LC3-II in a concentration-dependent manner at all analyzed time points transformation.

Animal/Disease Models: C57BL/6 J mice (6 weeks old, 22 to 25 g) [3]
Doses: 20 mg/kg
Route of Administration: intraperitoneal (ip) injection for 21 days
Experimental Results: LC3-II and p62 were Dramatically increased in the liver High clomipramine-treated mice were compared with vehicle-treated mice.

Absorption, Distribution and Excretion
Well absorbed from the GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine.
Urine (51-60%) and feces via biliary elimination (24-32%)
~ 17 L/kg (range: 9-25 L/kg). Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk.
Clomipramine hydrochloride appears to be well absorbed from the GI tract following oral administration. However, extensive first-pass metabolism decreases its oral bioavailability to about 50%. The oral capsules and solution of clomipramine hydrochloride reportedly are bioequivalent. Food does not appear to substantially affect the bioavailability of clomipramine from the capsules.
In one case report, plasma clomipramine concentrations were measured in an infant whose mother was receiving clomipramine hydrochloride 125 mg daily during pregnancy. ... After the first week postpartum, the mother's dosage of clomipramine hydrochloride was increased to 150 mg daily and the concentration of clomipramine in milk was 80-160% of the concurrent plasma clomipramine concentration at steady state. ...
Peak plasma clomipramine concentrations of approximately 56-154 ng/mL (mean: 92 ng/mL) usually occur within 2-6 hours (mean: 4.7 hours) following oral administration of a single 50-mg dose of clomipramine hydrochloride. Like other tricyclic antidepressants, clomipramine exhibits considerable interindividual variation in plasma concentrations achieved with a given dose due, at least in part, to genetic differences in the metabolism of the drug.
Following multiple-dose oral administration of clomipramine, steady-state plasma concentrations of the drug generally are achieved within about 1-2 weeks. Steady-state plasma desmethylclomipramine (the principal metabolite) concentrations may be achieved at about the same time as steady-state plasma clomipramine concentrations or later. In some cases, plasma desmethylclomipramine concentrations have been observed to continue to increase during 4-6 weeks of administration of a constant dosage of clomipramine hydrochloride. Plasma concentrations of desmethylclomipramine generally exceed those of the parent drug following multiple daily dosing of clomipramine hydrochloride.
For more Absorption, Distribution and Excretion (Complete) data for Clomipramine (13 total), please visit the HSDB record page.

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Metabolism / Metabolites
Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N-demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N-oxide formed by N-oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N-demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical relevance remains unknown.
The exact metabolic fate of clomipramine has not been fully elucidated. Clomipramine appears to be extensively metabolized to desmethylclomipramine and other metabolites and their glucuronide conjugates. Desmethylclomipramine, the principal metabolite, is formed by N-demethylation of clomipramine. Other metabolites of clomipramine include 8-hydroxyclomipramine, 2-hydroxyclomipramine, and clomipramine N-oxide, which appear to be formed via 8-hydroxylation, 2-hydroxylation, and N-oxidation, respectively. The metabolites of desmethylclomipramine include 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which apparently are formed via 8-hydroxylation and N-demethylation, respectively. Although desmethylclomipramine is pharmacologically active, its efficacy in obsessive-compulsive disorder is not known. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine also are pharmacologically active but the clinical importance of their presence remains unknown.
The hydroxylation of clomipramine and desmethylclomipramine appears to be under genetic control (similar to that of debrisoquine and sparteine). In healthy adults who were phenotyped for debrisoquine hydroxylation, extensive metabolizers were distinguishable from poor metabolizers with regard to the extent of hydroxylation of desmethylclomipramine. Blood concentrations of desmethylclomipramine were higher than expected in a limited number of patients who subsequently were found to be poor metabolizers. Limited data suggest that CYP2D6, a cytochrome P-450 isoenzyme implicated in the sparteine/debrisoquine oxidation polymorphism, is involved in the 8-hydroxylation of clomipramine and desmethylclomipramine and in the 2-hydroxylation of clomipramine. In addition, demethylation of clomipramine may involve CYP2C, which is implicated in the S-mephenytoin oxidation polymorphism, and CYP1A2.
The fate of clomipramine (CMI) and its main demethylated metabolite demethylclomipramine (DCMI) was studied in two strains of Swiss mice (NMRI and CD1) after intraperitoneal injection. A study of its distribution among various tissues showed that fixation was most marked in lungs, perirenal fat and kidneys, and only moderate in the brain. The pharmacokinetic parameters of both molecules were determined in brain tissue and plasma. Absorption was rapid (tmax CMI = 14 min), metabolism prompt (tmax DCMI = 17 or 18 min according to the breed) and elimination rapid from both plasma and brain tissue. The first two stages were similar in the two strains, but elimination of CMI from both plasma and brain was faster in the NMRI mice (plasma t1/2 = 53 min against 165 min in the CD1 mice). Both values were well below that reported for man (mean plasma t1/2 = 24 hr). ...
Clomipramine has known human metabolites that include 2-hydroxy-clomipramine, 8-hydroxy-clomipramine, 10-hydroxy-clomipramine, and N-Desmethylclomipramine.
Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N-demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N-oxide formed by N-oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N-demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical contribution remains unknown.
Route of Elimination: Urine (51-60%) and feces via biliary elimination (24-32%)
Half Life: Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism).

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Biological Half-Life
Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism).
The elimination half-life of clomipramine averages approximately 32 hours (range: 19-37 hours) and that of desmethylclomipramine averages about 69 hours (range: 54-77 hours) following a single, 150-mg oral dose of the drug.
To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs after IV or oral administration of a single dose. 6 male and 6 female Beagles. Clomipramine was administered IV (2 mg/kg), PO (4 mg/kg) after food was withheld for 15 hours, and PO (4 mg/kg) within 25 minutes after dogs were fed. ... For clomipramine, after IV administration, elimination half-life was 5 hours ...
/The objective of this study was/ to determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs following single-dose and repeated-dose oral administration at various dosages. ... Clomipramine was administered orally at a dose of 1, 2, or 4 mg/kg to 3 male and 3 female dogs, first as a single dose and then, after an interval of 14 days, twice daily for 10 days. ... Terminal half-life increased slightly (1.6-fold for clomipramine and 1.2-fold for desmethylclomipramine) with repeated-dose administration but remained short in all groups (< or = 4 hours).

Toxicity Summary
Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α₁-receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type.

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Interactions
Limited data suggest that demethylation of clomipramine may be reduced with chronic alcohol consumption. In one study, the clearance of clomipramine via demethylation was decreased substantially and the ratio of blood clomipramine to desmethylclomipramine concentrations at steady state was higher in recently detoxified alcoholic patients (abstinence periods ranged from 4-20 weeks) compared with a control group of patients with no history of alcoholism.
The plasma concentration of clomipramine has been reported to be increased by the concomitant administration of haloperidol; plasma levels of several closely related tricyclic antidepressants have been reported to be increased by the concomitant administration of methylphenidate or hepatic enzyme inhibitors (eg, cimetidine, fluoxetine) and decreased by the concomitant administration of hepatic enzyme inducers (eg, barbiturates, phenytoin), and such an effect may be anticipated with clomipramine as well. Administration of clomipramine has been reported to increase the plasma levels of phenobarbital, if given concomitantly.
Several tricyclic antidepressants have been reported to block the pharmacologic effects of guanethidine, clonidine, or similar agents, and such an effect may be anticipated with clomipramine because of its structural similarity to other tricyclic antidepressants.
Close supervision and careful adjustment of dosage are required when clomipramine is administered with anticholinergic or sympathomimetic drugs.
For more Interactions (Complete) data for Clomipramine (11 total), please visit the HSDB record page.

[1]. The tricyclic antidepressant Clomipramine increases plasma glucose levels of mice. J Pharmacol Sci. 2003 Sep;93(1):74-9.

[2]. Comparative study of the inhibitory effect of antidepressants on cholinesterase activity in Bungarus sindanus (krait) venom, human serum and rat striatum. J Enzyme Inhib Med Chem. 2008 Dec;23(6):912-7.

[3]. Federica Cavaliere,The tricyclic antidepressant Clomipramine inhibits neuronal autophagic flux. Sci Rep. 2019 Mar 19;9(1):4881.

Therapeutic Uses
Tricyclic Antidepressive Agents; Serotonin Uptake Inhibitors
Clomipramine hydrochloride capsules are indicated for the treatment of obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD). The obsessions or compulsions must cause marked distress, be time consuming, or significantly interfere with social or occupational functioning, in order to meet the DSM-III-R (circa 1989) diagnosis of OCD. /Included in US product label/
/VET THER/ The efficacy and tolerability of clomipramine in the treatment of separation anxiety in dogs was tested in a prospective, randomized, double-blind, placebo-controlled, parallel-group, international multicenter clinical trial. For a diagnosis of separation anxiety, dogs had to exhibit at least one of the following signs in the absence of their owner: destruction, defecation, urination and/or vocalization, as well as the behaviour suggestive of "hyper-attachment" to their owner. A total of 95 dogs were randomized to receive one of the three treatments for 2-3 months: "standard-dose" clomipramine (1 to <2 mg/kg, PO, q. 12 hr); "low-dose" clomipramine (0.5 to <1 mg/kg, PO, q. 12 hr); and placebo (PO, q. 12 hr). All dogs received behavioural therapy. Dogs were examined at four time points (days 0, 28, 56 and 84) after the initiation of therapy. Improvement in each dog's behaviour at days 28, 56 and 84 was evaluated in comparison to its behaviour at day 0.The results showed that, compared to placebo, dogs receiving standard-dose clomipramine were rated improved at least three times faster for the signs destruction, defecation and urination. At most time points, more dogs in the standard-dose clomipramine group were rated improved for the signs destruction, defecation and urination, and in an owner's global assessment of the dog's overall behaviour (p<0.05 at certain time points). However, there were no statistically significant differences at any time point between the standard dose and the placebo groups in the sign vocalization. The low-dose clomipramine group produced no statistically significant effect when compared with placebo. Mild and transient vomiting was noted as a side effect of clomipramine in a small number of dogs.It is concluded that addition of standard-dose (1 to <2 mg/kg, PO, q. 12 hr) clomipramine to conventional behavioural therapy for 2-3 months ameliorated the signs of separation anxiety in dogs.

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Drug Warnings
/BOXED WARNING/ Suicidality and Antidepressant Drugs: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of clomipramine or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Clomipramine hydrochloride capsules are not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD).
Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants. This risk may persist until clinically important remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled studies of antidepressants (ie, selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders. An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older. It currently is unknown whether the suicidality risk extends to longer-term use (ie, beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.
The risk of suicidality in FDA's pooled analysis differed across the different psychiatric indications, with the highest incidence observed in the major depressive disorder studies. ...The average risk of such events was 4% among children and adolescents receiving these drugs, twice the risk (2%) that was observed among those receiving placebo. ... In addition, although there was considerable variation in risk among the antidepressants, a tendency toward an increase in suicidality risk in younger patients was found for almost all drugs studied. It is currently unknown whether the suicidality risk in pediatric patients extends to longer-term use (i.e., beyond several months).
As a result of this analysis and public discussion of the issue, FDA has directed manufacturers of all antidepressants to add a boxed warning to the labeling of their products to alert clinicians of this suicidality risk in children and adolescents and to recommend appropriate monitoring and close observation of patients receiving these agents. The drugs that are the focus of the revised labeling are all drugs included in the general class of antidepressants, including those that have not been studied in controlled clinical trials in pediatric patients, since the available data are not adequate to exclude any single antidepressant from an increased risk. In addition to the boxed warning and other information in professional labeling on antidepressants, FDA currently recommends that a patient medication guide explaining the risks associated with the drugs be provided to the patient each time the drugs are dispensed.
For more Drug Warnings (Complete) data for Clomipramine (57 total), please visit the HSDB record page.

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Pharmacodynamics
Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α₁ and β₁ receptors are sensitized, α₂ receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain.

C19H23N2CL

314.85232

314.154

303-49-1

Clomipramine hydrochloride;17321-77-6;Clomipramine-d3;136765-29-2

2801

Off-white to light yellow ointment

1.1±0.1 g/cm3

434.2±45.0 °C at 760 mmHg

191.5-192
189.5 °C

216.4±28.7 °C

0.0±1.0 mmHg at 25°C

1.582

5.39

0

2

4

22

346

0

CN(C)CCCN1C2=CC=CC=C2CCC3=C1C=C(C=C3)Cl

GDLIGKIOYRNHDA-UHFFFAOYSA-N

InChI=1S/C19H23ClN2/c1-21(2)12-5-13-22-18-7-4-3-6-15(18)8-9-16-10-11-17(20)14-19(16)22/h3-4,6-7,10-11,14H,5,8-9,12-13H2,1-2H3

3-(2-chloro-5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N,N-dimethylpropan-1-amine

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.)