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
It is very well absorbed orally and the peak serum concentration can be attained in 1 to 2 hours after extravascular administration. When ibuprofen is administered immediately after a meal there is a slight reduction in the absorption rate but there is no change in the extent of the absorption. When orally administered, the absorption of ibuprofen in adults is very rapidly done in the upper GI tract. The average Cmax, Tmax and AUC ranges around 20 mcg/ml, 2 h and 70 mcg.h/ml. These parameters can vary depending on the enantiomer form, route, and dose of administration.
Ibuprofen is rapidly metabolized and eliminated in the urine thus, this via accounts for more than 90% of the administered dose. It is completely eliminated in 24 hours after the last dose and almost all the administered dose goes through metabolism, representing about 99% of the eliminated dose. The biliary excretion of unchanged drug and active phase II metabolites represents 1% of the administered dose. In summary, ibuprofen is excreted as metabolites or their conjugates. The elimination of ibuprofen is not impaired by old age or the presence of renal impairment.
The apparent volume of distribution of ibuprofen is of 0.1 L/kg.
The clearance rate ranges between 3-13 L/h depending on the route of administration, enantiomer type and dosage.
Ibuprofen is rapidly absorbed after oral admin, & peak concns in plasma are observed after 15-30 min. The half-life in plasma is about 2 hr. Ibuprofen is extensively (99%) bound to plasma proteins, but the drug occupies only a fraction of the total drug-binding sites at usual concns. Ibuprofen passes slowly into the synovial spaces & may remain there in higher concn as the concns in plasma decline. In experimental animals, ibuprofen & its metabolites pass easily across the placenta. The excretion of ibuprofen is rapid & complete. More than 90% of an ingested dose is excreted in the urine as metabolites or their conjugates.
ENTERO-HEPATIC CIRCULATION OF (14)C-IBUPROFEN & ITS METABOLITES MAY HAVE OCCURRED IN DOGS RECEIVING REPEATED ORAL DOSES ... SINCE LEVELS IN BILE ... WERE 40-FOLD THOSE IN PLASMA.
AFTER ORAL DOSES OF 400 MG IBUPROFEN, SERIAL BLOOD SAMPLES WERE TAKEN (5 MALE VOLUNTEERS, 4 ARTHRITIC PATIENT). EVIDENCE SHOWED 2 COMPARTMENT MODEL: NO EVIDENCE SHOWN OF DRUG ACCUM IN PERIPHERAL COMPARTMENT.
The enantiomeric composition of ibuprofen in plasma was investigated following oral administration of 200 mg of the racemic drug in a conventional tablet or 300 mg in a novel controlled release pellet formulation to 4 healthy volunteers, aged 24 to 37 yr, in a randomized, crossover study. The plasma concentration time profiles suggest that drug release from the controlled release preparation was suitably modified and that the fluctuation between the peaks and troughs observed following a conventional tablet formulation were reduced. The plasma concentrations of (+)-ibuprofen (S-ibuprofen) were greater than those of (-)-ibuprofen (R-ibuprofen) following either formulation, and the enantiomeric plasma ratio (S/R) was reduced, both in magnitude and variability, following the controlled release preparation. The proportion of the total area under the plasma concentration time curves, due to (S)-ibuprofen, were slightly reduced following the controlled release formulation compared to the tablet formulation. The importance of a consideration of stereochemistry in bioequivalence studies of chiral drugs is discussed.
For more Absorption, Distribution and Excretion (Complete) data for IBUPROFEN (11 total), please visit the HSDB record page.

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Metabolism / Metabolites
Ibuprofen is rapidly metabolized and biotransformed in the liver to the formation of major metabolites which are the hydroxylated and carboxylated derivatives. As soon as it is absorbed, the R-enantiomer undergoes extensive enantiomeric conversion (53-65%) to the more active S-enantiomer _in vivo_ by the activity of alpha-methylacyl-CoA racemase. Ibuprofen metabolism can be divided in phase I which is represented by the hydroxylation of the isobutyl chains for the formation of 2 or 3-hydroxy derivatives followed by oxidation to 2-carboxy-ibuprofen and p-carboxy-2-propionate. These oxidative reactions are performed by the activity of the cytochrome P450 isoforms CYP 2C9, CYP 2C19 and CYP 2C8. Therefore, these enzymes participate in the oxidation of the alkyl side chain to hydroxyl and carboxyl derivatives. From this enzymes, the major catalyst in the formation of oxidative metabolites is the isoform CYP 2C9. The metabolic phase I is followed by a phase II in which the oxidative metabolites may be conjugated to glucuronide prior to excretion. This activity forms phenolic and acyl glucuronides.
TWO MAJOR METABOLIC PATHWAYS IN MAN & IN ANIMALS PROCEED BY OXIDATIVE ATTACK OF ISOBUTYL SIDE CHAIN; THEY ARE HYDROXYLATION OF THE TERTIARY CARBON TO YIELD A STABLE TERTIARY ALCOHOL, & OXIDATION OF 1 OF THE 2 GEMINAL METHYL GROUPS TO YIELD THE ACID.
IBUPROFEN GIVES 2-(4-(2-CARBOXYPROPYL)PHENYL)PROPIONIC ACID & 2-(4-(2-HYDROXY-2-METHYLPROPYL)PHENYL)PROPIONIC ACID IN MAN. /FROM TABLE/
The pharmacokinetics of oral ibuprofen following a dose of 0.8 g given 3 times a day for 14 days were studied in 7 functionally anephric patients (aged 34-66 yr) undergoing hemodialysis. No accumulation of ibuprofen plasma concns & an absence of intact ibuprofen in dialysate indicated clearance through metabolic pathways. The metabolites did accumulate significantly with mean plasma levels of 249 mcg/ml for the carboxy derivatives & 57 mcg/ml for the hydroxy derivatives of ibuprofen. However, both were detected in the dialysate. Dialysis clearance calculated by arterial & venous difference was found to agree with actual recovery in dialysate for both metabolites. Side effects were not observed in any subject.
R-enanatiomer undergoes extensive enantiomeric conversion (53-65%) to the more active S-enantiomer in vivo. Metablized by oxidation to 2 inactive metabolites: (+)-2[4'-(2-hydroxy-2-methylpropyl)phenyl]propionic acid and (+)-2-[4'-(2-carboxypropyl)phenyl]propionic acid. Very small amounts of 1-hydroxyibuprofen and 3-hydroxyibuprofen have been recovered from urine. Cytochrome P450 2C9 is the major catalyst in the formation of oxidative metabolites. Oxidative metabolites may be conjugated to glucuronide prior to excretion.
Route of Elimination: Ibuprofen is rapidly metabolized and eliminated in the urine.
Half Life: 2-4 hours

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Biological Half-Life
The serum half-life of ibuprofen is 1.2-2 hours. In patients with a compromised liver function, the half-life can be prolonged to 3.1-3.4 hours.
... After oral admin ... the half-life in plasma is about 2 hr.

Toxicity Summary
The exact mechanism of action of ibuprofen is unknown. Ibuprofen is a non-selective inhibitor of cyclooxygenase, an enzyme invovled in prostaglandin synthesis via the arachidonic acid pathway. Its pharmacological effects are believed to be due to inhibition cylooxygenase-2 (COX-2) which decreases the synthesis of prostaglandins involved in mediating inflammation, pain, fever and swelling. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Inhibition of COX-1 is thought to cause some of the side effects of ibuprofen including GI ulceration. Ibuprofen is administered as a racemic mixture. The R-enantiomer undergoes extensive interconversion to the S-enantiomer in vivo. The S-enantiomer is believed to be the more pharmacologically active enantiomer.

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Toxicity Data
LD50: 1255mg/kg (Oral, Mouse) (A308)

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Interactions
IN RABBITS AND IN HEALTHY HUMANS, IBUPROFEN ADMINISTERED BEFORE TOLBUTAMIDE ANTAGONIZED TOLBUTAMIDE HYPOGLYCEMIA.
WHEN SULFAMETHIZOLE WAS COADMINISTERED TO DOGS WITH IBUPROFEN, BETA-ELIMINATION HALF-LIFE FOR SULFAMETHIZOLE WAS INCREASED APPROXIMATELY 10 TIMES COMPARED TO THE CONTROL VALUE. RESULTS SUGGEST THAT THE INCREASED TERMINAL HALF-LIFE OF SULFAMETHIZOLE CAUSED BY IBUPROFEN IS MAINLY A RESULT OF COMPETITIVE INTERACTIONS BETWEEN THEM AT THE RENAL SECRETORY LEVEL.
In several short-term, controlled studies, ibuprofen did not have a substantial effect on the prothrombin time of patients receiving oral anticoagulants; however, because ibuprofen may cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time and because bleeding has occurred when ibuprofen and coumarin derivative anticoagulants were administered concomitantly, the drug should be used with caution and the patient carefully observed if the drug is used concomitantly with any anticoagulant /such as/ warfarin or /the thrombolytic agent streptokinase.
To study a potential interaction between digoxin and two non-steroid anti-inflammatory drugs, indomethacin (50 mg three times daily) and ibuprofen (600 mg three times daily) were given for 10 days to 10 and 8 patients, respectively, on chronic digoxin treatment. Serum digoxin measured by fluorescence polarisation immunoassay increased significantly (p < 0.05) during treatment with indomethacin from pre-treatment values of 0.73 + or - 0.34 nmol/l (mean + or - standard deviation) to a mean value of 1.02 + or - 0.43 nmol/l, while administration of ibuprofen did not change the steady state serum concentration of digoxin. The result demonstrates that some non-steroidal anti-inflammatory drugs such as indomethacin increase serum digoxin to levels high in the therapeutic range. This should be taken into consideration when co-administering other drugs known to increase the serum concentration of digoxin such as several antiarrhythmics.
For more Interactions (Complete) data for IBUPROFEN (17 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 636 mg/kg
LD50 Rat ip 626 mg/kg
LD50 Rat sc 740 mg/kg
LD50 Rat rectal 530 mg/kg
For more Non-Human Toxicity Values (Complete) data for IBUPROFEN (8 total), please visit the HSDB record page.

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

Therapeutic Uses
Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors
Ibuprofen ... /is/ indicated for reduction of fever. /Included in US product labeling/
Ibuprofen ... /is/ used for relief of the pain and inflammation of acute gouty arthritis and acute calcium pyrophosphate deposition disease (pseudogout; chondrocalcinosis articularis; synovitis, crystal-induced). Only immediate-release dosage forms are recommended for relief of acute attacks because of their more rapid onset of action relative to delayed-release or extended-release dosage forms. /NOT included in US product labeling/
Ibuprofen ... /is/ indicated for relief of mild to moderate pain, especially when anti-inflammatory actions may also be desired, e.g., following dental, obstetric, or orthopedic surgery, and for relief of musculoskeletal pain due to soft tissue athletic injuries (strains or sprains). Only immediate-release dosage forms are recommended for relief of acute pain because of their more rapid onset of actin relative to delayed-release or extended-release dosage forms. /Included in US product labeling/
For more Therapeutic Uses (Complete) data for IBUPROFEN (28 total), please visit the HSDB record page.

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Drug Warnings
Ibuprofen should be used with caution in patients with peptic ulcer disease, GI perforation or bleeding, bleeding abnormalities (especially in patients who may be adversely affected by prolongation of bleeding time), impaired renal function, hypertension, or compromised cardiac function.
CAUTION IN THE USE OF IBUPROFEN IN SYSTEMIC LUPUS ERYTHEMATOSUS IS ADVISED, PARTICULARLY IF THERE IS HISTORY OF SALICYLATE INTOLERANCE.
Ibuprofen is not recommended for use by pregnant women, or by those who are breast-feeding their infants.
IBUPROFEN ELEVATES BILIRUBIN, ALKALINE PHOSPHATASE, ASPARTATE AMINOTRANSFERASE (SGOT), AND ALANINE AMINOTRANSFERASE (SGPT) ABOVE THE NORMAL RANGE, AND CAUSES ISOLATED CASES OF JAUNDICE. /FROM TABLE/
For more Drug Warnings (Complete) data for IBUPROFEN (14 total), please visit the HSDB record page.

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Pharmacodynamics
Ibuprofen has multiple actions in different inflammatory pathways involved in acute and chronic inflammation. The main effects reported in ibuprofen are related to the control of pain, fever and acute inflammation by the inhibition of the synthesis of prostanoids by COX-1 and COX-2. Pain relief is attributed to peripheral affected regions and central nervous system effects in the pain transmission mediated by the dorsal horn and higher spinothalamic tract. Some reports have tried to link the pain regulation with a possible enhancement on the synthesis of endogenous cannabinoids and action on the NMDA receptors. The effect on pain has been shown to be related to the cortically evoked potentials. The antipyretic effect is reported to be linked to the effect on the prostanoid synthesis due to the fact that the prostanoids are the main signaling mediator of pyresis in the hypothalamic-preoptic region. The use of ibuprofen in dental procedures is attributed to the local inhibition of prostanoid production as well as to anti-oedemic activity and an increase of plasma beta-endorphins. Some reports have suggested a rapid local reduction of the expression of COX-2 in dental pulp derived by the administration of ibuprofen. The administration of ibuprofen in patients with rheumatic diseases has shown to control joint symptoms. Ibuprofen is largely used in OTC products such as an agent for the management of dysmenorrhea which has been proven to reduce the amount of menstrual prostanoids and to produce a reduction in the uterine hypercontractility. As well, it has been reported to reduce significantly the fever and the pain caused by migraines. This effect is thought to be related to the effect on platelet activation and thromboxane A2 production which produces local vascular effects in the affected regions. This effect is viable as ibuprofen can enter in the central nervous system. In the investigational uses of ibuprofen, it has been reported to reduce neurodegeneration when given in low doses over a long time. On the other hand, its use in Parkinson disease is related to the importance of inflammation and oxidative stress in the pathology of this condition. The use of ibuprofen for breast cancer is related to a study that shows a decrease of 50% in the rate of breast cancer.

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.)