L6 - Drug Metabolism and Renal Excretion

Question 1

How can drug leave the body?

Answer 1

Mainly by urine, bile secretion can be significant sometimes, minor contributions by sweat and milk

Question 2

Xenobiotics

Answer 2

Foreign Chemicals

Question 3

Where are drugs metabolised?

Answer 3

Majority by the liver, although it can also occur in GI tract, lungs, and plasma

Question 4

What is the purpose of drug metabolism, molecularly?

Answer 4

Convert parent drugs into more polar metabolites, that are therefore less lipid soluble, so rate of elimination can increase

Question 5

Example of a drug which is converted to another form which is more/same/less active?

Answer 5

Codeine to Morphine (increase in activity) - CYP2D6

Diazepam to Nordiazepam (no change)

Question 6

Phase I Metabolism

Answer 6

Oxidation, reduction, hydrolysis (catabolic)

Question 7

Phase II Metabolism

Answer 7

Conjucation with glucuronyl, suphate, methyl, acetate (anabolic)

Question 8

Metabolism of Aspirin

Answer 8

Aspirin 
*Deacetylation*
Salicylic Acid
*glucuronidation*
Glucuronide

Question 9

Glucuronidation

Answer 9

Completed by UDP-glucuronyl transferase

Transfer of glucuronic acid component of UDP-glucuronic acid to substrate

Question 10

Cytochrome P450

Answer 10

Phase I enzyme
Monooxygenases, haem proteins located in ER of hepatocytes
Superfamily of 74 gene families

1. Drugs enter cycle with R-H group (where R is just rest of drug molecule)
2. O2 provides 2 O for the reaction
3. One O added to drug to yield R-OH, other O combines with 2H+ to make H2O

Question 11

UDP-Glucuronyl Transferase

Answer 11

Phase II Enzyme

UDP-glucuronic acid, glucuronic acid group, conjugated to reactive group (such as OH, SH, NH2)

Question 12

Glomerular Filtration of Drugs

Answer 12

Occurs freely for drugs with MW < 20,000 (few exceed this)

Occurs only to unbound drugs in plasma

Question 13

Tubular Secretion

Answer 13

Up to 20% of renal plasma actually flows through a glomerulus, remaining 80% is delivered to proximal tubule by peritubular capillaries
Drugs transported by:
Organic Anion Transporter (OAT)
Organic Cation Transported (OCT)
In proximal tubule epithelial cells - competition can occur

Question 14

Tubular Reabsorption

Answer 14

Influenced by:
Lipid solubility - highly lipid soluble drugs difficult to excrete and they are reabsorped
Polarity - highly polar drugs excreted without reabsorption
Urinary Flow Rate - diuresis decreases resabsorption
Urinary pH - ionisation can influence absorption, pH > 7 causes increased excretion of acids, pH < 7 causes increased excretion of bases