8. Volume of Distribution (Vd)
Relates dose
administered to
concentration achieved
in the blood stream
Affected by changes in
blood flow, body
composition and protein
binding
Determines size of initial
or loading dose of a drug
to achieve a target
concentration
Lipophilic drugs generally
have large Vd
9. Clearance (Cl)
Volume of blood from which drug is removed over time
Represents the intrinsic ability of organs to eliminate drug from
blood
Determines the size of the daily maintenance dose required to
maintain a target concentration
10. Half-life
• Length of time required for concentration of drug in the
blood stream to be reduced to half of the original
concentration
• Assumes first order elimination-a constant proportion of
dose eliminated per unit of time
• Determines dosing interval
• Approximately five half-lives are required to reach steady-
state
12. First-Pass
Effect Drug is
biotransformed by
enzymes prior to
reaching systemic
circulation
Reduces
bioavailability
Sites
•GI tract
•Liver
•usually greatest
for drugs which
are extensively
and efficiently
metabolized
14. Absorption Factors
Physiologic Factors
Membrane
•Phospholipid bilayer
•Hydrophilic surfaces with lipophilic centers
•Surface area
Transport process
•Passive diffusion
•Facilitated diffusion
•Active transport
Physical/Chemical Properties of the Drug
Oil/water partition coefficient
•Lipophilic vs hydrophilic
•Ionization at pH of absorption site vs blood stream
•Unionized form absorbed
18. Properties of the GI tract
Stomach
Acidic
Limited surface area
Primary site for oral drug disintegration and
dissolution
Duodenum
Less acidic to neutral pH
Large surface area
Rich blood supply to maintain concentration
gradient
Primary site of oral drug absorption
20. Distribution Factors
Physiologic Factors
Blood flow
• Cardiac output
Body Composition
• Lean vs fat
Protein Binding
• alpha1 acid glycoprotein
• Albumin
Physical/Chemical Factors of Drug
O/W partition coefficient
• Lipophilic drugs
Degree of ionization
• pKa of drug vs pH of body
27. Hepatic
Metabolism
• Phase I
◦ Usually occur first and introduce or expose a functional group on
the drug molecule increasing polarity
◦ Include oxidation, reduction, hydrolysis
◦ Cytochrome P-450
◦ Inhibition
◦ Induction
• Phase II
◦ Conjugating reactions
◦ Glucuronide
◦ Entero-hepatic recycling
◦ Less affected by age, other chemicals
29. Excretion
Removal of intact drug
Non-volatile
Water soluble
Low molecular weight
No or slow biotransformation
Primarily accomplished by kidney
Blood flow
Nephron
30. Renal Excretion
• Glomerular Filtration
◦ Passive diffusion
◦ Limited by protein binding (large molecule)
◦ Driven by hydrostatic pressure
◦ Tubular Secretion
◦ Increases excretion
◦ Active process
◦ requires energy and carrier
◦ Two carrier systems
◦ Acids, Bases
◦ Reabsorption
◦ Reduces excretion
◦ Requires
◦ Unionized form
◦ Lipophilic
31.
32. Pharmacokinetic
Parameters
• Bioavailability
◦ Extent of drug absorption
◦ Limited by
◦ Disintegration and dissolution of drug from dosage form
◦ Absorption characteristics of drug
◦ Dosage form
◦ Route of administration
◦ Stability of active ingredient at absorption site
◦ Extent of biotransformation prior to reaching systemic
circulation
36. Cytochrome P450 System
Most important function is its ability to activate molecular oxygen
Increases aqueous solubility of the product for its transport and
excretion
Usually transforms in ways that
lead to detoxification
some cases may lead to cytotoxic,
mutagenic or carcinogenic properties
37. Cytochrome P450 Induction
Increases metabolism of other drug substrates
Reduces serum concentrations of those drugs
Reduces effect of parent drug
Produces more metabolites
• if active or toxic may cause toxicity
38. /
Cytochrome P450 Inhibition
Decreases metabolism of other drug substrates
Increases serum concentrations of those drugs
Increases effect of parent drug may cause toxicity
39. P-glycoprotein
Efflux pump in esophagus, stomach,
and small intestine that pumps drugs
back into the GI lumen
Think CYP450
More important factor in drug absorption than
intestinal CYP3A4
Most CYP3A4 substrates are also P-
glycoprotein substrates
Same with inducers/inhibitors
40. Pharmacogenetics
•CPIC creates freely available, peer-reviewed, evidence-based pharmacogenetic guidelines
•HOW available genetic test results should be used to optimize drug therapy
Clinical Pharmacogenetics
Implementation
Consortium (CPIC)
•The location pharmacogenetic commentary matters
•Most important: Boxed Warning
•Important: Dosage and Administration, Contraindications, Warnings and Precautions, Adverse Effects, Drug
Interactions
•Summary of pharmacogenetic information in drug labels: Pharmacogenomic Biomarkers in Drug Labeling
FDA: Drug Label
•Collects, curates, and disseminates knowledge about genetic variation on drug responses
•PharmGKB publishes evidenced-based pathways
•Includes a detailed pathway description
•Can be pharmacodynamic or pharmacokinetic
PharmGKB
42. Clopidogrel, Cont.
• Yes
CPIC guidelines available
• Bioactivates clopidogrel
Role of CYP2C19
• Ineffective clopidogrel therapy à myocardial infarction, stroke, or
death
Risk from this drug-gene
association
• CYP2C19 poor or intermediate metabolizers
Actionable phenotypes
• Consider alternative antiplatelet agent (i.e., prasugrel, ticagrelor)
Therapeutic options for
actionable phenotypes
43. CYP2C19 Information
Phenotype Frequency Genotypes Examples
Ultrarapid Metabolizer ~2-5% Has two increased function alleles *17/*17
Rapid Metabolizer ~2-30% Has one increased function allele and one normal
function allele
*1/*17
Normal Metabolizer ~35-50% Has two normal function alleles *1/*1
Intermediate Metabolizer ~18-45% Has one decreased function allele and either one
normal function allele or increased function allele
*1/*2, *1/*3, *2/*17
Poor Metabolizer ~2-15% Has two no function alleles *2/*2, *3/*3, *2/*3