Pharmacokinetics - Lecture 2 Flashcards by Ari Strick

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

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Weak Acid Characteristics

WA takes ionized form as pH increases (more basic)

WA takes non-ionized form as pH decreases (more acidic)

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Weak Base Characteristics

WB favors ionized form as pH decreases (more acidic)

WB favors non-ionized form as pH increases (more basic)

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What is pKa?

50% ionized, 50% non-ionized

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Weak Acids Favors Non-Ionic or Ionic

Stomach = non-ionic
Intestine = ionic
Plasma = ionic

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Weak Bases favors Non-ionic or Ionic

Stomach = ionic
Intestine = ionic
Plasma = ionic

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For each pH unit from the pKa, this changes the N/I ratio by…

10 fold

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Is WA easily absorbed from stomach to plasma?

Yes

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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)

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Types of Carrier-Mediated Transport

Facilitated diffusion

Active transport

Receptor-mediated endocytosis

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Carrier-Mediated Transport

Proteins that bind to drugs to transfer across

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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

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What type of substrate specificity does carrier-mediated transport have?

Broad

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Facilitated Diffusion

Protein transporter (uniporter)
Energy independent
Bi-vectorial
SoLute Carrier transporters (SLC)

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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

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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 >>> 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