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8th Edition, September 27, 2012

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Active, Most Current

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ISBN: 978-1-84184-857-0
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Product Details:

  • Revision: 8th Edition, September 27, 2012
  • Published Date: September 27, 2012
  • Status: Active, Most Current
  • Document Language: English
  • Published By: CRC Press (CRC)
  • Page Count: 524
  • ANSI Approved: No
  • DoD Adopted: No

Description / Abstract:


Pharmacogenetics, Adverse Drug Reactions, and Personalized Medicine

Pharmacogenetics is the study of the role that inheritance plays in the individual variation in drug response. The response spectrum of a drug may range from life-threatening adverse drug reactions (ADRs) to inadequate therapeutic effects. For the clinician, this concept is relevant when asking why a drug is expectedly effi cacious in one segment of the population, ineffective for another, and toxic or even fatal for a third. Identifi cation of genetic variations that result in differences in drug bioavailability, biotransformation and, ultimately, clinical response is the key to the new era of "personalized medicine." Personalized medicine promises to deliver safer, more effective therapies to patients by down-playing the one-drug-fi ts-all theory, in exchange for recognizing the impact of a person's specifi c genetic make-up on the pharmacodynamics (PD) and pharmacokinetics (PK) of a specifi c drug, and integrating this information to develop a personalized therapeutic plan (1).

PK describes what the body does to a drug to make it available for use. A drug's PK properties are determined by genes that direct the disposition [absorption, distribution, metabolism, excretion (ADME)] of a drug in the body (2). Drug-metabolizing enzymes, specifi cally those of the cytochrome p450 family, and drug transporter proteins, such as P-glycoprotein (P-gp) transporters, play a key role in this process. These particular enzymes are governed by allelic variations within both similar and ethnically diverse populations. The most common functional consequence of these variations is concentration-related toxicity, either due to the accumulation of prodrug (consider an azathioprine patient with nonfunctional ThiopurineS-methyltransferase (TMPT) alleles will have debilitating myelosuppression) or increased, adverse clinical effect in rapid metabolizers (ultra-rapid codeine-converting mothers with a specifi c CYP2D6*2 × 2 allele can inadvertently kill their breastfed infants by overdosing them with the morphine endproduct).

PD describes what a drug does to the body, that is, the clinical impact. For example, variation in the intrinsic amount of VKORC1 gene product (vitamin K epoxide reductase) that an individual has will impact the effect that warfarin has on bleeding tendency. Certain alleles/haplotypes are more common in specifi c ethnic populations. Haplotype-specifi c guidelines have been published to determine the ideal starting dose to attain and maintain a therapeutic International Normalized Ratio (INR).

In children, we must consider not only differences in genotype, but to some degree, variation in gene expression during growth and development (3). Although TMPT enzyme activity is most likely present at birth, and CYP2D6 and CYP3A4 are acquired in the fi rst few weeks of life, delayed maturation of other drugmetabolizing enzymes can contribute to concentration-dependent toxicities, and altered concentrations of circulating plasma proteins can affect drug distribution (cephalosporins in neonates).