Ibuprofen Pharmacokinetics and Pharmacodynamics

Nurofen is a branded product manufactured by Reckitt Benckiser which contains the active constituent ibuprofen. (Royal Society of chemistry 2010). Nurofen has become a worldwide over the counter power brand for mild to moderate pain and is available in a variety of formulations, with the focus of this essay being the standard nurofen tablets which contain 200mg of ibuprofen. Ibuprofen, also known as: (2RS)-2-[4-(2-Methylpropyl]propanoic acid is a non steroidal anti-inflammatory drug (NSAID) which was initially patented in the UK by the Boots company in the 1960s before developing into an over the counter drug in the 1980s(ROYAL SOCIETY OF CHEMISTRY 2010); It is now one of the most widely used and efficient over the counter drugs with antipyretic, analgesic and anti-inflammatory effects (RANG et.al 2007). The aim of the following review essay is to incorporate and summarise some of the vast amount of literature produced from the studies of ibuprofen to look at the mode of administration, absorption, mechanism of action and elimination of the active constituent (Ibuprofen) in Nurofen.

Ibuprofen has three primary effects on the human body; firstly it has an anti-inflammatory effect in that it is able to bring about an alteration of the inflammatory reaction in order to reduce swelling and blood flow. Secondly ibuprofen has an analgesic effect in that it is able to reduce the sensation of pain by inhibiting pain signalling chemicals which reach the brain. Finally it has a antipyretic effect as it has the ability to reduce body temperature, the mechanism by which ibuprofen initiates these responses will be discussed further into the essay (RANG et al 2007) Due to these three effects ibuprofen has a wide therapeutic window and has become a very useful medicine for effective pain management across many conditions such as: dental pain, muscular pain, menstrual pain, headaches and back pain just to list a few (RAINSFORD 1999). In particular Ibuprofen, in higher doses, has been found to have effective pain management and reduction of joint swelling in chronic arthritic conditions as ibuprofen accumulates in joints that are inflamed; The analgesic action of ibuprofen is also reinforced by its ability to penetrate and remain within the CNS as its un bound free form and hence it is available in sites of the body where anti-inflammatory and analgesic responses are required. (RAINSFORD 2009)

Standard 200mg Nurofen is administered orally as a tablet with standard daily doses being up to 1200mg daily. Standard Nurofen contains ibuprofen acid as opposed to other brands of Nurofen such as Nurofen express which contains sodium formulations of ibuprofen that dissolves faster in the stomach, enhancing its bioavailability (DEWLAND 2009). The Ibuprofen present Nurofen in administered as a racemic or diasteroisomeric mixture which means that it exists as two non super imposable optical isomers (ROYAL SOCIETY OF CHEMISTY 2010), this includes the S(+) enantiomer which is the active form involved in the inhibition of prostaglandin synthesis and the R(-) enantiomer which has no known effect on prostaglandin synthesis inhibition but is thought to have anti-inflammatory actions (RAINSFORD 2009). 40-60% of the R(-) form is converted to the active S(+) form which occurs in the liver, intestine and adipose tissue commencing oral administration (RAINSFORD 1999). Therefore in a standard dose of 200mg, only 100 mg would be the active pharmaceutical component s (+) ibuprofen, despite this 60% of the S(-) enantiomer is metabolically converted to the S(+) form resulting in a total of 160mg of the S(+) enantiomer. Standard Nurofen tablets are made up of a core and a coat, as well as the active constituent the tablet contains many compounds, shown by figure 3, in order to give satisfactory taste and also to bulk up the tablet as the dose of ibuprofen required for a therapeutic effect is very small amount and would therfore be difficult to handle (ROYAL SOCIETY OF CHEMISTRY).

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Ibuprofen is a weak acid and consequently is protonated in the acidic conditions of the stomach which facilitates passage across the mucosa and generally rapid absorption in the upper GI tract (RANG et.al 2007) most absorption takes place in the small intestine due to the extensive surface area of the microvilli shown as a graphical representation in figure 3; it is then transported in bulk flow via the blood stream (RAINSFORD 2009). Peak values for the R(-) and S(+) enantiomers in the plasma and serum being achieved within 1-2hours (RAINSFORD 2009). It has almost complete bioavailability shown by Cheng et.al (1994) who administered the same doses of ibuprofen and concluded the absolute bioavaliablilities to be 83% for the R(-)

Ibuprofen has a pKa of 4.4

Ibuprofen is almost fully bound (99%) to purified albumin and plasma at therapeutic concentrations.(DAVIES 1998). It is suggested that tissue binding is a lot less represented by the fact that the distribution volume (Vd/F) calculated after oral administration was between 6.37 and 23.5L which equates to 0.1 to 0.2 L/Kg, the low distribution volume is due to the ibuprofen being extensively bound to plasma proteins (DAVIES 1998). The binding interaction site for ibuprofen has been found to be at site two at serum albumin with the association constant for the binding of ibuprofen being 106 M-1 (DAVIES 1998). More recent studies by ASCENZI et.al has proposed the idea that ibuprofen binds to three independant sites on human serum heme albumin shown in figure 2, however this is still under investigation. The distribution of ibuprofen with patients suffering from rheumatoid arthritis has resulted in proposed site of action being the synovial fluid with theories suggesting that ibuprofen enters the synovial cavity in an unbound form in contrast to diffusion out of the synovial fluid possibly involving protein-bound ibuprofen (DAVIES 1998). DAY et.al (1988) found that the tmax for plasma was shorter than in synovial fluid however the binding or ibuprofen to protein is greater in plasma due to the lower concentrations of albumin in synovial fluid. Through investigations into the distribution of the drug, ibuprofen has also been found in the cerebrospinal fluid in response to the involvement that the CNS in the analgesic and antipyretic effects of NSAIDs (RAINSFORD 1999).

A bond would usually form between carbon 8 and 12 to form a 5 membered ring of prostaglandin but ibuprofen inhibits this conversion. The primary pharmacodynamic action of ibuprofen in the control acute pain, inflammation via binding to the active site and inhibiting fatty acid enzymes COX-1 and COX-2 which convert arachidonic acid into prostaglandins, shown in figure 4 and so hence the inhibition of prostaglandins which are involved in bringing about an inflammatory response and attach to nerve endings, sending pain messages to the brain(THE ROYAL SOCIETY OF CHEMISTRY 2010). Ibuprofen is a non selective cyclooxgenase inhibitor and so it inhibits both COX 1 and COX 2 (DEWLAND 2009). COX 1 is an enzyme that is expressed in the majority of tissues and plays an important role in many vital processes of the human body such as homeostasis, platelet aggregation, renal blood flow auto regulation and the production of prostaglandins to name a few (RANG et.al 2007). COX-2 enzyme is involved the inflammatory response, it becomes activated in inflammation cells and the isoform of this enzyme is responsible for the production of prostanoid mediators of inflammation (RANG et.al 2007). Ibuprofen is able to inhibit these enzymes by entering and attaching to the hydrophobic channel of COX enzymes and forming hydrogen bonds at position 120 with arginine residues and hence preventing arachidonic acid from entering the catalytic domain (RANG et.al 2007) This mechanism also leads to a antipyretic pharmalogical action which is achieved via the inhibition of E-type prostaglandins (PGE2) in the preoptic region of the hypothalamus which is located in the base of the brain; pyrogens such as lytic products and bacterial lipopolysaccarides produced from leucocyes activate the production of COX2 derived PGE2, Ibuprofen inhibits COX2 and hence causes a antipyretic effect (RAINSFORD 2009). Ibuprofen is also able to reduce inflammation as COX 2 enzymes are involved in vasodilatation and oedema and ibuprofen is able to inhibit these enzymes and hence suppressing the pain, swelling an increased blood flow associated with inflammation figure 3 shows the inflammatory activity of R(-) and S(+) ibuprofen; In addition to this STUHLMEIER 1998 investigated the hypothesis that the ability of ibuprofen in blocking cyclooxygenase was not the only mechanism of action, this journal proved that ibuprofen inhibits the translocation and activation of NF-kB, which is a transcription factor central to inflammation reactions by resulting in the up regulation of many genes involved in inflammation, into the nucleus by stabilising the NF’kB/IkBα complex in the cytoplasm (STUHLMEIER 1998).

Metabolism of ibuprofen occurs rapidly in the liver, intestine and adipose tissue commencing oral administration via the invesion of R(-) ibuprofen to S(+) ibuprofen (RAINSFORD 1999); this inversion is caused by activation of R (-) ibuprofen with ATP Mg to form an AMP-derivative which then goes onto be esterified with coenzyme A via the catalysis of acyl-CoA syntetase. The R ibuprofen CoA is then involved in epimerization to form S-ibuprofen CoA and finally is hydrolysed via the catalysis of a hydrolase enzyme to form S-ibuprofen (RAINSFORD 2009). Ibuprofen is not excreted as an unchanged molecule from the human body it is achieved via oxidative drug metabolism (RAINSFORD 1999). Phase one metabolism of ibuprofen including the R (-) and s(+) enatiomers involves isobutyl chains being hydrolysed to 2 or 3-hydroxy derivatives which is followed by oxidation to 3-carboxy-ibuprofen and p-carboxy-2-proprionate via the catalysis of the enzymes cytochromes P450 2C9 (CYP-2C9) and CYP-2C8. Phase one metabolism is then followed by phase two where phenolic and acyl glucuronides are formed in addition to a minor route of conjugation with taurine, this is stereospecific to the S(+) enantiomer as a consequence of the formation of thioester CoA (RAINSFORD 2009). Ibuprofen is metabolised rapidly after oral administration and then is excreted by the kidneys and eliminated in the urine as mainly metabolites and less than 1% being unchanged ibuprofen and 14% as conjugated ibuprofen (MICROMEDEX 2010); Due to Ibuprofen being a weak acid it is actively secreted in the renal tubule and consequently is more rapidly secreted (RANG et.al). Ibuprofen is more rapidly excreted in alkaline urine the high Ph within the tubule promotes ionisation and inhibits reabsorption. The elimination process takes less than 24 hours, the remainder of the drug is excreted in the stool as both unmetabolised and unabsorbed ibuprofen (FDA).Ibuprofen also has a plasma half life of roughly two hours showing that it has a very rapid elimination time.