Session III of TIP

1TIP 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 1974.

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.

2TIP 2009 Gephart

Figure 1: Structures of

aryl- and

heteroarylpropionic acid

derivatives. (Lemke,

Williams, Roche, & Zito,

2008)

3TIP 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

4TIP 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 (pKa = 4.4) is extensively

bound to plasma proteins (99%) and will

interact with other acidic drugs that are

protein bound.

5TIP 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 ω1-, and ω2-oxidation of the p-isobutyl side chain, followed by alcohol oxidation of the primary alcohol resulting from ω–oxidation to the corresponding carboxylic acid.

6TIP 2009 Gephart

(Lemke,

Williams,

Roche, & Zito,

2008)

7TIP 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.

8TIP 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.

9TIP 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.

10TIP 2009 Gephart

Analgesic

Anti-inflammatory

Reversible

inhibitors of COX

Nonselective

inhibitor of COX

(adverse effects)

Analgesic ceiling

11TIP 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: http://www.fda.gov/cder/drug/infopage/ibuprofen/default.htm

12TIP 2009 Gephart