Drug Metabolism

Question 1

Drug metabolism leads to formation of metabolites that are more _____________ than the parent compound but less _____________.

Answer 1

Drug metabolism leads to formation of metabolites that are more POLAR than the parent compound but less ACTIVE/INACTIVE

*Metabolites are occasionally more reactive than the parent compound

Question 2

Give an example of a drug that is NOT metabolized.

Answer 2

Aspirin is NOT metabolized. It can be excreted directly as the parent molecule.

Question 3

Give an example of a drug that is broken down and excreted.

Answer 3

Acetaminophen is broken down and excreted in the body.

Question 4

Give an example of a drug that has an active metabolite.

Answer 4

Codeine is a prodrug => inactive until metabolized.

Once metabolized codeine transforms into its active form—morphine.

Question 5

Give an example of a drug with rapid inactivation.

Answer 5

Succinylcholine is rapidly inactivated in the body. It provides brief but complete muscular relaxation during surgical anesthesia.

Question 6

What is the function of the xenobiotic metabolizing system?

Answer 6

The xenobiotic metabolizing system handles all environmental xenobiotics including toxins, drugs, carcinogens, fats, bilirubin, etc

Question 7

Describe the principle function of phase I xenobiotic metabolism.

Answer 7

Role:

• Render lipophilic molecules more polar/hydrophilic
• To provide function groups that can serve as a reactive substrate for Phase II metabolism

Reactions:

• Enzymatic oxidation, reduction, hydrolysis
  
  • Oxidation is by far the most common reaction

Question 8

Describe the main function of phase II xenobiotic metabolism.

Answer 8

Phase II xenobiotic metabolism principally involves conjugation of Phase I metabolites to large, polar molecules such as glucuronic acid, so that metabolites can be readily excreted by the body.

Question 9

What is the role of the cytochrome P450 family?

Answer 9

The cytochrome P450 family is a super family of genes that encode enzymes responsible for Phase II metabolism of xenobiotics.

• In general CYP families 1-4 encode enzymes that metabolize exogenous substrates (drugs)
• The remaining 16 families (20 total) encode enzymes that metabolize endogenous substrates (from the body).

Question 10

What are the most common isoforms of CYP and where are they expressed?

Answer 10

Most CYPs are expressed in the liver and the most common isoforms are CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 => metabolize 95% of drugs

• CYP 3A4 => most abundantly expressed and responsible for 60% of drug metabolism.

Question 11

What factors alter drug metabolism?

Answer 11

1) Previous exposures to chemicals can dramatically alter drug metabolism in patients
2) Diet, over the counter medications, dietary supplements etc..
- Dark leafy greens increase drug metabolism due to potent P450 inducers
- Grapefruit juice contains furanocoumarins that inhibit CYP3A4 metabolism of drugs
3) Acute or chronic use of one drug can dramatically alter metabolism of other drugs in a patient

Exhaustive list:

• genetics
• species differences
• sex differences / disease states
• other drugs (including EtOH), food, environmental factors
• age
• developmental stage
• plasma protein binding
• tissue-specific accumulation
• physiological barriers
• active transport across membranes

Question 12

___________ is the most common conjugation reaction of Phase II metabolism and is carried out by the liver enzyme __________

Answer 12

GLUCOURONIDATION is the most common conjugation reaction of Phase II metabolism and is carried out by the liver enzyme UDPLGT (uridine diphosphate glucuronyl transferase)

• There is very low UDPLGT activity at birth and it rises linearly until adulthood where it plateaus, but declines in older age (like the P450s)

Question 13

What is neonatal hyperbilirubinemia?

Answer 13

Neonatal hyperbilirubinemia is an inability of newborns (especially premature babies) to metabolize bilirubin to the bilirubin glucuronid conjugate via UDPLGT => leads to CNS damage.

*Caused by low glucouronidation

Question 14

What is “gray baby” syndrome?

Answer 14

Gray baby syndrome is caused by Chloramphenicol toxicity.

Chloramphenicol causes a deficiency in UDPLGT, leading to excessive free drug in the blood/tissues and drug associated toxicities.

*A low glucouronidation syndrome

Question 15

What is Crigler-Naijar syndrome?

Answer 15

Crigler-Naijar syndrome is a genetic deficiency in hepatic UDPLGT, which affects babies, causing jaundice and death in early childhood.

*A low glucouronidation syndrome

Question 16

What is the role of Beta- glucuronidase?

Answer 16

Beta- glucuronidase is present in the mucosa of the small intestine.

It hydrolyzes glucuronate conjugates, releasing free drug, which can be reabsorbed by the GI => leads to “enter hepatic circulation” of the drug, which prolongs retention time of drugs and their biological effects.

Question 17

How does N-acetylation conjugation represent human variation in drug metabolism?

Answer 17

N-acetylation conjugation is catalyzed by N-acetyltransferases => cytosolic in liver, kidney, lung, and intestine.

Humans are polymorphic for acetylation => fast and slow acetylators in the human population
- Slow acetylators => homozygous recessive; susceptible to dose dependent drug toxicities

• Slow acetylators are particularly susceptible to toxicities from isoniazid (TB), sulfamethazine (antibacterial), p-aminosalicyclic acid (TB), and hydralazine (high BP)

Question 18

What disease states affect drug metabolism (4)?

Answer 18

1) Radiation
2) Change in intestinal microflora
3) β-Glucuronidase in gut mucosa
4) hepatic drug metabolism is also impaired with certain disease states.
- Malaria
- Schistosomiasis
- Cancer (even if not in the liver itself)
- Hepatitis
- Jaundice
- Cirrhosis

Question 19

Why are the very old/young more sensitive to drugs/toxicants?

Answer 19

Major determinant in their increased sensitivity to drugs is a decreased rate of biotranformation:

1) Increased and/or slower absorption
- Lower CO => 30%
- Decreased blood flow => 40-50%
- Altered GI motility

2) Distribution
- Hypoalbuminemia => 20% decrease/ reduced synthesis
- Qualitative changes in drug binding sites
- Decreased relative muscle mass
- Increased percent body fat and total body water

Question 20

What factors specifically affect drug metabolism in just the elderly?

Answer 20

Factors affecting the elderly

• Metabolism => reduced hepatic enzyme activity, mass, and blood flow
• Excretion => reduced renal blood flow from decreased CO, glomerular flow rate, tubular secretory activity and number of nephrons
• Receptors => decrease in number, affinity, and qualitative responsiveness

Question 21

What are the major transporters in active transport across membranes?

Answer 21

1) P-glycoprotein (PgP/MDR1) are related ABC transporters (large multi-gene, multi-sub family: includes CFTR)
- Primarily transport parent molecules that are amphiphilic
- Transport large and diverse groups of structurally and functionally unrelated molecules out of cells

2) MRP: MPR and related ABC transporters are large multi-gene, multi-sub family , closely related to MDR proteins (see above)
- Primarily transport Phase II conjugates of drugs and/or conjugated drug metabolites
- Transports large and diverse group of molecules out of cells

Question 22

List Phase II conjugation reactions (4).

Answer 22

1) Sulfate conjugation
- Second to glucuronidation
- Catalyzed by sulfotransferases
2) Glutathione conjugation
- Glutathione-S-transferases (GSTs)
3) Methyl conjugattion
- Methyltransferases
- S-adenosylmethionine (SAM) as methyl donor.
4) Amino acid conjugation
- Glycine, glutamine