Following the separate administration of the individual enantiomers of fluoxetine to experimental animals the duration of activity differs, (S)-

and (R)-fluoxetine acting for ~24 and ~8 hours respectively. Suggest possible reasons why this could occur. (S)- and (R)- fluoxetine are used for the treatment of depression and are selective serotonin uptake inhibitors that it inhibits the 5-HT receptors The duration of activity differs in (S)- and (R)- fluoxetine because of the way the molecules bind to the enzyme active site differs between enantiomers due to the difference of the special arrangements of chemical groups attached to chiral centre. Furthermore the difference of duration of activity between the (S)- and (R)- fluoxetine may be due the (S)fluoxetine binding more potently to plasma protein compared to (R)- fluoxetine, consequently the likelihood of (R)- fluoxetine reaching the liver and being metabolised in the liver by enzymes to its active for norfluoxetine increases. Moreover, CYP2D6 is a poor metaboliser of (R)- fluoxetine which, gets metabolised by several of CYP liver enzymes, thus the metabolism of (R)- fluoxetine takes place at a faster rate. (S)- and (R)- fluoxetine are metabolised to (S)- and (R)- norfluoxetine, these enantiomers share similar mode of actions with regards to the serotonin reuptake at the 5-HT receptor however (R)- fluoxetine is approximately 20 times less effective. The metabolism of fluoxetine is mediated by cytochrome P450 2D6 (CYP2D6). Why is it important to know that a drug is metabolised by this particular isoform of CYP? The CYP2D6 is an enzyme is that is part of the cytochrome P450 family of enzymes; CYP2D6 is involved in the oxidative metabolism of fluoxetine. Furthermore, the CYP2D6 shows a high number of genetic variations between individuals, consequently the metabolism of fluoxetine by the CYP2D6 enzyme may vary. Fluoxetine is a potent inhibitor of the CYP2D6 enzyme where it gets converted to the active substrate norfluoxetine. Some patients may be ultra metabolisers of fluoxetine and thus may experience exaggerated pharmacological responses whereas intermediate and poor metabolisers may experience weakened responses. This is because some patient may genetically predisposed to have less or no CYP2D6 enzyme production. The function and the drug metabolism action of CYP2D6 differ between medicines. For example, CYP2D6 is involved in the conversion of the pro-drug codeine into the active form morphine. Moreover, CYP2D6 is involved in the metabolism of nearly 20% of medicines available in clinical use, consequently it is important the metabolic pathway of fluoxetine to prevent drug toxicity in patients who are using other drugs that also get metabolised by CYP2D6. However, Research has shown that CYP2D6 is not susceptible to enzyme induction. Furthermore, some people may have a deficiency of the enzyme CYP2D6, therefore, the metabolism of the enzyme may not occur thus it may be dangerous to give them medications like fluoxetine, codeine and tamoxifen which are all metabolised in some by the CYP2D6 enzyme. This is because it may cause accumulation of the drug in the blood and tissue fluid, which can cause toxicity. http://www.pharmgkb.org/gene/PA128 http://www.pharmgkb.org/pathway/PA161749012