Session III of TIP 1 TIP 2009 Gephart

 The synthesis of ibuprofen was originally reported in 1964 from p-isobutylacetophenone, but the drug was not marketed in the United States until  Ibuprofen became the first prescription non-steroidal anti- inflammatory drug (NSAID) to become available as an over the counter analgetic in almost 30 years and is available under a number of brand names.  It is marketed as the racemic mixture, although biological activity resides almost exclusively in the S-(+)-isomer. Ibuprofen is more potent than aspirin but less potent than indomethacin in anti-inflammatory and prostaglandin biosynthesis inhibition assays, and it produces moderate degrees of gastric irritation. 2 TIP 2009 Gephart

Figure 1: Structures of aryl- and heteroarylpropionic acid derivatives. (Lemke, Williams, Roche, & Zito, 2008) 3 TIP 2009 Gephart

 The substitution of an α -methyl group on the alkanoic acid portion of acetic acid derivatives enhances anti- inflammatory actions and reduces many side effects.  For example, the acetic acid analogue of ibuprofen, ibufenac (p-isobutylphenylacetic acid), is less potent and more hepatotoxic than ibuprofen  The stereochemistry associated with the chiral center in the arylpropionic acids, but lacking in the acetic acid derivatives, plays an important role in both the in vivo and in vitro activities of these drugs.  The (+)-enantiomer of ibuprofen possess greater activity in vitro than the (–)-isomer 4 TIP 2009 Gephart

 Ibuprofen is rapidly absorbed on oral administration, with peak plasma levels being generally attained within 2 hours and a duration of action of less than 6 hours.  Ibuprofen (pK a = 4.4) is extensively bound to plasma proteins (99%) and will interact with other acidic drugs that are protein bound. 5 TIP 2009 Gephart

 Metabolism occurs rapidly, and the drug is nearly completely excreted in the urine as unchanged drug and oxidative metabolites within 24 hours following administration.  Metabolism by CYP2C9 (90%) and CYP2C19 (10%) involves primarily ω -, and ω 1 -, and ω 2 -oxidation of the p-isobutyl side chain, followed by alcohol oxidation of the primary alcohol resulting from ω –oxidation to the corresponding carboxylic acid. 6 TIP 2009 Gephart

(Lemke, Williams, Roche, & Zito, 2008) 7 TIP 2009 Gephart

 When ibuprofen is administered as the individual enantiomers, the major metabolite isolated is the S-(+)-enantiomer whatever the configuration of the starting enantiomer. Interestingly, the R-(–)- enantiomer is inverted to the S-(+)- enantiomer in vivo via an acetyl–coenzyme A intermediate, accounting for the observation that the two enantiomers are bioequivalent in vivo. 8 TIP 2009 Gephart

 Non-aspirin NSAID’s are reversible inhibitors of COX. (unlike aspirin, which is an irreversible inhibitor).  All currently available OTC NSAIDs are nonselective COX inhibitors, and inhibit both COX-1 and COX-2 to varying degrees.  Anti-inflammatory actions of NSAID’s are related to their ability to inhibit COX-2. 9 TIP 2009 Gephart

 Side effects such as gastrointestinal (GI) bleeding and renal toxicity are a result of the inhibition of COX-1 and are well known complications of NSAID therapy.  By inhibiting COX-1, the NSAIDs prevent the formation of thromboxane from arachadonicacid, and thereby prevent thromboxane-induced platelet aggregation.  Aspirin has an irreversible anti-platelet effect, while other NSAIDs, including ibuprofen, have a reversible anti-platelet effect.  Concurrent use of aspirin and ibuprofen may change the pharmacodynamic effect of either drug depending on the timing of dosing of each drug. 10 TIP 2009 Gephart

 Analgesic  Anti-inflammatory  Reversible inhibitors of COX  Nonselective inhibitor of COX (adverse effects)  Analgesic ceiling 11 TIP 2009 Gephart

 Much of the text in this PowerPoint has been adapted from the following resources:  Lemke, T. L., Williams, D. A., Roche, V. F., & Zito, S. W. (2008). Foye's Principles of Medicinal Chemistry. Philadelphia: Wolters Kluwer.  U.S. FDA. (2006, September 8). New Information about Taking Ibuprofen and Aspirin Together. Retrieved February 13, 2009, from U.S. Food and Drug Administration: en/default.htm 12 TIP 2009 Gephart