Drug compounds have included stable heavy isotopes of carbon, hydrogen, and other elements, mostly as quantitative tracers while the drugs were being developed. Because deuteration may have an effect on a drug's pharmacokinetics and metabolic properties, it is a cause for concern [1].

Absorption, Distribution and Excretion
Ibuprofen is well absorbed orally, reaching peak plasma concentrations 1 to 2 hours after extravascular administration. Immediate administration after a meal slightly reduces absorption, but the overall absorption remains unchanged. In adults, ibuprofen is rapidly absorbed primarily in the upper gastrointestinal tract after oral administration. The mean Cmax, Tmax, and AUC are approximately 20 mcg/ml, 2 h, and 70 mcg·h/ml, respectively. These parameters vary depending on enantiomer form, route of administration, and dose. Ibuprofen is rapidly metabolized and primarily excreted in the urine; therefore, over 90% of the administered dose is excreted in the urine. Ibuprofen is completely excreted within 24 hours of the last dose, with almost all of the administered dose being metabolized, approximately 99% of the excreted dose. Biliary excretion of the parent drug and active phase II metabolites accounts for 1% of the administered dose. In summary, ibuprofen is excreted as metabolites or their conjugates. Age or renal impairment does not affect ibuprofen clearance.
The apparent volume of distribution of ibuprofen is 0.1 L/kg.
Clearance ranges from 3 to 13 L/h, depending on the route of administration, enantiomer type, and dose.
Ibuprofen is rapidly absorbed after oral administration, reaching peak plasma concentrations after 15–30 minutes. The plasma half-life is approximately 2 hours. Ibuprofen is extensively bound to plasma proteins (99%), but at commonly used concentrations, the drug occupies only a small fraction of the total drug binding sites. Ibuprofen enters the synovial cavity slowly and may maintain high concentrations thereas as plasma concentrations decrease. In laboratory animals, ibuprofen and its metabolites readily cross the placenta. Ibuprofen is excreted rapidly and completely. Over 90% of the ingested dose is excreted in the urine as metabolites or their conjugates.
In dogs repeatedly given ibuprofen orally, enterohepatic circulation of 14C-ibuprofen and its metabolites may have occurred…because the concentration in bile is 40 times that in plasma.
A series of blood samples were collected after oral administration of 400 mg ibuprofen (5 male volunteers, 4 arthritis patients). Evidence suggested a two-compartment model: no evidence of drug accumulation in the peripheral compartment was found.
In a randomized crossover study, four healthy volunteers aged 24 to 37 years were orally administered either 200 mg of racemic ibuprofen in conventional tablet form or 300 mg of a novel controlled-release granule formulation to investigate the enantiomeric composition of ibuprofen in plasma. Plasma concentration-time curves showed that the controlled-release formulation provided adequate improvement in drug release and reduced the peak-trough fluctuations observed in the conventional tablet formulation. Plasma concentrations of (+)-ibuprofen (S-ibuprofen) were higher than those of (-)-ibuprofen (R-ibuprofen) after administration of both formulations, and the numerical value and variability of the enantiomeric plasma ratio (S/R) were reduced after administration of the controlled-release formulation. The area under the plasma concentration-time curve for (S)-ibuprofen was slightly lower in the controlled-release formulation compared to the tablet. This article discusses the importance of considering stereochemistry in bioequivalence studies of chiral drugs. For more complete data on the absorption, distribution, and excretion of ibuprofen (11 types), please visit the HSDB record page. Metabolism/Metabolites Ibuprofen is rapidly metabolized and biotransformed in the liver, producing major metabolites, namely hydroxylated and carboxylated derivatives. After absorption, the R-enantiomer undergoes extensive enantiomeric conversion (53-65%) in vivo via the action of α-methylacyl-CoA racemic enzymes, converting to the more active S-enantiomer. Ibuprofen metabolism can be divided into two stages: In the first stage, the isobutyl chain is hydroxylated to generate 2- or 3-hydroxy derivatives, which are subsequently oxidized to 2-carboxy-ibuprofen and p-carboxy-2-propionate. These oxidation reactions are catalyzed by cytochrome P450 isoenzymes CYP2C9, CYP2C19, and CYP2C8. Therefore, these enzymes are involved in the oxidation of alkyl side chains to hydroxyl and carboxyl derivatives. CYP2C9 is the main catalyst for the formation of oxidative metabolites. Following the first metabolic stage is the second stage, where oxidative metabolites may bind to glucuronic acid and be excreted. This activity can form phenols and acyl glucuronides. Both major metabolic pathways in humans and animals involve oxidative attack on the isobutyl side chain; these are the hydroxylation of the tertiary carbon to form a stable tertiary alcohol, and the oxidation of one of the two geminal methyl groups to form an acid. Ibuprofen in humans produces 2-(4-(2-carboxypropyl)phenyl)propionic acid and 2-(4-(2-hydroxy-2-methylpropyl)phenyl)propionic acid. /Excerpt from table/ This study conducted a 14-day oral pharmacokinetic study of ibuprofen in seven functionally anorexic patients (aged 34-66 years) undergoing hemodialysis. These patients received 0.8 g of ibuprofen orally three times daily. No ibuprofen accumulation was detected in plasma, and no intact ibuprofen was detected in the dialysate, indicating that ibuprofen is primarily cleared via metabolic pathways. Ibuprofen metabolites do accumulate significantly, with mean plasma concentrations of 249 μg/mL for the carboxyl derivative and 57 μg/mL for the hydroxy derivative. However, both metabolites are detectable in the dialysate. Dialysis clearance calculated from the concentration difference between arterial and venous blood is consistent with the actual recovery rates of both metabolites in the dialysate. No side effects were observed in any subjects. The R-enantiomer undergoes extensive enantiomeric transformation (53-65%) in vivo, converting to the more active S-enantiomer. Ibuprofen is oxidatively metabolized to two inactive metabolites: (+)-2-[4'-(2-hydroxy-2-methylpropyl)phenyl]propionic acid and (+)-2-[4'-(2-carboxypropyl)phenyl]propionic acid. Trace amounts of 1-hydroxyibuprofen and 3-hydroxyibuprofen are detectable in urine. Cytochrome P450 2C9 is the primary catalyst for the formation of oxidative metabolites. Oxidative metabolites may bind to glucuronic acid before excretion.
Excretion route: Ibuprofen is rapidly metabolized and mainly excreted in the urine.
Half-life: 2-4 hours
Biological half-life
The serum half-life of ibuprofen is 1.2-2 hours. In patients with impaired liver function, the half-life can be prolonged to 3.1-3.4 hours.
...After oral administration...the plasma half-life is approximately 2 hours.

Toxicity Summary
The exact mechanism of action of ibuprofen is not fully understood. Ibuprofen is a non-selective cyclooxygenase inhibitor, an enzyme involved in prostaglandin synthesis via the arachidonic acid pathway. Its pharmacological action is thought to be through inhibition of cyclooxygenase-2 (COX-2) to reduce the synthesis of prostaglandins involved in inflammation, pain, fever, and swelling. Its antipyretic effect is likely due to its action on the hypothalamus, leading to increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Inhibition of COX-1 is believed to be the cause of some of ibuprofen's side effects, including gastrointestinal ulcers. Ibuprofen is administered as a racemic mixture. The R-enantiomer undergoes extensive interconversion in vivo to the S-enantiomer. The S-enantiomer is considered to be the more pharmacologically active enantiomer.

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Toxicity Data
LD50: 1255 mg/kg (oral, mouse) (A308)Interactions
In rabbits and healthy humans, administration of ibuprofen prior to tolbutamide antagonized tolbutamide-induced hypoglycemia.
When sulfamethoxazole was co-administered with ibuprofen in dogs, the β-elimination half-life of sulfamethoxazole increased approximately 10-fold compared to the control. These results indicate that the ibuprofen-induced prolongation of the sulfamethoxazole terminal half-life is primarily due to a competitive interaction between the two at renal secretion levels.
In several short-term controlled studies, ibuprofen did not significantly affect prothrombin time in patients taking oral anticoagulants; however, because ibuprofen may cause gastrointestinal bleeding, inhibit platelet aggregation, and prolong bleeding time, and because bleeding has occurred when ibuprofen is used in combination with coumarin derivative anticoagulants, caution should be exercised and patients should be closely monitored if ibuprofen is used in combination with any anticoagulant (such as warfarin or the thrombolytic streptokinase). To investigate the potential interaction between digoxin and two nonsteroidal anti-inflammatory drugs (NSAIDs) (indomethacin, 50 mg three times daily), 10 and 8 patients receiving long-term digoxin treatment were given indomethacin (50 mg three times daily) and ibuprofen (600 mg three times daily), respectively, for 10 days. Serum digoxin concentrations, measured by fluorescence polarization immunoassay, were significantly elevated during indomethacin treatment (p < 0.05), increasing from 0.73 ± 0.34 nmol/L (mean ± standard deviation) to a mean of 1.02 ± 0.43 nmol/L, while ibuprofen administration did not alter steady-state serum digoxin concentrations. This result suggests that certain nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, can increase serum digoxin concentrations to higher levels within the therapeutic range. This should be considered when used concomitantly with other drugs known to increase serum digoxin concentrations, such as several antiarrhythmic drugs. For more complete data on drug interactions with ibuprofen (17 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 636 mg/kg
Intraperitoneal LD50 in rats: 626 mg/kg
Subcutaneous LD50 in rats: 740 mg/kg
Rectal LD50 in rats: 530 mg/kg
For more complete data on non-human toxicity values for ibuprofen (out of 8), please visit the HSDB records page.

[1]. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019;53(2):211-216.

Therapeutic Uses

Non-narcotic analgesic; Non-steroidal anti-inflammatory drug; Cyclooxygenase inhibitor
Ibuprofen…/For/fever reduction. /Included on US product label/
Ibuprofen…/For/relief of pain and inflammation caused by acute gouty arthritis and acute calcium pyrophosphate deposition disease (pseudogout; articular cartilage calcification; crystal-induced synovitis). Because immediate-release formulations act faster than sustained-release or controlled-release formulations, it is recommended to use the immediate-release formulation only for acute attacks. /Not included on US product label/
Ibuprofen…/For/relief of mild to moderate pain, especially in cases requiring anti-inflammatory effects, such as after dental, obstetric, or orthopedic surgery, and for musculoskeletal pain caused by soft tissue injuries (strains or sprains). Because immediate-release formulations act faster than sustained-release or controlled-release formulations, it is recommended to use the immediate-release formulation only for acute pain. /Included in US Product Labels/
For more complete data on the therapeutic uses of ibuprofen (28 in total), please visit the HSDB record page.

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Drug Warnings
Ibuprofen should be used with caution in patients with peptic ulcers, gastrointestinal perforation or bleeding, abnormal bleeding (especially those who may be adversely affected by prolonged bleeding), impaired renal function, hypertension, or impaired cardiac function.
Ibuprofen should be used with caution in patients with systemic lupus erythematosus, especially those with a history of salicylates intolerance.
Ibuprofen is not recommended for use in pregnant or breastfeeding women.
Ibuprofen can increase bilirubin, alkaline phosphatase, and aspartate aminotransferase. Elevated levels of AST (SGOT) and ALT (SGPT) may lead to jaundice in some cases. /Excerpt from Table/
For more complete data on the drug warnings of ibuprofen (14 in total), please visit the HSDB record page.

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Pharmacodynamics
Ibuprofen plays multiple roles in different inflammatory pathways involved in acute and chronic inflammation. It has been reported that ibuprofen's primary action is to control pain, fever, and acute inflammation by inhibiting the synthesis of prostaglandins from COX-1 and COX-2. Its analgesic effect is attributed to its influence on peripheral affected areas and the central nervous system, involving pain transmission mediated by the dorsal horn of the spinal cord and higher spinothalamic tracts. Some reports attempt to link pain modulation to enhanced endocannabinoid synthesis and its effects on NMDA receptors. Studies have shown that ibuprofen's effects on pain are related to cortical evoked potentials. Its antipyretic effect is allegedly related to the inhibition of prostaglandin synthesis, as prostaglandins are the primary signaling mediators of fever in the hypothalamus-preoptic area. The use of ibuprofen in dental surgery is attributed to its local inhibition of prostaglandin production, anti-edema effects, and increased plasma β-endorphin levels. Some reports show that ibuprofen can rapidly reduce COX-2 expression in dental pulp. The use of ibuprofen in patients with rheumatic diseases has been shown to control joint symptoms.
Ibuprofen is widely used in over-the-counter medications, such as for treating dysmenorrhea. It has been shown to reduce prostaglandin levels and decrease uterine contractility during menstruation. Furthermore, ibuprofen has been reported to significantly reduce fever and pain associated with migraines. This effect is thought to be related to ibuprofen's influence on platelet activation and thromboxane A2 production, thereby creating a local vasculature effect in the affected area. This effect is plausible because ibuprofen can enter the central nervous system. Clinical studies of ibuprofen have reported that long-term low-dose use can reduce neurodegenerative changes. On the other hand, the use of ibuprofen in Parkinson's disease is associated with the importance of inflammation and oxidative stress in the pathology of this disease. Studies using ibuprofen to treat breast cancer have shown a 50% reduction in breast cancer incidence.

C17H9D8N3S

303.45

206.13

1189866-35-0

31121-93-4 (hydrochloride salt);79261-49-7 (potassium salt)

3672

Colorless, crystalline stable solid

64-66°C

3.5

1

2

4

15

203

0

S1C2C=CC=CC=2N=C(C2C=CC=CC1=2)N1C([2H])([2H])C([2H])([2H])NC([2H])([2H])C1([2H])[2H]

HEFNNWSXXWATRW-UHFFFAOYSA-N

InChI=1S/C13H18O2/c1-9(2)8-11-4-6-12(7-5-11)10(3)13(14)15/h4-7,9-10H,8H2,1-3H3,(H,14,15)

2-[4-(2-methylpropyl)phenyl]propanoic acid

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.)