Drug Metabolism
- Mostly in the liver
- Some inside some cells. For example, in gut epithelial cells
- Increases water-solubility and therefore is more easily excreted by the kidneys
- Metabolite is usually (but not always) biologically INACTIVE
- Hepatic metabolism:
o Phase I
o Phase II
- Many drugs are lipophilic – kidney cannot excrete efficiently
Phase I and II metabolism
- Phase I and phase II metabolism are often sequential but not always
o Don’t need to have both phases together
- From the parent drug Phase I adds or exposes a
functional group.
o Make it polar and more water soluble
o Also tends to make the metabolite more
reactive, therefore phase I may make the
metabolite more toxic than original drug
- Phase II is also called conjugation
- Adds a substituent group through conjugation reaction, catalysed by transferase enzyme
- This again increases its water solubility and therefore higher chance of kidney excretion
- Key to notice difference between I and II is the transferase enzyme which is only in II
PHASE I METABOLISM
- Consists of hydrolysis, oxidation and reduction reactions
- Introduces or exposes polar groups
o increases water solubility of the metabolite (and therefore renal excretion)
o more chemically reactive, so can be more toxic
- Usually abolishes drug activity (unless pro-drug)
Examples of phase I metabolism
- Hydrolysis
o Esterases
o Amidases
- Oxidation
o Cytochrome P450 monooxygenase system
o Alcohol dehydrogenase
- Reduction
o NADPH-cytochrome P450 reductase
, Cytochrome P450 monooxygenase system
- Super-family of related enzymes
- Cyt P450 enzymes found embedded in the smooth endoplasmic reticulum
- Involved in production of cholesterol, steroid hormones and prostaglandins
o And detoxification of drugs
- Made in the liver
o Some made in the small intestine, lungs, placenta & kidney
- Three main groups involved in drug metabolism: CYP1, CYP2 & CYP3
- Examples:
o CYP1A2 (e.g. metabolism of paracetamol, caffeine, theophylline)
o CYP2C9 (e.g. metabolism of ibuprofen, warfarin)
o CYP2C19 (e.g. metabolism of omeprazole, phenytoin)
o CYP2D6 (e.g. metabolism of codeine)
o CYP3A4, CYP3A5 (e.g. metabolism of cyclosporin, nifedipine, simvastatin)
Importance of cytochrome P450
- Responsible for metabolism of 70-80% of drugs in clinical use
- Responsible for differences in drug pharmacokinetics and response
- Differences in drug metabolism by cytochrome P450 might be because of:
o Genetic polymorphism
o Inhibition
o Induction
Cytochrome P450 Genetic Polymorphism
- e.g. CYP2C9 there are 33 variants
- Polymorphism caused by variation in enzyme activity or in clinical response
- Can either be loss of function mutations (less metabolism), caused by:
o Decreased expression
o Gene deletion
- Or gain of function mutations (more metabolism), caused by:
o Gene duplication
o Change in protein-coding region of gene
Inhibitors and Inducers
- Inhibitors – prevents metabolism, results in more parent drug in the system
o Grapefruit juice
o Alcohol (acute)
o Sodium valproate (epilepsy)
o Omeprazole (proton-pump inhibitor)
o Erythromycin (antibiotic)
o Metronidazole (antibiotic)
- Inducers – results in more metabolism and more production of enzymes
o Cigarette smoke
o Alcohol (chronic)
o St John’s Wort (herbal remedy)
o Carbemazepine (epilepsy)
o Rifampicin (for TB)
- Mostly in the liver
- Some inside some cells. For example, in gut epithelial cells
- Increases water-solubility and therefore is more easily excreted by the kidneys
- Metabolite is usually (but not always) biologically INACTIVE
- Hepatic metabolism:
o Phase I
o Phase II
- Many drugs are lipophilic – kidney cannot excrete efficiently
Phase I and II metabolism
- Phase I and phase II metabolism are often sequential but not always
o Don’t need to have both phases together
- From the parent drug Phase I adds or exposes a
functional group.
o Make it polar and more water soluble
o Also tends to make the metabolite more
reactive, therefore phase I may make the
metabolite more toxic than original drug
- Phase II is also called conjugation
- Adds a substituent group through conjugation reaction, catalysed by transferase enzyme
- This again increases its water solubility and therefore higher chance of kidney excretion
- Key to notice difference between I and II is the transferase enzyme which is only in II
PHASE I METABOLISM
- Consists of hydrolysis, oxidation and reduction reactions
- Introduces or exposes polar groups
o increases water solubility of the metabolite (and therefore renal excretion)
o more chemically reactive, so can be more toxic
- Usually abolishes drug activity (unless pro-drug)
Examples of phase I metabolism
- Hydrolysis
o Esterases
o Amidases
- Oxidation
o Cytochrome P450 monooxygenase system
o Alcohol dehydrogenase
- Reduction
o NADPH-cytochrome P450 reductase
, Cytochrome P450 monooxygenase system
- Super-family of related enzymes
- Cyt P450 enzymes found embedded in the smooth endoplasmic reticulum
- Involved in production of cholesterol, steroid hormones and prostaglandins
o And detoxification of drugs
- Made in the liver
o Some made in the small intestine, lungs, placenta & kidney
- Three main groups involved in drug metabolism: CYP1, CYP2 & CYP3
- Examples:
o CYP1A2 (e.g. metabolism of paracetamol, caffeine, theophylline)
o CYP2C9 (e.g. metabolism of ibuprofen, warfarin)
o CYP2C19 (e.g. metabolism of omeprazole, phenytoin)
o CYP2D6 (e.g. metabolism of codeine)
o CYP3A4, CYP3A5 (e.g. metabolism of cyclosporin, nifedipine, simvastatin)
Importance of cytochrome P450
- Responsible for metabolism of 70-80% of drugs in clinical use
- Responsible for differences in drug pharmacokinetics and response
- Differences in drug metabolism by cytochrome P450 might be because of:
o Genetic polymorphism
o Inhibition
o Induction
Cytochrome P450 Genetic Polymorphism
- e.g. CYP2C9 there are 33 variants
- Polymorphism caused by variation in enzyme activity or in clinical response
- Can either be loss of function mutations (less metabolism), caused by:
o Decreased expression
o Gene deletion
- Or gain of function mutations (more metabolism), caused by:
o Gene duplication
o Change in protein-coding region of gene
Inhibitors and Inducers
- Inhibitors – prevents metabolism, results in more parent drug in the system
o Grapefruit juice
o Alcohol (acute)
o Sodium valproate (epilepsy)
o Omeprazole (proton-pump inhibitor)
o Erythromycin (antibiotic)
o Metronidazole (antibiotic)
- Inducers – results in more metabolism and more production of enzymes
o Cigarette smoke
o Alcohol (chronic)
o St John’s Wort (herbal remedy)
o Carbemazepine (epilepsy)
o Rifampicin (for TB)
