Introduction to Drug Metabolism

8/12/2019 Introduction to Drug Metabolism

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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/104-9691624-1273520


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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!

Introduction to Drug Metabolism

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