A4

Probably not, but very wide interpatient variability 2-3% of Caucasians 15-25% of Orientals 4% of Blacks 5-8% of Caucasians Lower in other races

Warfarin, propranolol, phenacetin, Fluvoxamine clozapine, theophylline, TCAs (desmethylation)

Diazepam, tolbutamide, phenytoin, TCAs (desmethylation)

Unknown

Codeine, dextromethorphan, haloperidol, thioridazine, perphenazine, nortriptyline, desipramine, fluoxetine, norfluoxetine, TCAs (hydroxylation), beta-blockers such as timolol and metoprolol, type 1C antiarrhythmics encainide, flecainide TCAs (desmethylation), triazolam, alprazolam, midazolam, carbamazepine, terfenadine, quinidine, lidocaine, erythromycin, cyclosporin

Fluvoxamine, fluoxetine, sertraline

Fluoxetine, paroxetine, sertraline, fluphenazine

Very likely all SSRIs

(norfluoxetine particularly), nefazodone, ketoconazole

Depending on whether the isoenzyme is absent or present, individuals are classified as extensive or poor metabolizers of the reference compound.

The clinical importance of genetic polymorphism depends on factors such as the health status of the patient and the concomitant administration of any drugs which might act as a substrate or inhibitor of a particular isoenzyme. For example, a depressed patient who metabolizes an SSRI (selective serotonin reuptake inhibitor) slowly will have higher plasma concentrations of that drug than another patient who metabolizes the drug at the normal rate. However, this is unlikely to be clinically significant given the high therapeutic index of the SSRIs. In contrast, TCAs have a low therapeutic index and the active metabolites of amitriptyline (nortriptyline) and imipramine (desipramine) are usually hydroxylated via the cyto-chrome P450 2D6 pathway. Slow metabolizers of desmethylated TCAs will experience TCA accumulation, which may result in potentially toxic cardiovascular effects. Conversely, patients who are fast metabolizers may experience subtherapeutic plasma drug concentrations.

Another factor which should be considered is the relative importance of the defective metabolic pathway in the overall metabolism of a drug. For example, paroxetine is metabolized by at least two pathways and the suboptimal activity of one enzyme has a relatively minor effect on the elimination of the drug. For the other SSRIs, the hepatic enzymes responsible for oxidization have not been clearly identified. However, these agents have a high affinity for the cytochrome P450 system and drug-drug interactions may be important under certain circumstances.

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