drug metabolism f. keyhanfar ph.d, d.i.c.. metabolism (biotransformation)...
TRANSCRIPT
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DRUG METABOLISMDRUG METABOLISMF. Keyhanfar Ph.D,
D.I.C.
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METABOLISM (BIOTRANSFORMATION)------------------------------------
Acetaminophen, NSAIDs inhibit cyclo-oxygenase
Amitriptylline & Cimetidine
Phenytoin
Diazepam -
Dopa & Carbidopa
Succinycholine
Isoniazid
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TerminologyTerminology Metabolism: (Gk: metabole: change)Metabolism: (Gk: metabole: change) Metabolite: metabolism produce metaboliteMetabolite: metabolism produce metabolite Xenobiotics: xeno (Gk: foreign)… bioticsXenobiotics: xeno (Gk: foreign)… biotics Inhibition Inhibition (Latin inhibitus, ): to prohibit from (Latin inhibitus, ): to prohibit from
doing somethingdoing something Induction (Induction (Latin inducere): to induce: to call Latin inducere): to induce: to call
forth or bring about by influence or forth or bring about by influence or stimulationstimulation
Cytochrome P450s (CYPs)Cytochrome P450s (CYPs)
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METABOLISM (BIOTRANSFORMATION)------------------------------------
The processes by which foreign molecules (Xenobiotics) are
chemically altered by a living organism.
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METABOLISM (BIOTRANSFORMATION)
• The body recognizes these molecules and, if it is unable to eliminate
them unchanged, is able to increase their water
solubility by a variety of enzymic reactions
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Result------------
• Water soluble metabolites
• Increased Excertion
• Reduced Biological Half-life
• Minimum Toxicity
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Phase I Phase IIDRUG METABOLITE CONJUGATE
Expose or introduce a Conjugate the functional functional group that groups exposed or introduced can be conjugated by during Phase I biotransformation Phase II enzymes
Small in water solubility Large in water solubility
• Termination of Pharmacological activity or introduce toxicity
• The rate and extent to which a drug is metabolized determines the dose of the drug and the duration of the effect of the drug
Rate limiting/Affected by genetic and
environmental factors
Active/Inactive/Toxic/Mutagenic/Carcinogen
OH OGlucuronide
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Two-phase biotransformation
Phase I (functionalization) reactions: Oxidation, Reduction, and hydrolytic reactions
(makes the drug more polar, but not necessarily inactive)
Phase II (conjugation) reactions: Conjugation to polar groups: glucuronidation,
sulfation, acetylation (most of these result in drug inactivation)
•Ultimate effect is to facilitate elimination
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BIM
M11
8
• Phase I Reactions– Oxidation– Reduction– Hydrolytic cleavage– Alkylation (Methylation)– Dealkylation– Ring cyclization– N-carboxylation– Dimerization– Transamidation– Isomerization– Decarboxylation
Cytochromes P-450 (CYP)
Flavin Monooxygenase (FMO)
Monoamine Oxidase (MAO)
Aldehyde dehydrogenase
Alchohol dehydrogenase
Various amidases/esterases
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BIM
M11
8
Drug Metabolism - Phase II
• Conjugation reactions– Glucuronidation by UDP-Glucuronosyltransferase:
(on -OH, -COOH, -NH2, -SH groups)
– Sulfation by Sulfotransferase:
(on -NH2, -SO2NH2, -OH groups)
– Acetylation by acetyltransferase:
(on -NH2, -SO2NH2, -OH groups)
– Amino acid conjugation
(on -COOH groups)– Glutathione conjugation by Glutathione-S-transferase:
(to epoxides or organic halides)– Fatty acid conjugation
(on -OH groups)– Condensation reactions
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An Example of Drug An Example of Drug MetabolismMetabolism
Non – specificNon – specificHydrolytic enzymeHydrolytic enzyme
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Complex Metabolism
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Metabolism
Hepatic microsomal enzymes (oxidation, conjugation)
Extrahepatic microsomal enzymesExtrahepatic microsomal enzymes (oxidation, conjugation)(oxidation, conjugation)
Hepatic non-microsomal enzymesHepatic non-microsomal enzymes (acetylation, sulfation,GSH, (acetylation, sulfation,GSH, alcohol/aldehyde dehydrogenase,alcohol/aldehyde dehydrogenase,hydrolysis, ox/red)hydrolysis, ox/red)
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Important CYP Isoforms (12 )
• CYP3A4 & 3A5 & 3A7
• CYP2D6
• CYP1A1 &1A2
• CYP2A6
• CYP2B6
• CYP2C8 & 2C9 & 2C19
• CYP2E1
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Important CYP Isoforms (12 )
• CYP3A4 VERAPAMIL (CA CHANNEL BLOCER)
• CYP2D6 VERAPAMIL
• CYP1A1 &1A2
• CYP2A6
• CYP2B6• CYP2C8 & 2C9 VERAPAMIL
• CYP2C19
• CYP2E1
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Important CYP Isoforms• CYP3A4
Midazolam, triazolam, cyclosporine, erythromycin, Ca channel blockers THE MOST PREDOMINANT IN HUMAN – AMOUNT IN THE LIVER & VARIETY OF DRUG BEING SUBSTRATES
50% of all CYP-mediated drug oxidations
also involved in the greatest number of drug-drug interactions.
active site is large , accept substrates up to M.wt = 1200
drugs bind in different regions of the enzyme active sites
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CYP3A4Two drugs are metabolized by this enzyme.
Will coadministration result in a
drug–drug interation ?
drugs bind in different regions of the enzyme active sites
Two drugs can occupy the active site simultaneously both being available for metabolism by the enzyme.
absent interations
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CYP3A5
Amino acid sequence is similar to that of CYP3A4,
It is not present in all individuals.
Patients expressing both CYP3A4 & 3A5
Shows increased metabolism of
CYP3A substrate
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CYP3A7Expressed only in the fetus
Disappears following birth and replaced by CYP3A4 & 3A5
Different enzyme expression patterns and thus different drug metabolism capabilities throughout
the various stages of life.
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CYP2D6
Tricyclic antidepressants, codeine, dextromethorphan, antipsychotics
antiarrhythmics etc
Its relative abundance in the liver is low.
Exhibit genetic polymorphism
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MetabolismMetabolism
• Amitriptylline is metabolized by CYP1A2
• Cimetidine inhibits CYP1A2
• Coadministration results in elevated Amitriptylline levels
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Cimetidine, Ritonavir, amiodarone, diltiazem, ketoconazole
Inhibit CYP3A4
Cimetidine, Fluoxetine, amiodarone
Inhibit CYP2D6
Cimetidine, Ketoconazole, Omeprazole
Inhibit CYP2C19
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Potent InhibitorsPotent Inhibitors• Fluoroquinolones (ie: ciprofloxacin)
• H2Blockers (ie: most notably cimetidine)
• Imidazoles (ie fluconazole)
• INH
• Ritonavir
Mnemonic: “cip, cim, con, INH, and rit”
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Barbiturates, Carbamazepine, Phenytoin, pioglitazone, glucocorticoids, …
Induce CYP3A4 & 3A5
Phenobarbital, dexamethasone
Induce CYP2A6 & 2B6 & 2C9
Smoking , Omeprazole
Induce CYP1A1 &1A2
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Potent InducersPotent InducersNeuroleptics:
• Carbamazepine
• Phenobarbital
• Phenytoin
AND:
• Rifampin
Mnemonic: “carb, barb, pheny, and rif”
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Hydrolysis• Esters & Amides Hydrolyzed by :
ESTERASES & AMIDASES
Found in :
Cytosol of cells in tissues
Plasma & microsomes
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Metabolic Overloading
• Chemical being metabolised by an alternate pathway, not necessarily comparable
to metabolic stress in human
exposure situations
• The chemical may be unmetabolised
and accumulate
or stored in the body or be
excreted unchanged.
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First order kinetics
A constant fraction of drug is eliminated per unit of time.
When drug concentration is high, rate of disappearanceis high.
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Zero order kinetics
Rate of elimination is constant.
Rate of elimination is independent of drug concentration.
Constant amount eliminated per unit of time.
Example: Alcohol
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Aspirin, Ethanol
Phenytoin
Metabolism rate is constant
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Phase II Metabolism (conjugation)
GlutathioneGlucuronidation
SulfationGlycine
Acetylation Methylation
Coenzymes needed: various
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Sulfation may produce active metabolite
N
N
NH2
O
H2N N
N
N
NHO
H2N N
S
O
HO
O
Minoxidil Minoxidil-sulfate
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Paracetamol Overdose
• Most common drug taken in overdose
• Few symptoms or early signs• As little as 12g can be fatal• Hepatic and renal toxin
–Centrolobular necrosis• More toxic if liver enzymes induced
or reduced ability to conjugate toxin
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Acetaminophen and p-Aminophenols
Acetanilide, 1886(accidental discovery ofantipyretic activity; high toxicity)
Phenacetin or acetophenetidin, 1887 (nephrotoxic, methemoglobinemia)
Acetaminophen, 1893
Recognized as active metabolite of acetanilide and phenacetin in 1948 (Brodie &Axelrod); popular in US since 1955
70-90%75-80%
HNCOCH 3
OH
HN
COCH 3
OC 2H5
NH2
OC 2H5
HN
COCH 3 NH2
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Acetominophen Metabolism
~60% ~35%
CYP2E1*CYP1A2CYP3A4
NAPQIN-acetyl-p-benzoquinone imine
*induced by ethanol, isoniazid
Protein adducts,Oxidative stressToxicity
HN
COCH 3
OH HN
COCH 3
OSO 3H
HN
COCH 3
OO CO 2H
OH
OHHO
N
O
COCH 3
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Paracetamol Metabolism
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Management• General measures
• <8 hours– Take level after four hours
– Start N-aceylcysteine– Patients are usually declared fit for discharge from medical care on completion
of its administration.
– Patients should be advised to return to hospital if vomiting or abdominal pain develop or recur
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N-acetylcysteine
• Supplies glutathione
• Dosage for NAC infusion - ADULT– (1) 150mg/kg IV infusion in 200ml 5% dextrose over 15 minutes,
then– (2) 50mg/kg IV infusion in 500ml 5% dextrose over 4 hours, then– (3) 100mg/kg IV infusion in 1000ml 5% dextrose over 16 hours
• Side-effects– Flushing, hypotension, wheezing, anaphylactoid reaction
• Alternative is methionine PO (<12 hours)
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•Acetaminophen overdose results in more calls to poison control centers in the United States than overdose with any other pharmacologic substance.
•The American Liver Foundation reports that 35% of cases of severe liver failure are caused by acetaminophen poisoning which may require organ transplantation.
•N-acetyl cysteine is an effective antidote, especially if administered within 10 h of ingestion [NEJM 319:1557-1562, 1988]
•Addition of N-acetyl cysteine to acetaminophen tablets proposed to prevent liver toxicity. [British Medical Journal, Vol. 323, Sept. 15, 2001]
Acetaminophen Toxicity
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Metabolism
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Factors affecting drug metabolism
• Drug metabolism can be affected by:
– First pass effect
– Hepatic blood flow
– Liver disease
– Drugs which alter liver enzymes
Main site of drug metabolism = LIVER
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The phenomenon of
“first pass effect”
or
“first pass metabolism”
and its clinical relevance
Some drugs are ineffective when given orally – examples: nitroglycerine, nor-adrenaline, insulin
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Drug Admin: Formulation
• First Pass EffectBlood from the gastrointestinal tract passes through the liver before entering any other
organs. During this first pass through the liver, a fraction of the drug (in some cases nearly all) can
be metabolized to an inactive or less active derivative. The inactivation of some drugs is so
great that the agents are useless when given orally.
(e.g.. lidocaine)
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Factors affecting drug metabolism
• Genetic factors– e.g acetylation status
• Other drugs– hepatic enzyme inducers– hepatic enzyme inhibitors
• Age– Impaired hepatic enzyme activity
• Elderly• Children < 6 months (especially premature babies)
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Factors affecting biotransformation
• age (reduced in aged patients & children)
• sex (women slower ethanol metabilizers)
• species (phenylbutazone 3h rabbit, 6h horse, 8h monkey, 18h mouse, 36h man); biotransformation route can change
• clinical or physiological condition
• other drug administration (induction (not CYP2D6 ) or inhibition)
• food (charcoal grill ++CYP1A)(grapefruit juice --CYP3A)
• first-pass (pre-systemic) metabolism
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Factors Influencing Activity and Level of CYP Enzymes
Nutrition 1A1;1A2;2E1; 3A3; 3A4,5
Smoking 1A1;1A2
Alcohol 2E1
Drugs 1A1,1A2; 2A6; 2B6; 2C; 2D6; 3A3, 3A4,5
Environment 1A1,1A2; 2A6; 1B; 2E1; 3A3, 3A4,5
Genetic Polymorphism
1A; 2A6; 2C9,19; 2D6; 2E1
Red indicates enzymes important in drug metabolism
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EnantiomerDrug Shape
– Lock and Key phenomenon for the drug and its receptor site
– More than half of all useful drugs are chiral molecules and exist as enantiomeric pairs
Ex: Carvedilol has a single chiral center and two enantiomers
S(-) isomer – potent Beta receptor blockerR(+) isomer – 100-fold weaker at Beta
receptor– One drug enantiomer is often more susceptible than the
other to drug-metabolizing enzymes• One enantiomer could have a longer or shorter
duration of action than the other
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Racemic mixtures
Drug Shape
– As of now, most clinical studies of drugs have only tested racemic mixtures (two enantiomer
pairs)
– 55% of drugs are only available as racemic mixtures where a patient is receiving 50% inactive
or actively toxic drug
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Pharmacogenetics• For pharmacokinetics,
change may occur in– drug transporters
–drug metabolizing enzymes
» more active enzymes
» Inactive enzymes
» semi-active enzymes
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Succinylcholine
● Used during anesthesia to induce muscle Used during anesthesia to induce muscle paralysisparalysis
● Paralysis usually lasts minutes, but in some Paralysis usually lasts minutes, but in some individuals, it may last up to one hourindividuals, it may last up to one hour
● Due to altered kinetics of Due to altered kinetics of pseudocholinesterase pseudocholinesterase
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Isoniazid
● Used in the treatment of tuberculosisUsed in the treatment of tuberculosis● Observed variation in the amount of unchanged Observed variation in the amount of unchanged
isoniazid in the urineisoniazid in the urine● Differences were due to an individuals ability to Differences were due to an individuals ability to
convert isoniazid to acetylisoniazid.convert isoniazid to acetylisoniazid.● Caused by mutations in the Caused by mutations in the N-acetyltransferase-2 N-acetyltransferase-2
enzyme (NAT2) on chromosome 8enzyme (NAT2) on chromosome 8● Some individuals develop isoniazid toxicity Some individuals develop isoniazid toxicity
manifested as peripheral neuropathymanifested as peripheral neuropathy