L2: Metabolism and time course of drugs

Question 1

What is the major site of drug metabolism?

Answer 1

The liver is the major site of drug metabolism but other organs can also metabolize drugs e.g. kidneys, lungs, and adrenal glands.

Question 2

What must happen to lipids to be excreted?

Answer 2

Many lipid-soluble drugs must be converted into a water-soluble form (polar) to be excreted. However, Some drugs are not metabolized at all and excreted unchanged (hard drugs).

Question 3

What does the metabolism of drugs lead to?

Answer 3

Metabolism of drugs may lead to:
1) Conversion of the active drug into inactive metabolites → termination of drug effect.

2) Conversion of the active drug into active metabolites → prolongation of drug effect e.g. codeine (active drug) is metabolized to morphine (active product).
3) Conversion of the inactive drug into active metabolites (prodrugs) e.g. enalapril (inactive drug) is metabolized to enalaprilat (active metabolite).
4) Conversion of non-toxic drugs into toxic metabolites (e.g. paracetamol is converted into the toxic product N-acetylbenzoquinone).

Question 4

What are the reactions that the drug may undergo to be metabolized?

Answer 4

Phase I reactions

Phase II reactions

Question 5

What happens if the drug is not liable to conversion into water-soluble by phase I?

Answer 5

it must enter phase Il to increase solubility and enhance elimination.

Question 6

What are the processes included in phase I reactions?

Answer 6

oxidation, reduction, and hydrolysis.

Question 7

What are the enzymes catalyzing phase I reactions?

Answer 7

cytochrome P450, aldehyde and alcohol dehydrogenase, deaminases, esterases, amidases, and epoxide hydratases.

Question 8

What is the set of enzymes that is responsible for the majority of phase I reactions? And where is it present?

Answer 8

cytochrome P450 (CYP450) enzyme system located primarily inside membranous vesicles (microsomes) on the surface of the smooth endoplasmic reticulum of parenchymal liver cells.

Question 9

What are other sites of CYP450 activity?

Answer 9

kidney, testis, ovaries, and GIT.

Question 10

What is a source of variability of drug metabolism in humans?

Answer 10

Genetic polymorphism of medically important CYP450 enzymes.

Question 11

Are drugs metabolized by one CYP450 Enzyme or many CYP450 enzymes?

Answer 11

Drugs may be metabolized by only one CYP450 enzyme (e.g. metoprolol by
CYP2D6) or by multiple enzymes (e.g. warfarin).

Question 12

Is microsomal oxidation induced by certain drugs and environmental substances?

Answer 12

Yes, Some drugs and environmental substances can induce (increase activity) or inhibit certain CYP450 enzymes leading to significant drug interactions.

Question 13

Is non-microsomal oxidation induced by certain drugs and environmental substances?

Answer 13

No, only microsomal oxidation is affected

Question 14

What are examples of non-microsomal oxidation?

Answer 14

xanthine oxidase (converts xanthine to uric acid)

monoamine oxidase (MAO) (oxidizes catecholamines and serotonin).

Question 15

Microsomal enzyme induction

Answer 15

• Microsomal inducers increase the rate of metabolism of some drugs leading to a decrease in their serum levels and therapeutic failure.
• Induction usually requires prolonged exposure to the inducing drug

Question 16

What are examples of inducing agents?

Answer 16

phenytoin, rifampicin, phenobarbitone, carbamazepine,

smoking, chronic alcohol intake, St John’s Wort,

Question 17

What are clinical examples of microsomal enzyme induction?

Answer 17

• Rifampicin accelerates the metabolism of contraceptive pills leading to the failure of contraception.
• Phenytoin accelerates the metabolism of cyclosporine-A leading to graft rejection.

Question 18

What are examples of inhibiting agents?

Answer 18

macrolide antibiotics (e.g. erythromycin), ciprofloxacin, cimetidine, ketoconazole, ritonavir, grapefruit juice.

Question 19

What are clinical examples of microsomal enzyme inhibition?

Answer 19

• Ciprofloxacin inhibits the metabolism of warfarin (anticoagulant) leading to the accumulation of warfarin and bleeding.
• Erythromycin inhibits the metabolism of theophylline leading to toxicity of theophylline (cardiac arrhythmia).

Question 20

What is the concept of Phase II reactions?

Answer 20

It involves the coupling of a drug or its metabolite to a water-soluble substrate (usually glucuronic acid) to form a water-soluble conjugate.

Question 21

What is the set of enzymes that is responsible for the majority of phase II reactions?

Answer 21

Glucuronyl transferase

Question 22

Where is the set of glucoronyl transferase enzymes present?

Answer 22

This set of enzymes is also located inside liver microsomes and is the only phase Il reaction that is inducible by drugs and is a possible site of drug interactions e.g:  phenobarbital induces glucuronidation of thyroid hormone and reduces their
plasma levels.

Question 23

What is the role of intestinal bacteria in the prolongation of the duration of some drugs?

Answer 23

Some glucuronide conjugates secreted in bile can be hydrolyzed by intestinal bacteria and the free drug can be reabsorbed again (enterohepatic circulation), this can extend the action of some drugs.

Question 24

What are other examples of non-glucuronide conjugation reactions?

Answer 24

sulphate conjugation (steroids), 
glycine conjugation (salicylic acid),
glutathione conjugation (ethacrynic acid).

Question 25

How are contraceptive pills metabolized? And what is the role of intestinal bacteria in this?

Answer 25

Contraceptive pills contain estrogen, which is metabolized by glucuronide conjugation and excreted in bile as a conjugate, Intestinal bacteria hydrolyze this conjugate to form free estrogen again which is reabsorbed and attain a long duration of action (so contraceptive pills are given once daily).

Question 26

What happens if a woman took contraceptive pills with broad-spectrum antibiotics (kills the intestinal bacteria)?

Answer 26

estrogen will lose its long duration of action and pregnancy can occur.

Question 27

What is the definition of first-pass metabolism?

Answer 27

metabolism of drugs at the site of administration before reaching systemic circulation e.g. the liver after oral administration, the lung after inhalation, the skin after topical administration, etc.

Question 28

Examples of hepatic first-pass metabolism for different drugs.

Answer 28

 Complete: lidocaine.
 Partial: propranolol, morphine, nitroglycerine
 None: atenolol and mononitrates

Question 29

How to avoid hepatic first-pass metabolism?

Answer 29

• By increasing the dose of the drug.

- By giving the drug through other routes e.g. sublingual, inhalation, or i.v.

Question 30

What is the definition of bioavailability?

Answer 30

 it is the fraction of the drug that becomes available for systemic effect after administration, The bioavailability of drugs given i.v. is 100%

Question 31

What are the factors that affect bioavailability?

Answer 31

 Factors affecting absorption.
 Factors affecting metabolism.
 First-pass metabolism.