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  • Image not available. Hepatic elimination of drugs is primarily dependent on three variables: activity of metabolizing enzymes, plasma protein binding, and liver blood flow, each of which could be altered significantly in patients with liver diseases.
  • Image not available. Hepatic extraction ratio represents a conceptual measure of the efficiency of extraction of drug from the blood by the liver, and is not a measure of the metabolic capacity of the liver per se.
  • Image not available. Increased systemic bioavailability is primarily a concern for orally administered drugs that have a high hepatic extraction ratio.
  • Image not available. Both phase I and II enzymes have been associated with altered drug exposure.
  • Image not available. Evaluation of patient's liver function for assessment of need of dosage adjustment is difficult, with most clinicians opting for use of the Child-Pugh classification.
  • Image not available. Genetic polymorphisms affecting the drug metabolizing enzymes represent an additional patient-specific factor to consider in optimization of drug therapy.
  • Image not available. There are few examples of how metabolic genotypes or phenotypes can determine dosage of individual drugs.
  • Image not available. There have been increased attempts to incorporate pharmacogenetics in clinical studies during drug development and in regulatory review.

Upon completion of the chapter, the reader will be able to:

  • 1. List the three primary variables affecting hepatic elimination of drugs
  • 2. Discuss the concept of hepatic extraction ratio
  • 3. Determine, based on the extraction ratio, whether the hepatic clearance of a drug is limited by perfusion versus protein binding and intrinsic clearance
  • 4. Discuss the emerging role of the hepatic transporters in drug elimination
  • 5. Explain the role of the biliary tract in drug elimination
  • 6. Discuss the role of different liver function assessments in dosage regimen design
  • 7. Explain the impact of liver disease on drug bioavailability
  • 8. Explain the impact of liver disease on drug excretion via the kidneys
  • 9. List examples of how metabolic polymorphisms may impact drug efficacy and toxicity
  • 10. Discuss the difference between phenotype and genotype as it pertains to altered metabolic capacity
  • 11. Discuss the limitation of relying on a single genepolymorphism for optimization of drug therapy
  • 12. Discuss, using specific examples, the potential cost savings associated with the use of pharmacogenomic-guided dosing
  • 13. List the drugs that have revised labeling based on pharmacogenetic information
  • 14. Explain the controversy and challenges in applying pharmacogenetics to clinical practice
  • 15. List the tests currently available for testing genetic differences in metabolic capacities in patients

Although there are different patient-related variables that can change the pharmacokinetics of drugs and potentially require dosage regimen modification, the most common dosing changes likely occur with alterations in elimination capacity of the two primary eliminating organs, the liver and the kidneys. This chapter will focus on the changes in drug pharmacokinetics and pharmacodynamics resulting from altered hepatic drug metabolism in patients with hepatic dysfunction, and the implications for dosing. In addition, genetic changes in metabolic capacity of the patient also affect drug elimination from the liver, and examples of how pharmacogenetics have impacted dose modification and labeling ...

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