Elementary Drug Metabolism and Renal Excretion of Drugs

Question 1

What are the four processes influencing drug disposition?

Answer 1

Absorption
Distribution
Metabolism
Excretion

Question 2

How do most drugs leave the body, and in what form do they do this?

Answer 2

Most drugs leave the body in the urine, and they leave as unchanged (e.g. highly charged) or more usually as chemically transformed compounds rendered more polar by metabolism.

Excretion by the bile is occasionally significant.

Question 3

What does drug metabolism do to parent drugs?

Answer 3

Convert parent drugs to more polar metabolites that are not readily reabsorbed by the kidney (from the renal tubules), facilitating excretion

Question 4

What does drug metabolism do to drug metabolites?

Answer 4

Convert drugs to metabolites that are usually pharmacological less active than the parent compound.

Question 5

Less frequently metabolites may…?

Answer 5

Be converted from inactive prodrugs to active compounds (e.g. enalapril to enalaprilat), or gain activity (e.g. codeine to morphine)

have unchanged activity (e.g. diazepam to nordiazepam)

possess a different type, or spectrum, of action (e.g. aspirin [anti-inflammatory and antiplatelet activity] vs. its metabolite, salicylic acid, [anti-inflammatory, not antiplatelet activity])

Question 6

What is the main organ of drug metabolism?

Answer 6

Liver

But lungs, GI tract and plasma have some activity too

Question 7

What happens in phase 1 of drug metabolism?

Answer 7

Oxidation
Reduction
Hydrolysis

Makes drug more polar, adds a chemically reactive group (a ‘handle’) permitting conjugation (‘functionalization’)

Question 8

What happens in phase 2 of drug metabolism?

Answer 8

Conjugation

Adds an endogenous compound increasing polarity

Question 9

What does drug metabolism (phase 1 and 2 etc) produce?

Answer 9

Metabolites that are more polar than the parent drug

Question 10

What mediates oxidation reactions in phase 1 of many lipid soluble drugs?

Answer 10

Haem proteins in the ER of the liver hepatocytes

They comprise a ‘superfamily’ (74 gene families) – classified (on the basis of amino acid sequence similarities ) as CYP followed by a defining set of numbers and letters. CYP450 monooxygenases

e.g. CYP3A4

Question 11

What mediates glucuronidation in phase 2 reactions?

Answer 11

UDP-glucuronyl transferase

Question 12

Give an example of a slow and fast renal excretion drug?

Answer 12

Slow = diazepam 
Fast = penicillin

Question 13

What are the 3 basic processes involved in renal execution?

Answer 13

glomerular filtration
active tubular secretion
passive reabsorption by diffusion across the tubular epithelium

Question 14

Describe glomerular filtration of drugs?

Answer 14

Occurs freely for drugs that have a molecular weight less than 20000, provided they are not bound to a large plasma protein. The charge of the drug is unimportant.

Question 15

What type of molecules can enter the filtrate via glomerular filtration?

Answer 15

Only unbound drugs

Question 16

What percentage of renal plasma flow is filtered through glomerular and tubular?

Answer 16

20% by glomerular

80% by peritubular capillaries of the proximal tube

Question 17

What do the epithelial cells of the proximal tubule contain?

Answer 17

2 independent transporter systems that actively secrete drugs into the lumen of the nephron

Question 18

What are the two transporter systems called and what do they do?

Answer 18

Organic anion transporter (OAT) - handles acidic drugs (e.g. penicillins) endogenous acids (e.g uric acid) and the marker for renal plasma flow (i.e. para-aminohippuric acid; PAH)

Organic cation transporter (OCT) - Handles basic drugs (e.g. morphine)

Question 19

Drugs that are highly protein bound can be excreted by tubular secretion that is mediated by specific transporters that are saturable, true or false?

Answer 19

True

Question 20

What percentage of water filtered at the glomerulus is reabsorbed by the tubule?

Answer 20

99%

Question 21

Concentration of the urine favours/discourages passive reabsorption of drugs across the distal tubule by diffusion

Answer 21

Concentration of the urine favours passive reabsorption of drugs across the distal tubule by diffusion

Question 22

What are the factors influencing tubular reabsorption of drugs and their metabolites?

Answer 22

lipid solubility – drugs with high lipid solubility will be extensively reabsorbed and excreted slowly
polarity – highly polar drugs will be excreted without reabsorption
urinary flow rate – diuresis decreases reabsorption
urinary pH – the degree of ionisation of weak acids and bases can strongly influence their reabsorption
- Alkaline pH – increases excretion of acids
- Acidic pH - increases excretion of bases