3 - Metabolism Flashcards
What is metabolism?
Conversion of a drug to a more polar, water soluble, ionized substance, usually w/ reduced pharmacological activity and toxicity (exception is a prodrug)
____ is the main organ of biotransformation
Liver
What are the sites of metabolism?
- Bloodstream
- Kidneys
- Brain
- Muscle tissue
- Walls of GI tract
- Lungs
What are the 2 types of hepatic metabolism? What are examples of each?
1) Phase 1 - oxidation, hydrolysis, reduction (in order from most to least prevalent)
2) Phase 2 - glucuronidation, acetylation, sulfation
What must happen to a drug to undergo phase 2 metabolism?
Must be activated, generally by a phase 1 reaction
What does it mean when an active drug is metabolized to an active metabolite?
Don’t have to dose as frequently
How are barbiturates metabolized?
Glucuronidation and oxidation
How are benzodiazepines metabolized?
1) N-dealkylation to biologically active metabolite
2) Hydroxylation to active metabolite
3) Glucuronidation to inactive metabolite
How is morphine metabolized?
Glucuronidation to morphine-6-glucuronide (active metabolite) or morphine-3-glucuronide (inactive metabolite)
How is codeine metabolized?
10% is demethylated to morphine
How are tranquilizing agents (anti-psychotic agents) metabolized?
Majority is oxidized, some undergoes glucuronidation
How is cocaine metabolized?
Plasma esterases
How is ethanol metabolized?
Oxidation (zero order process)
What is required for oxidation?
- NADPH
- Molecular oxygen
- Heme-protein
Important phase 1 oxidation reactions are performed by ______ found in ______
Mixed function oxidases found in smooth endoplasmic reticulum
Why is it called cytochrome P450?
Absorbs light at wavelength 450 nm
What is the key element in the oxidative process?
Hemeprotein cytochrome
What is the difference btwn ferrous and ferric iron?
- Ferrous = Fe2+
- Ferric = Fe3+
Which families of CYP enzymes are responsible for drug metabolism?
Families 1, 2, and 3
What are the 6 major CYP P450 isoenzymes responsible for the majority of drug metabolism in humans?
1) CYP1A2
2) CYP2C8/9/10
3) CYP2C18/19
4) CYP2D6
5) CYP2E1
6) CYP3A4
What are the substrates of CYP1A2?
- Phenacetin
- Theophylline
What are the substrates of CYP2C8/9/10?
- Hexobarbital
- Phenytoin
What are the substrates of CYP2C18/19?
- Diazepam
- Mephenytoin
What are the substrates of CYP2D6?
- Imipramine
- Propranolol
What is the substrate of CYP2E1?
Acetaminophen
What are the substrates of CYP3A4?
- Erythromycin
- Cyclosporin
CYP____ metabolizes chemicals and toxins
1A2
Smoking induces CYP____ resulting in ____
- 1A2
- Resulting in activation of benzpyrene, a carcinogen in cigarette smoke
- This means higher levels of drugs may be required by smokers than non-smokers
Which CYP enzymes exhibit genetic polymorphism?
- 2C9 and 2C19
- 2D6
- 2E1
Where in the body is the majority of CYP3A4 found?
Gut
Which CYP enzymes are affected by nutrition?
- 1A2
- 2E1
- 3A3
Which CYP enzyme is affected by alcohol? What does this mean?
- 2E1
- Causes glutatione depletion, leading to accumulation of NAPQ1 (lethal byproduct of acetaminophen) => severe liver damage
Which CYP enzymes are affected by drugs?
- 1A2
- 2C
- 2D6
- 3A3
What are the 2 major reduction reactions?
1) Nitro-reduction
2) Azo-reduction
Where are reduction reactions carried out?
Intestinal microflora
Which drugs commonly undergo reduction reactions?
Orally administered
Where are hydrolysis reactions and by what?
By respective esterases in liver or by esterases in plasma and other tissues
What do esterases do?
Hydrolyze esters to alcohols and carboxylic acids
What do phase 2 reactions involve and what do they normally result in?
- Involve chemical conjugation or synthesis
- Generally increase water solubility and result in pharmacological deactivation
What occurs in a conjugation reaction?
Compound/metabolite is combined w/ endogenous molecule
Where does glucuronidation occur?
Endoplasmic reticulum
Where does sulfation occur?
Cytosol
Where does acetylation occur?
Cytosol
Where does methylation occur?
- Cytosol
- Endoplasmic reticulum
Where does glutathione conjugation occur?
- Cytosol
- Endoplasmic reticulum
What are some factors that contribute to variability in drug response?
- Genetic factors (most common)
- Concomitant drugs (2nd most common)
- Weight
- Ethnicity
- Gender
- Diet
- Compliance
- Concomitant disease
Is the CYP P450 the same in adults and children?
No, so children can’t be treated the same way adults are
What could result from CYP2D6 gene duplication?
Lethal levels of morphine in the blood, b/c CYP2D6 metabolizes codeine to morphine
What can accumulation of morphine in an infant cause?
- CNS depression
- Respiratory failure
- Death
What is the function of SLC28A3 (sodium-coupled nucleoside transporter 28A3)? Where is it found?
- Transports pyrimidines, purines, and anti-cancer drugs; demonstrated role in anthracycline transport
- Expressed throughout body, including heart
What is the function of SLC28A3 L461L?
L461L is a protective allele that reduces SLC28A3 expression, reduces anthracycline uptake, and reduces generation of toxic metabolites
What can altered glucuronidation lead to?
Accumulation of toxic anthracycline metabolites
How is isoniazid metabolized and what is important about this?
- Metabolized by N-acetyltransferase
- Metabolite is not active, so rate and extent of metabolism will affect efficacy of the drug
Is total body water and extracellular fluid greater in newborns or in adults?
Newborns
Do elderly individuals have more lean body mass or more body fat in relation to body weight?
Greater body fat
Do newborns have increased or decreased glucuronidation reactions?
Decreased
How does half life of a drug change as you age? What else changes w/ age?
- High at birth, goes down as you age to an adult, and increases again in elderly
- Vd and protein binding
What affect can a low protein diet have on drug metabolism?
Decreases drug metabolizing capacity b/c of lack of amino acids
What affect can decreased lipid intake have on drug metabolism?
Decreases essential fatty acids, so decreases metabolism of ethylmorphine and hexobarbitone
What affect can a high glucose intake have on drug metabolism?
Inhibits barbiturate metabolism
What affect does food have on bioavailability?
Increases bioavailability b/c increases splanchic (organ) blood flow which increases uptake
Which foods are inducers of the CYP P450 system?
- Charcoal broiled meats
- Smoked fish
Which food inhibits intestinal P450 enzymes and what affect does this have on cyclosporine?
- Grapefruit juice
- Increases bioavailability of cyclosporine
Which drugs are mostly affected by the action of grapefruit juice of CYP3A?
- Antihistamines
- Benzodiazepines
- Immunosuppressants
What can happen if a px is taking nifedipine and terazosin for BP control and consumes grapefruit juice?
Px will experience hypotension b/c grapefruit juice blocks metabolism of the drugs
What components of grapefruit juice are thought to affect CYP P450?
- Flavanoids
- Furanocoumarins
Effect of grapefruit juice appears to last for at least __ days following ingestion
3
What effect does St. John’s Wort have on CYP P450?
Induces CYP3A
What is St. John’s Wort used for?
Treating mild to moderate depression
What is ginseng used for?
Normalizer, energizer, and stress reducer
What can ginseng interact w/?
- Antidepressants
- Warfarin
- Steroids
What can ginko and garlic interact w/?
Warfarin, can increase bleeding time
Should drugs and herbs be mixed?
No
Do all drugs follow the Michaelis-Menten kinetics?
Yes
What is important to note about increasing the dose of a drug that exhibits Michaelis-Menten kinetics?
Doubling the dose will dramatically increase the plasma concentration, likely putting it at toxic concentrations, so must be careful when increasing dose
Why can cause a metabolite to have reduced pharmacological activity?
- Metabolite is more water soluble than parent compound, so has less capacity to cross membranes
- Metabolite has lost most of its original intrinsic pharmacological activity
Does skin have CYP P450 enzymes?
Yes, can metabolize compounds in ointments
Phase 2 reactions occur w/ _____
CYP P450 system
Can a metabolite have a longer half life than its parent compound?
Yes
___ has many of the same properties as morphine
Morphine-6-glucuronide
Is codeine a pro-drug?
Yes, becomes activated into morphine through demethylation
Since codeine is normally given w/ caffeine, would taking codeine w/ a cup of coffee increase bioavailability?
No
Describe the process of P450 action
- Drug binds to P450 ferric complex
- Electron from NADPH reacts w/ the complex
- Oxygen binds to complex
- Free radical forms
- Oxygen is removed
- Drug comes off
Why must a compound be active to undergo glucuronidation?
Must have a site to accept the glucuronic acid
Is it possible to have 0% drug concentration but still have a pharmacological effect?
Yes b/c drug can go inside a cell into a reservoir and be sequestered later
