pharmacogenomics - factors affecting drug action

Question 1

Describe the One Size Fits All concept of drugs

Answer 1

Most prescription & OTC drugs have a wide therapeutic margin
One-sizedose

• Simpletoprescribe
• Possiblywillwork
• Possiblywon’tbetoxic

Success rate in 50-70% range

Question 2

Describe Pharmacogenomic Information in Labeling

Answer 2

Pharmacogenomic information can include, but not limited to:

• Description of polymorphic enzymes
• Prevalence or frequencies of alleles, genotypes, haplotypes, or other genomic markers
• +/- predictive values of genomic marker (safety/efficacy)
• Effect of genotype on important PK parameters, such as clearance, half-life, and AUC

Changes in dose based on genotype

Question 3

Pharmacogenomics in Drug Labels

Answer 3

• Drug metabolizing enzymes
• Drug targets
• Drug toxicity

Question 4

What are Factors Affecting Absorption?

Answer 4

• IV compatibility and dilution problems
• chelators
• changes in gastric pH
• alterations in gastric emptying time
• alterations in GI transit time
• P-gp substrate

Question 5

Describe the changes in gastric pH wrt its decrease/increase

Answer 5

increase pH =>Antacids, H2 blockers, PPIs
decrease weak acid absorption, increase weak base absorption

decrease pH => infections will cause increase weak acid absorption and weak base absorption

Question 6

What can cause alterations in GI transit time?

Answer 6

• Laxatives, Narcotics (anti-diarrheal)

Question 7

What causes • Alterations in gastric emptying time?

Answer 7

• Gastrokinetic Agents (Metoclopramide)

Question 8

What is the role of P-gp Mutations?

Answer 8

Significantly influence plasma levels achieved with oral drug delivery

Question 9

Describe organic anion transporting polypeptides (OATP) Where are they expressed, action and polymorphism associated?

Answer 9

• expressed in sinusoidal membrane of hepatocytes
• mediate the active cellular influx of a variety of therapeutic drugs, such as statins
• The single nucleotide polymorphism (SNP) SLCO1B1 c. 521T>C has been associated with markedly increased plasma levels of simvastatin, rosuvastatin, pravastatin, and atorvastatin

Question 10

A majority of Phase I/II Drug Metabolism involve what?

Answer 10

CYP action

Question 11

What are 3 effects of Phase I/II Drug Metabolism to consider before prescribing them?

Answer 11

• Consequences vary by drug (in/active metabolites and new action/toxic metabolites)
• multiple gene copies
• polymorphisms in structure (varying substrate capacity)

Question 12

How are drugs distributed?

Answer 12

Plasma protein (albumin & α + β globulins)

Bound drug inactive but a reservoir

Question 13

Displacement wrt to distribution causes what?

Answer 13

increase in free drug

Question 14

Describe the CYP induction

Answer 14

decrease in substrate T^1/2

• DNA promotor leads to increase in mRNA therefore protein synthesis
• Concurrent drugs or environmental factors with alcohol and smoking inducing enzymes

Question 15

Describe CYP inhibition

Answer 15

increase substrate T^1/2

• Act at heme-iron center and/or lipophilic sites
• Usually competitive and reversible • Potency = Strong vs. Weak
• Not necessarily isozyme substrate • e.g. fluconazole; Diflucan
• Suicide inhibitors - long-lasting action • e.g. “micins” erythromycin