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Introduction to DrugMetabolism
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Reference Sources
The Pharmacological Basis ofTherapeutics Goodman and Gilman
(lot of info, not cheap) Introduction to Drug Metabolism
Gibson and Skett(lots of metabolism info, cheap)
both available at www.amazon.com
http://exec/obidos/search-handle-url/index=books&field-author=Skett%2C%20Paul/104-9691624-1273520http://exec/obidos/search-handle-url/index=books&field-author=Skett%2C%20Paul/104-9691624-1273520http://exec/obidos/search-handle-url/index=books&field-author=Skett%2C%20Paul/104-9691624-12735208/12/2019 Introduction to Drug Metabolism
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Lipophilic Nature
allows passage through biological
membranesaccess to site of action
BUT hinders excretion
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Renal Excretion
Renal excretion of unchanged drug plays small role in elimination of drug
In the kidney, lipophilic compounds arelargely reabsorbed back into systemiccirculation during passage through renal
tubules Needs to be water soluble (hydrophilic)
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Metabolism
The metabolism of drugs and
other xenobiotics into morehydrophilic metabolites isessential for the elimination of
these compounds from thebody and termination of theirbiological activity.
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Biotransformation
Generates more polar (water soluble),inactive metabolites
Readily excreted from body
Metabolites may still have potentbiological activity (or may have toxic
properties)
Generally applicable to metabolism ofall xenobiotics as well as endogenouscompounds such as steroids, vitaminsand fatty acids
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Phase I and Phase II Metabolism
Phase I functionalization reactions
Phase II conjugation reactions
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Phase I Converts the parent drug to a more
polar metabolite by introducing orunmasking a functional group (-OH, -NH2, -SH).
Usually results in loss of pharmacological activity
Sometimes may be equally or moreactive than parent
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Prodrug
Pharmacologically inactive Converted rapidly to active metabolite
(usually hydrolysis of ester or amidebond)
Maximizes the amount of active speciesthat reaches site of action
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Phase II (conjugation reactions)
Subsequent reaction in which a covalentlinkage is formed between a functionalgroup on the parent compound orPhase I metabolite and an endogenoussubstrate such as glucuronic acid,sulfate, acetate, or an amino acid
Highly polar rapidly excreted in urineand feces
Usually inactive - notable exception ismorphine 6-glucuronide
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Site of Biotransformation
Enzymatic in nature Enzyme systems involved are localized
in liver Every tissue has some metabolic
activity
Other organs with significant metaboliccapacity are gi tract, kidneys and lung
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First-Pass Metabolism
Following nonparenteral administrationof a drug, a significant portion of thedose may be metabolically inactivated
in either the intestinal endothelium orthe liver before it reaches the systemiccirculation
Limits oral availability of highlymetabolized drugs
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Endoplasmic Reticulum(microsomal) and Cytosol
With respect to drug metabolizingreactions, two sub cellular organellesare quantitatively the most important:the endoplasmic reticulum and thecytosol.
The phase I oxidative enzymes are almostexclusively localized in the endoplasmic
reticulum.Phase II enzymes are located
predominantly in the cytosol.
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Phase I MetabolismIncludes oxidation, reduction, hydrolysis, andhydration and isomerization (plus rarer misc.)
Many drugs undergo a number of thesereactions
Main function of Phase I metabolism isto prepare the compound for phase IImetabolism
Mixed function enzyme system found inmicrosomes of many cells (esp liver,kidney, lung, intestine) performs manydifferent functionalization reactions
C h 4 0
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Cytochrome P450Monooxygenase System
Superfamily of heme containing proteins Involved in metabolism of diverse
endogenous and exogenous compounds Drugs Environmental chemicals Other xenobiotics
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Cytochrome P450 Nomenclatureand Multiple Forms
~1000 currently known cytochromeP450s, about 50 active in humans
Basis of nomenclature system isdivergent evolution sequencesimilarity between the cytochromeP450s
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categorized into 17 families (CYPs) sequences > 40% identical
identified by Arabic number, CYP 1, CYP 2 further into subfamilies
sequences >55% identical
identified by a letter, CYP1 A , CYP2D may have different, individual isoforms
identified by another Arabic number,CYP2D 6, CYP3A 4
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These are the types of reactions performed by the Cytochrome P450 system
Aromatic hydroxylationPhenobarbital, amphetamine Aliphatic hydroxylation Ibuprofen, cyclosponine Epoxidation Benzo [a] pyrene
N-Dealkylation Diazepam O- Dealkylation Codeine S- Dealkylation 6-Methylthiopurine
Oxidative Deamination Diazepam, amphetamine N-Oxidation Chlorpheniramine S-Oxidation Chlorpromazine,
cimetidine
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Phase I Metabolism SummaryVirtually every possible chemical reaction thata compound can undergo can be catalyzed bythe drug metabolizing enzyme systems
The final product usually contains achemical reactive functional group OH,NH2, SH, COOH.
This functional group can be actedupon by the phase II or conjugativeenzymes.
Main function of Phase I metabolism
is to prepare the compound for phase II
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Phase II Metabolism
Phase II is usually the truedetoxification of drugs
Occurs mostly in cytosol
Gives products that are generally watersoluble and easily excreted
Includes sugar conjugation, sulfation,methylation, acetylation, amino acidconjugation, glutathione conjugation
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Glucuronidation
Most widespread, important of theconjugation reactions Cofactor UDP glucuronic acid is in
high abundance Closely related to glycogen synthesis Found in all tissues of the body
Other sugars, glucose, xylose or ribosemay be conjugated
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Glutathione Conjugation Glutathione is a protective compound
(tripeptide, Gly-Cys-Glu) within thebody for removal of potentially toxicelectrophilic compounds
Many drugs are, or are metabolized in phase I to, strong electrophiles React with glutathione to form non-
toxic conjugates Glutathione conjugates may be
excreted directly in urine or bile, butare usually metabolized further
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Stereoselective Reactions
Many drugs in use are optically active Optical isomers of many drugs are
metabolized differentlyWarfarin exists as R- and S-isomers, the
S isomer disappears from the plasma at
a faster rate than the R isomer
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Factors affecting Drug
Metabolism
Environmental Determinants
InductionInhibition
Disease Factors Age and Sex Genetic Variation
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Environmental Determinants Activity of most drug metabolizing
enzymes can be modulated by exposureto certain exogenous compounds
DrugsDietary micronutrient (food additives,nutritional or preservative)Environmental factors (pesticides, industrialchemicals)
Can be in the form of induction orinhibition
Contributes to interindividual variability
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Induction of Drug Metabolism
Enzyme induction is the process by whichexposure to certain substrates (e.g., drugs,environmental pollutants) results in
accelerated biotransformation with acorresponding reduction in unmetabolizeddrug.
(some substance stimulates the synthesis ofthe enzyme and the metabolic capacity isincreased -drug gets metabolized faster )
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Induction of Drug Metabolism
Many currently used drugs are well known toinduce their own metabolism or themetabolism of other drugs. Some examples
are the anticonvulsant medications phenobarbital and carbamazepine, and evenSt. Johns Wort.
Cigarette smoking can cause increasedelimination of theophylline and othercompounds.
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Consequences of Induction
Increased rate of metabolism Decrease in drug plasma concentration Enhanced oral first pass metabolism Reduced bioavailability If metabolite is active or reactive,
increased drug effects or toxicity
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Therapeutic Implications ofInduction
Most drugs can exhibit decreasedefficacy due to rapid metabolism
but drugs with active metabolites can
display increased drug effect and/ortoxicity due to enzyme induction
Dosing rates may need to be increased
to maintain effective plasmaconcentrations
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Inhibition of Drug Metabolism
Drug metabolism is an enzymatic
process can be subjected to inhibition. Drugs and other substances can inhibit
the metabolism of other drugs.
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Some types of inhibition Competition between substrates for enzyme
active siteConcentration of substrates
Affinity for binding site (drug with hiaffinity for an enzyme will slow themetabolism of any low affinity drug)
Irreversible inactivation of enzyme
Complex with heme iron of CYP450(cimetidine, ketoconazole)Destruction of heme group (secobarbital)
Depletion of cofactors such as NADH2 for phase II enzymes
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Therapeutic Implications of
Inhibition May occur rapidly with no warning Particularly effects drug prescribing for
patients on multidrug regimens Knowledge of the CYP450 metabolic
pathway provides basis for predictingand understanding inhibition
Esp drug drug interaction
http://www.hospitalist.net/highligh.htm
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CYP1A2 Affected Drugs, Inducers, and Inhibitors
Affected Drugs Inducers Inhibitors
TricyclicantidepressantsPropranololF-WarfarinTheophylline
Omeprazole(Prilosec)PhenobarbitalPhenytoinRifampinSmokingChar-broiled meats
Quinoloneantibiotics, esp.ciprofloxacinGrapefruit juice
Note: CYP1A2 is the only isoform known to be affected bytobacco smoking. Example: smoking induces formation of CYP1A2 enzymes causing smokers to require higher doses of theophylline than non-smokers.
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Disease FactorsLiver Disease Cirrhosis, Alcoholic liver
disease, jaundice, carcinoma Major location of drug metabolizing enzymes Dysfunction can lead to impaired drug
metabolism-decreased enzyme activity First pass metabolism effected may inc 2-4 xbioavailiability
Results in exaggerated pharmacological
responses and adverse effectsCardiac failure causes decreased blood
flow to the liverHormonal diseases, infections and
inflammation can change drug
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Age
Newborns and infants metabolizedrugs relatively efficiently but at a rate
generally slower than adults Full maturity appears in second
decade of life Slow decline in function associated
with aging
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Sex
Responsiveness to certain drugs isdifferent for men and women
Pregnancy induction of certaindrug metabolizing enzymes occurs insecond and third trimester
Hormonal changes duringdevelopment have a profound effect ondrug metabolism
G i V i i
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Genetic Variationhttp://www.private-rx.co.uk/invivo/pharmacogenetics.shtml
wide variability in the response to drugsbetween individuals consequences of such variation may be
therapeutic failure or an adverse drug
reaction genetic diversity is the rule rather than
the exception with all proteins,including drug metabolizing enzymes
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allelic variants with different catalytic
activities from that of the wild-type formhave been identified
inheritance leads to subpopulations(genetic polymorphisms) with differentdrug metabolizing abilities
lack of activityreduction in catalytic abilityenhanced activity
frequency of the polymorphism oftenvaries according to the ethnic ancestry ofthe individual
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CYP2D6 is extensively studied, the gene
for CYP2D6 is highly polymorphic
Its expression leads to 3 phenotypes(phenotype is the expression of geneticmake-up)
Extensive metabolizers (EMs) havefunctional enzyme activityIntermediate metabolizers (IMs) havediminished enzyme activity
Poor metabolizers (PMs) have little or noactivity
5-10% of Caucasians and 1-2% of
Asians exhibit the PM phenotype
Debrisoquine formerly used in the
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Debrisoquine, formerly used in thetreatment of hypertension, is metabolizedby CYP2D6 to 4-hydroxydebrisoquine
Remarkable interindividual variation in pharmacological effect of the drug
Urine of volunteers given debrisoquine wasexamined for presence of 4-hydroxydebrisoquine One subject had a very low conversion of parent
drug to metabolite
was very sensitive to the antihypertensive effects ofdebrisoquine
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Drugs linked to this phenotype should be
given in lower doses to PM individuals than
EM to reduce risk of overdose and toxiceffects.
On the other hand
Codeine is oxidized to morphine byCYP2D6 necessary for codeines analgesic effect PMs may have no therapeutic effect
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And now, back to the patient?
Do these apply? Age and Sex
DiseaseEnvironment other drugs
Genetic variationDefinitely an individual!