Pharmacogenetics: What PAs need to understand and why by ProQuest

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                                GENOMICS IN PA PRACTICE
                                                              L AW R E N C E C A R E Y, P h a r m D



                                  Pharmacogenetics: What PAs need
                                  to understand and why
                he field of pharmacogenetics                 of our pharmacologic dilemmas. A                               due to a lack (or variant form) of

      T         changes on what seems to be
                a daily basis. The constant
      coming forward of groundbreaking
                                                             few of the drugs metabolized by the
                                                             CYP450 system are listed in Table 1.
                                                                Transport proteins Other genetic
                                                                                                                            some enzyme responsible for metab-
                                                                                                                            olism of that particular agent. This
                                                                                                                            can be seen in the metabolism of
      information underscores the need for                   influences exist. Drug-transport pro-                          6-mercaptopurine, in which a lack
      practicing PAs to have a fundamental                   teins, such as P-glycoprotein, may also                        of thiopurine methyltransferase may
      understanding of basic pharmacoge-                     affect drug response. P-glycoprotein                           result in toxicity requiring significant
      netic concepts. These concepts are not                 is one of the most recognized drug-                            dose reductions.
      entirely new; the idea of a pharmaco-                  transport proteins to exhibit genetic                            Adverse impact PAs must under-
      genetic influence was first explained in               polymorphism. In addition to acting                            stand the principles of pharmacogenetics
      the 1950s. However, with the advent                    as an efflux pump to get toxic sub-                            because of the possible adverse impact
      of newer drugs, as well as a better un-                stances out of cells, P-glycoprotein                           genes can have on patients’ response
      derstanding of existing drugs, pharma-                 has a role in the distribution of che-                         to medication. When a drug “fails” or
      cogenetics takes on greater importance                 motherapeutic agents, digoxin, cy-                             causes significant toxicity, most unre-
      as clinicians realize the impact it can                closporine, and protease inhibitors.                           sponsive patients (as well as the clini-
      have on patient care.                                  P-glycoprotein can also affect drug                            cians treating them) assume that the
         Cytochrome P-450 system We must                     absorption via its presence in the GI                          drug, acting as an isolated entity, is re-
      start at the beginning. A large part of                tract, hepatocytes, kidney, and blood-                         sponsible. In reality, this response may
      our current understanding of pharma-                   brain barrier. For instance, cellular                          be due to a patient-specific pharmacoge-
      cogenetics is centered on the cyto-                    overexpression of P-glycoprotein caus-                         netic issue rather than to the drug.
      chrome P-450 (CYP450) system, the                      es decreased absorption and increased                            The problems with impaired metab-
      major drug-metabolizing system of the                  efflux of certain therapeutic agents out                       olism are not limited to niche-area
      body. Genes responsible for encoding                   of cells, which may result in treatment                        drugs, such as chemotherapy agents;
      CYP enzymes are identified by the let-                 failure resulting from reduced activity                        we are seeing the results of impaired
      ters “CYP,” as are the enzymes them-                   of the drug. More important, underex-                          medication metabolism in the primary
      selves. CYPs are the major enzymes                     pression may cause significant toxicity                        care arena as well. Ethnicity has been
      involved in drug metabolism and bio-                   at normal doses; for example, over-                            shown to have a significant influence
      activation. They account for approxi-                  whelming toxicity that occurs with use                         on how certain medications are me-
      mately 75% of total drug metabolism                    of a chemotherapeutic agent may be                             tabolized. Certain ethnic groups have
      and are responsible 
								
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