Drug metabolism Flashcards
Why do we need drug metabolism?
- Drugs tend to be lipophilic
- Must be metabolised to become more water soluble - excreted easily
- Metabolism tends to eliminate or reduce pharmacological and toxiocological activity
What is the major organ for drug metabolism?
Liver
What organs are involved in drug metabolism?
LIVER Gut Kidneys Skin Brain
What is hepatic first pass metabolism?
Metabolic conversion of drug into something different before drug enters general circulation
How can you combat the low bioavailability of a drug that undergoes extensive first pass metabolism?
IV admin
Why can first pass metabolism be pre-hepatic?
Intestines, stomach, oesophagus and buccal cavity have a small amount of metabolic capacity
What types of metabolic change are involved in phase I metabolism?
Oxidation
Reduction
Hydrolysis
What types of metabolic change are involved in phase II metabolism?
Glucuronidation Acetylation Amino acid conjugation Sulphation Methylation Glutathione conjugation
What is the role of phase I reactions?
- Oxidation/reduction introduce new FGs
- Hydrolysis unmasks FGs
- These FGs serve as a point of attachment for phase II reactions
- Often inactivate drugs but can also activate prodrugs
- Sometimes produce toxic metabolites
What is the cytochrome p450 enzyme system?
- Main system involved in phase I oxidising reactions
- Involved in metabolism of most drugs + endogenous compounds
- Humans - 57 enzymes
How can some drugs affect CYP450?
- Drugs can inhibit or induce CYP450
- Bad because changes ability of system to handle certain drugs
Where is CYP450 predominantly found?
Liver
Describe the basic reaction of CYP450
RH + NADPH + O2 + H+ —-> ROH (oxidised drug) + NADP+ + H20
Any aqueous environment has source of protons
Oxidation reactions involve a hydroxylation step catalysed by P450
What is N-demethylation?
- Oxidation of methyl group in nitrogen environment (N-methyl group)
- Very effective way of removing pharmacological activity
What is O-demethylation
Oxidation of O-methyl group by C450
What is N-oxidation?
- Generation of an amine oxide (oxide of tertiary amines)
- Enzyme = flavin containing monooxygenase
What is the medical relevance of flavin containing monooxygenase?
FCMO deficiency (fish odour syndrome):
- Humans generate trimethylamine in GIT (product of protein metabolism)
- Trimethylamine smells terrible
- In liver, FCMO converts trimethylamine into trimethylamine N-oxide (odourless) and polar tf can be excreted in urine
- Defective FCMO - produce trimethylamine but can’t metabolise and excrete it so they sweat and breathe it out
Where are FCMO and P450 enzymes found?
Inner membrane of ER
What do reductive reactions form?
2 amines
Far less common than oxidation
Where do reductive reactions usually happen and why?
- GIT
- Low oxygen environment
- Most reductases are bacterial enzymes colonising our gut
What is hydrolysis? What enzymes are involved?
Splitting a molecule with water
Esterases
Amidase
What is the aim of phase II metabolism?
Make drug less lipid soluble, more polar and easier to excrete
What do phase II enzymes need?
Conjugating agent
Usually large, polar, endogenous chemical
Target specific FG
Explain glucuronidation
Addition of sugar to foreign compound
CA = UDPGA
Enzyme = glucuronyl transferase
Sugar derivative of xenobiotic is POLAR so can be removed
What is the most common phase II reaction?
Glucuronidation
Why are molecules that have undergone glucuronidation often excreted in the bile?
Glucuronidation makes quite large molecular weight products so problem with glomerular filtration
Explain acetylation
Drug has amino group
CA = Acetyl CoA (acts as donor compound)
Enzyme = acetyl transferase
Acetyl group transferred to electron rich atom (N,O,S)
Explain methylation
CA = S-adenosyl methionine (donor)
Enzyme = methyl transferase
Methyl group transferred to electron rich atom (N,O,S)
Decreases polarity
Explain sulphation
Xenobiotic is taken with PAPS (CA - sulphate donor) Enzyme = sulphotransferases Transfer of sulphur to substrates to produce sulphuric acid derivative Very polar and water soluble
Explain glutathione conjugation
One of the most important processes toxicologically
Enzyme = glutathione transferase
Glutathione = tripeptide - glycine, glutamine, cysteine
Cysteine has thiol - reactive part
Reacts with damaging electrophilic intermediates generated during metabolism
Why is drug metabolism important?
- Reduces biological half-life of drug bc of phase I and II reactions
- Reduces duration of exposure
- Avoids accumulation of drug in body
- Can alter potency/duration of biological activity of chemical
- Pharmacology/toxicology of the drug is governed by its metabolism
What effect do phase I reactions have on drug polarity?
Little effect
What is PAPS?
3’-phosphoadenosine-5’-phosphosulphate
What reactions target -OH and -NH2 groups?
Acetylation
Glucuronidiation
Methylation
Sulphation
What functional group does amino acid conjugation target?
-COOH
What functional groups does glucuronidation target?
- OH
- COOH
- NH2
- SH
