Pharmacokinetics: Genetic variability

Pharmacokinetics is the study of how a drug is affected by the body, which includes a drug’s absorption, distribution, metabolism and excretion. Differences in drug effects among patients may be influenced by genetic differences in patients’ ability to respond to a drug. There have been numerous enzymes identified as important to drug metabolism. Genetic polymorphisms have been identified for many of these drug-metabolizing enzymes, particularly, the cytochrome P450 enzymes. Several of the more common Cytochrome P450 enzmes are: CYP2C9, CYP2C19 and CYP2D6. Differing phenotypes have been associated with deficient, reduced, normal, or increased activity in these enzymes leading to variable drug responses.

CYP2C9 is involved in the metabolism of many common drugs such as glypizide, phenytoin and warfarin. Differences in enzyme active lead to phenotypes that are poor metabolizers have reduced warfarin clearance and are at increased risk of excessive anticoagulation.

Cytochrome P450 2C19 enzymes are involved in the metabolism of proton pump inhibitors and antidepressants. Omeprazole is a drug metabolized to CYP2C19 to its inactive metabolite. Patients who are CYP2C19 poor metabolizers can have five-fold higher blood concentrations of omeprazole resulting in higher acid suppression reflux “cure” rates. Conversely, rapid metabolizers may experience therapeutic failure at standard doses.

The presence of polymorphisms in drug metabolism is diverse and complex, and may account for 20-95% of patient variability in drug responses.

Cytochrome P450 2D6 is particularly important to anesthesiologists and pain physicians as it metabolizes codeine, tramadol, oxycodone, and hydrocodone to active metabolites. Thus, patients deficient in 2D6 (or patients taking a 2D6 inhibitor) will have less analgesia.