View
213
Download
0
Category
Preview:
DESCRIPTION
It's copyright property
Citation preview
Drug Metabolism / Biotransformation
Dr Kiew LV
Objectives
• Define drug elimination and describe the two processes of elimination, i.e.metabolism and excretion
• List the major phase I and phase II reactions and give examples of enzymes (esp.CYP450 enzymes) involved in metabolism.
• Describe the effects of drug metabolism (esp. in liver) and the clinical relevance ofdrug metabolism.
General info ondrug metab.
General Rx steps+ exceptions
Enzyme info +Rx examples
MFO & Cyp450
En. Induction /inhibition
Genetics
Drug Elimination
• All processes which reducethe effective drug concentrationin the body fluids
• Two main mechanisms:
- Metabolism / biotransformation(in liver + other tissues)
- Excretion (in kidney & GIT)
Drug biotransformation / metabolism
• Conversion of drugs into another chemical species by body enzymes
• Purpose:– To inactivate drug (detoxification / remove drug’s therapeutic effects)
• Location: Mainly in liver cells (smooth endoplasmic reticulum, sER)
• General direction for conversion:
inactivate the drug and make the drug more polar / hydrophilic (for renalexcretion) via Phase I & Phase II metabolisms
Inactive** polardrug metaboliteDrug
Very polar inactive drugmetabolite conjugate
Phase I Rx Phase II Rx
Excreted if the metabolite is sufficiently polar Excreted
Inactive** polardrug metaboliteDrug
Very polar inactive drugmetabolite conjugate
Phase I Rx Phase II Rx
Excreted if the metabolite is sufficiently polar Excreted
H OH
Phase I Rx: + polar group
Phase II Rx:+ bigger polargroup (conjugate) bigger polar
group
excretion
excretion
Water soluble metabolite
Drug
** Although phase 1 reaction intends to deactivate drugs, the reaction may also:
– converts a pharmacologically inactive compound (a prodrug) topharmacologically active drug.e.g. levodopa → dopamine
enalapril → enalaprilatzidovudine → AZT-triphosphate
– turn an active drug into active / reactive / toxic metabolitese.g. diazepam → nordiazepam → oxazepam (more active)
paracetamol → N-acetyl-p-benzoquinoneimine (NAPQI)(reactive/toxic)
Inactive** polardrug metaboliteDrug
Very polar inactive drugmetabolite conjugate
Phase I Rx Phase II Rx
Excreted if the metabolite is sufficiently polar Excreted
Phase 1 Phase 2
Objective To add / unmask a polar functionalgroup to drug (e.g. –OH, –NH2, –SH, –COOH)
serves as the point to attack inphase II reaction
Drugs are either inactivated / activated
To add a conjugate to the polar functional groups of thephase I drug metabolite
phase II metabolites (much more polar & often inactive*)
* except for a few, e.g. morphine 6-glucuronide
Location sER sER sER sER Cytosol Cytosol Cytosol
Main Rx Oxidation reduction hydrolysis Glucuronidation(most common)
Sulphation Acetylation Glutathione(GSH)conjugation
Mainenzymes
Mixed-functionoxygenase(MFO)system
CytochromeP450reductase(part of MFO)
Esterase &Amidase
UDP-glucuronosyl -transferases(UGT)
Sulfo -transferases
N-acetyl -transferases
Bile acid-CoA: amino acidN-acyl –transferases
GlutathioneS -transferases
* cytoplasmic alcohol dehydrogenase: oxidize alcohol
Drug biotransformation / metabolism
Oxidation: add oxygen
Alkyl alcohol
Reduction: Add hydrogen / remove oxygen
-N=N- or -NO2 -NH2
azo nitro amines
Hydrolysis:breakdown molecule, + water
Ester Alcohol Acid
Glucuronidation: add glucuronic acid
Sulphation: add sulphate
Acetylation: add acetyl group
Glutathione conjugation: add glutathione (GSH)
e.g. drug metabolism: Paracetamol metabolism
P2 P2
P2
P1
N-acetyl-p-benzoquinoneimine(NAPQI):- Toxic paracetamol metabolite
- may accumulate in the liverwhen GSH is depleted fulminant liver failure
- GSH will deplete in cases of:- Paracetamol overdose- Fasting
- Antidote: acetylcysteine
* Around 5% paracetamol willtake this path
• Enzymes of the smooth ER (sER) of liver cells = microsomal enzymes
Reason: when isolated from liver cells for in vitro study, sER reform itself into vesiclescalled microsomes
• Main microsomal enzymes in the liver :enzymes of the mixed-function oxygenase (MFO) system
• MFO system : 4 components, catalyze drug oxidation
– Cytochrome P450– Cytochrome P450 reductase– NADPH as a proton carrier Drug-H + O2 + 2H+ + 2e– → Drug-OH + H2O– O2
• Other microsomal enzymes:catalyze reactions e.g. dehydrogenation, hydroxylation, epoxidation, oxygenation
Microsomal enzymes in the liver
Mixed-function oxygenase (MFO) systemCytochrome P450
- key enzymes in MFO system & phase 1drug metabolism
- important enzyme in pharmacogenetics /pharmacogenomics studies
- has many subtypes
Enzymes Substrates
CYP2E1 Acetaminophen
CYP2D6 dextromethorphan
CYP1A2 Acetaminophen,caffeine, polycyclichydrocarbons
CYP3A4(most abundant)
Acetaminophen,nifedipine, cyclosporine
CYP2C19 omeprazole
* Acetaminophen = paracetamol
Other locations for drug metabolism
Enzymes involved:MFO, monoamine oxidases (MAOs), Catechol-O-methyltransferase (COMT),
peroxidases, plasma cholinesterase etc.
Location Substrate / drug metabolized
GIT epithelial cells Tyramine, salbutamol, NA, adrenaline
Lung epithelial cells Prostaglandin E2
kidney epithelial cells Imipenam
Skin epithelial cells Betamethasone , Sulfamethoxazole
Plasma ACh, suxamethonium, procaine
Drugs /substance Target en. Effect on enzyme Influence on other drug’s activity
Phenobarbitone CYP450(CYP2B1)
Induction(
↑ warfarin metab.↓ warfarin effect
(pharmacokinetic drug tolerance)
Phenobarbitone CYP450(CYP3A4)
Induction ↑ paracetamol metab.
↑ N-acetylp-benzo-quinone imine (NAPQI)↑ toxicity
Phenytoin
Carbamazepine
Rifampicin
CYP450 Induction ↑ benzodiazepines & cyclosporin metab.
↓ benzodiazepines & cyclosporin effect
Polycyclichydrocarbon(chemicals incigarette smoke )
Cabbage
CYP450 Induction ↑ theophylline (bronchodilator) metab.↓ theophylline effect
(pharmacokinetic drug tolerance)
Metabolic enzyme induction vs. drug metabolism
Drugs /substances
Targetenzyme
Effect on enzyme Influence on other drug’s activity
Cimetidine
Sulphonamides
Ketoconazole
CYP450 Inhibition ↓ warfarin metab.↑ warfarin effect
Grapefruit juice
Alcohol(acute ingestion)
CYP450 Inhibition ↓ benzodiazepines & cyclosporin metab.
↑ benzodiazepines & cyclosporin effect
Metabolic enzyme induction / inhibition vs. drug metabolism
* Chronic ingestion ofalcohol induces CYP450
Genetic predisposition & drug metabolism
• Differences in genetic (inherited) makeup amongindividuals affect drug metabolism.
• Pharmacogenetics :The study on the genetic differences that cause the variation in patient drug response
• Variations in genetic makups of individual code different drug metabolizing enzyme subtypes that has different level ofactiveness
• Slow metabolizer: people with enzyme that process (metabolize) drugs slowly Accumulation of drug risk of toxicity
• Fast metabolizer: people with enzyme that process (metabolize) drugs quickly Fast elimination of drug risk of underdose
Pharmacogenomics : Study on the influence of genetic variation on drug response in patients bycorrelating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity.
Enzyme People e.g. drug effect
N-acetyltransferase
slow acetylators
fast acetylators
Isoniazid(treat tuberculosis)
Higher [plasma isoniazid],longer t1/2 in slow acetylators
Plasmapseudocholin-esterase
Low level enzyme
Normal level enzyme
Suxamethonium Prolonged muscle relaxationin individual with low levelenzyme (> 3hr vs. 6 min innormal)
cannot breathe on theirown as soon after surgery
need a ventilator for anextended time.
Cytochrome P450enzyme (CYP2D6)
Metabolizer type:
• Ultra-rapid• Extensive / fast• Intermediate• Poor
Codeine(changed intomorphine byenzyme)
Variable analgesic effects
Genetic predisposition affecting pharmacokinetics
Recommended