Lecture 10

Question 1

Excretion

Answer 1

• Removes a chemical from the body and prevents drug accumulation
• Liver and kidneys are the primary sites of excretion
• Metabolism, aka biotransformation, is important component of excretion since metabolites are usually charged, hydrophilic, and conjugated (larger)
• Metabolic changes alter the physicochemical properties of the drug and can make it more or less likely to be excreted

Question 2

Renal v.s. Biliary Secretion

Answer 2

• The one that occurs is a consequence of drug properties (ionization, adducts, etc.)
• Renal - excretion into urine, polar, glomerular filtration, active secretion, passive reabsorption/excretion
• Hepato/Biliary - excretion into bile (stable adducts), diffusion AND active transport

Question 3

Renal Drug Clearence

Answer 3

• Many can be excreted unchanged
• Clearance is proportional to renal function
• Metabolites MAY be excreted into urine

Question 4

Key Renal Excretion Mechanisms (3)

Answer 4

1. Glomerular Filtration - Bulk flow (remove)
2. Tubular Secretion - active transport (remove)
3. Tubular Reabsoprtion - passive reabsorption and active reabsoprtion

Question 5

Glomerular Filtration

Answer 5

• Non-selective, size limited
• Most “free” drugs are small enough to be filtered, MW cut off ~1000-2000
• Specialized pores/fenestrations and the size, shape, and charge affect the filtration
• Pressure gradient regulates filtration, very sensitive to blood pressure

Question 6

Tubule Secretion

Answer 6

• Diffusion AND active transport
• Passive diffusion utilized for small, uncharged molecules
• Active transport for large, ionized molecules allow for greater urine concentrations
• Depends on specific transport systems for acids or bases: transporters can be saturated, inhibited, require energy, or a specific carrier for a certain drug

Question 7

Tubule Reabsorption

Answer 7

• Mediated by passive diffusion
• The concentration gradient usually favor reabsorption
• Ionization of solutes, solute size, and solute liquid solubility may modulate passive reabsorption
• Passive reabsorption favors small, neutral, lipophilic molecules

Question 8

Renal Summary

Answer 8

• Renal elimination is a balance of transport between kidney tubules and plasma
• Multiple transport mechanisms (active and passive)
• Drug characteristics are important for renal elimination
• Slow decline in renal function (~1% per year) throughout adulthood occurs

Question 9

Hepato-Biliary Excretion

Answer 9

• Many drugs eliminated after hepatic metabolism
• Excretion is into bile which enters the feces
• Liver is optimized for drug metabolism and excretion
• About 5% of administered drug dose will enter bile passively and active secretion can increase this up to 95%

Question 10

General Pathway of Drug to Plasma to Bile

Answer 10

• Enters hepatocytes by passive diffusion or active transport from the plasma
• Drugs then transported to biliary epithelium by active secretory process
• Enterohepatic cycling then occurs where a drug is secreted into the bile and is reabsorbed from the intestine into the blood.

Question 11

Biliary Excretion

Answer 11

• Drugs enter hepatocytes actively or passively
• Hepatocytes secrete bile which flow to duaodenum for eleimination
• Conjugation from Phase II aids biliary excretion by increases the molecule’s polarity and molecular size
• Biliary excretion favors drugs with MW > 300
• Drug conjugates are not usually reabsorbed from the bile since they are poorly recognized by reuptake systems, too ionized, and too large
• Most drugs are excreted via the feces
• If reabsobed, enterohepatic cycles occur

Question 12

Other Routes of Secretion

Answer 12

• Milk - concerning for babies whose Phase I and II activity may not be fully developed until at least 6 years of age, sometimes later
• Lungs
• Intestines
• Sweat
• Saliva
• Other bodily fluids

Question 13

Drug Clearance

Answer 13

• Clearance is the decrease of drug in the bloodstream
• For most drugs, clearance is constant over the concentration range encountered in the clinical settings (1st order elimination)
• Total Clearance is an additive of the eliminations from all tissues

Question 14

Excretion Definition

Answer 14

Removal of drugs from the body

Question 15

Clearance Definition

Answer 15

The volume of plasma cleared of the drug per unit time.

Question 16

Glomerular Filtration Definition

Answer 16

Removal of drugs by bulk flow

Question 17

Tubular Secretion Definition

Answer 17

Active transport of drug from the blood into the urine

Question 18

Tubular Reabsorption Definition

Answer 18

Passive and active reabsorption of drug from tubules back into blood

Question 19

Enterohepatic Cycling Definition

Answer 19

Biliary excretion and intestinal reabsorption of a solute, sometimes with hepatic conjugation and intestinal deconjugation