Ibuprofen metabolism

Pettersen, J.E., Blessington, B. and Jellum, E. (1975), Ibuprofen metabolism studied by combined gas chromatography-mass spectrometry Dialysis fluid - a convenient medium for studies in drug metabolism. Scand. J. Clin. Lab. Invest., 35, Suppl. 143, 147 (Abstract). 

Ibuprofen is an interesting case, in that the (5)-(+)-form is an active analgesic, but the ( )-(—)-enantiomer is inactive. However, in the body there is some metabolic conversion of the inactive (I )-isomer into the active (5 )-isomer, so that the potential activity from the racemate is considerably more than 50%. Box 10.11 shows a mechanism to account for this isomerism. 

Fenoprofen (Nalfon) is chemically and pharmacologically similar to ibuprofen and is used in the treatment of rheumatoid arthritis, osteoarthritis, and mild to moderate pain. GI effects such as dyspepsia and pain are most common, although dizziness, pruritus, and palpitations may occur. GI bleeding, sometimes severe, has been reported, and interstitial nephritis has been rarely associated with this drug. Concomitant administration of aspirin decreases the biological half-Ufe of fenoprofen by increasing the metabolic clearance of hydroxy-lated fenoprofen. Chronic administration of pheno-barbital also decreases the drug s half-life. 

Common NSAIDs include aspirin, ibuprofen, indomethacin, naproxen, and ketoprofen. Even though anti-inflammatories generally target cyclooxygenase, there are apparent differences in the details of how they relieve pain. For example, aspirin acts by primarily inhibiting the COX-dependent synthesis of eicosanoids, which are end products of metabolism of essential fatty acids including prostaglandin... 

CYP2C9 2 8-20 (W) Reduced metabolism in Fluoxetine, Ibuprofen, Imipramine,... 

UGT 2 UGT2B7 IPD Reduced metabolism in 10-15% (W) population Ibuprofen, Naproxen, Irinotecan... 

Scheme 35 Metabolic chiral inversion of (R)-ibuprofen to the (S)-enantiomer.

In some cases an inert enantiomer is metabolized into its active enantiomer. For example, R-ibuprofen is inactive but is believed to be metabolized to the active analgesic S-ibuprofen. 

Ibuprofen Overdose of OTC ibuprofen manifests as a syndrome of coma, hyperkalemia with cardiac arrhythmias, metabolic acidosis, pyrexia, and respiratory and kidney failure. The treatment of adverse effects includes intubation, mechanical ventilation, fluid resuscitation, gastric lavage, and administration of activated charcoal.62 Interactions are similar to those of NSAIDs. Moclobemide enhances the effects of ibuprofen. 

G.B. Zuckerman, and C.C. Uy, Shock metabolic acidosis, and coma following ibuprofen overdose in a child. Ann. Pharmacother. 29 869-871, 1995. 

Ibuprofen, the anti-inflammatory (see Figure 2.19 for its structure), has two isomers but, cleverly, our bodies metabolize the inactive isomer to the active one so a simple mixture of the two forms is sold over the counter. Can you spot the asymmetric carbon atom ... 

Anandamide is rapidly hydrolysed enzymatically to arachidonic acid and ethanol-amine by a fatty acid amide hydrolase (FAAH) [50], The molecular characterization, cloning and expression of FAAH have been reported in a recent study [51]. FAAH can be blocked with either the general serine protease inhibitor phenyl methy(sulphonyl fluoride [38] or with the highly efficient methyl arachidonyl fluorophsphonate [52], The non-steroidal antiinflammatory ibuprofen in therapeutic doses, but not aspirin, sulindac or acetaminophen, also inhibits anandamide metabolism [53], This observation may have therapeutic implications. 

Bapuji AT, Rambhau D, Srinivasu P, Rao BR, Apte SS. Time dependent influence of diazepam on the pharmacokinetics of ibuprofen in man. Drug Metabol Drug Interact 1999 15(1) 71-81. 

A later single-dose study in eight patients with moderate to severe cirrhosis and a PT of 2-5 seconds above the npper limit of normal, showed an approximate doubling of the half-life compared to controls. Metabolic inversion of the inactive R-ibuprofen to the active S-ibupro-fen may also be impaired in hepatic cirrhosis, because the AUC ratio of R- to S-ibuprofen was significantly higher in patients with cirrhosis. Medicinal ibuprofen is supplied as a racemic mixture [39]. 

Some NSAIDs (e.g, diclofenac, ibuprofen, naproxen, piroxicam) are actively metabolized by CYP2C9, which may be a site of possible interaction with inhibitors and inducers of this isoenzyme. 

Ibuprofen, as shown in Scheme 11.8, affords an example of aliphatic hydroxylation. Other drugs similarly metabolized include terfenadine, pentobarbital, and cyclosporine. 

---