Pharmacokinetics - Lecture 2 Flashcards
Calculation of non-ionized/ionized ratios for WA and WB drugs
Non-ionized/ionized (N/I) ratio
Administer drug (pKa) —> tissue with a certain pH environment
Each pH unit from the pKa —> changes the N/I ratio by 10 fold
Weak Acid Characteristics
WA takes ionized form as pH increases (more basic)
WA takes non-ionized form as pH decreases (more acidic)
Weak Base Characteristics
WB favors ionized form as pH decreases (more acidic)
WB favors non-ionized form as pH increases (more basic)
What is pKa?
50% ionized, 50% non-ionized
Weak Acids Favors Non-Ionic or Ionic
Stomach = non-ionic Intestine = ionic Plasma = ionic
Weak Bases favors Non-ionic or Ionic
Stomach = ionic Intestine = ionic Plasma = ionic
For each pH unit from the pKa, this changes the N/I ratio by…
10 fold
Is WA easily absorbed from stomach to plasma?
Yes
Is WB easily absorbed from stomach to plasma?
No! It stays in the stomach due to ability to move across the membrane (which is hard because WB favors ionic, but ionic can’t cross membrane easily)
Types of Carrier-Mediated Transport
Facilitated diffusion
Active transport
Receptor-mediated endocytosis
Carrier-Mediated Transport
Proteins that bind to drugs to transfer across
How many genes are in the human genome? How many encode for transporters or related proteins
~2,000 genes or 6-9% of the genome
What type of substrate specificity does carrier-mediated transport have?
Broad
Facilitated Diffusion
Protein transporter (uniporter)
Energy independent
Bi-vectorial
SoLute Carrier transporters (SLC)
Active Transport
Transport drug against concentration gradient
Energy dependent (ATP)
Saturable (finite #)
Broad specificity
Susceptible to competitive inhibition
Transport continues until drug or ATP is depleted or transporter inhibited
Two types of active transport transporters
Primary
Secondary
Primary active transporters
Associated with active transport
Energy machinery within transporter
ATP Binding Cassette (ABC) transporter family
Secondary active transporters
Associated with active transport
Energy is provided NOT within the transporter
Ion-coupled transports
- symporter: same direction as substrate
- antiporter: opposite direction as substrate
SLC transporter family (same as facilitated diffusion fam)
ABC Transporters in Drug Disposition
Primary active transporters that mediate vectorial transport out of cell
Multi-Drug Resistance (MDR) proteins
Resistance to cancer chemo agents
Broad specificity - organic cations and neutral drugs
Mult-Drug Resistance-associates Proteins (MRP)
Efflux transporter for organic anions, phase 2 metabolites
Drug metabolism and excretion
SLC Transporters in Drug Disposition
Organic Anion Transporter (OAT) family
Organic Cation Transporter (OCT) family
OAT Family
OAT 1 and OAT 3
Antiporters
Anions
Basolateral (blood side) of epithelial cells
OCT Family
OCT2
Uniporter
Organic cations
NT reuptake transporters
Transports excess NT back to nerve ending
NET - norepinephrine transport, Na+ symport
DET - dopamine transport, Na+ symport
SERT - serotonin transport, Na+ symport
- SSRIs
- antidepressants target SERT
Receptor-Mediated Endocytosis
Membrane pinches off and drug filled vesicle is transported into the cell
Requires energy, active transporter
Used for transport of large polypeptide and proteins
Why do most drugs target the GI tract?
Relatively safe
Passive diffusion of lipid soluble drugs
Not saturable
No energy required for absorption
Drug Properties that affect absorption
Lipophilicity- higher, better absorbed; lower, poorly absorbed
N/I ratios <0.001 are poorly absorbed
Drugs ionized at all pHs are poorly absorbed
Even highly ionized drugs (N/I <0.001) will eventually be absorbed to some extent. Why?
Relatively high SA
Highly vascularized
Absorption from small intestine»_space;> stomach due to low SA and thick mucosa layer in stomach
Buccal cavity and distal rectum drugs absorbed via…
Directly to systemic venous circulation
Drugs absorbed via stomach, intestine, or proximal rectum…
Capillaries and portal vein to liver for first pass metabolism and remaining drug is transported to hepatic vein and systemic circulation
Pre-absorption metabolism and significance
Mucosal delivered drugs are susceptible to degradation
Significance: affects bioavailability of drug that is to be absorbed
Drug Distribution
Drug concentration at the site of action determines pharmacological effect
Concentration and pharmacological effect of drug distribution is determined by:
Where the drug is distributed
When it attains therapeutic concentration
Factors that affect drug distribution
