Pharmacokinetics II

Question 1

What is the purpose of metabolism (biotransformation)?

Answer 1

• decrease lipid solubility (i.e., make a drug more water soluble)
• increase ionization

Question 2

What event is caused by biotransformation?

Answer 2

increased body excretion

Question 2

What are three mechanisms/purposes of biotransformation?

Answer 2

• lipophilic –> hydrophilic
• active drug –> metabolite
  (metabolites can act as an active drug, active toxicant, or be inactive)
• pro-drug –> active drug

Question 3

How does metabolism occur?

Answer 3

Phase I
- reactions include oxidation (CYP 450), reduction, deamination, and hydrolysis

Phase II
- reactions that involve addition (i.e., conjugation) of subgroups to -OH, -NH2, and -SH functional groups on a drug molecule

Question 4

What is biotransformation?

Answer 4

• process by which chemicals (drugs) are modified by the organism
• usually occurs by enzymatic reaction
• present for endogenous as well as exogenous substrates (vitamins, steroids, hormones, drugs, etc.)

Question 5

What are three mechanisms of metabolism (alteration of drug)?

Answer 5

• lipophilic to hydrophilic
• first pass effect (oral administration)
• cytochrome P450

Question 6

Why is biotransformation necessary?

Answer 6

If no biotransformation, drugs/substances will stay in body for much longer; biotransformation can eliminate them from the body in hours

Question 7

How does the first-pass effect, and subsequent liver passes, affect a drug?

Answer 7

the drug passes through the liver several times, more and more gets metabolized and eventually eliminated

Question 8

What is path of blood circulation (first-pass)?

Answer 8

Oral administration –> GI Tract –> absorbed into portal vein –> Liver –> Hepatic Vein –> heart –> aorta:

–>hepatic artery –> liver –>….
or
–> i) celiac artery; ii) superior & inferior mesenteric arteries –> GI Tract –>….

Question 9

What is the importance of biotransformation?

Answer 9

• a key determinate of therapeutic half-life
• may produce “active metabolite”
• site of “drug-drug interaction” (drugs can increase half life of another drug/increase metabolism, inhibit other drugs, etc.)
• produces toxic metabolites for intermediates

Question 10

What are the results of biotransformation?

Answer 10

• stops pharmacological effect (of parent drug); with the exception of production of an active metabolite
• restricts distribution (remains in plasma, filtered by kidney)
• facilitates excretion

Question 11

What are the key organs involved in biotransformation - high capacity?

Answer 11

liver

Question 12

What are the key organs involved in biotransformation - medium capacity?

Answer 12

intestine, lung, kidneys

Question 13

What are the key organs involved in biotransformation - low capacity?

Answer 13

skin, testis, placenta, adrenals

*not that significant relative to liver

Question 14

Is the brain involved in biotransformation?

Answer 14

functional activity of enzymes for metabolism in brain is not clear right now - don’t know much

Question 15

Biotransformation can make a drug more hydrophilic, what is the result of this?

Answer 15

because it becomes hydrophilic, it does not cross biologic membranes very well, so stays in kidney and is excreted in the urine