DRUG METABOLISM (biotransformation)

 Structural changes that occur to a foreign molecule (xenobiotic) in the body

 Drugs should have certain lipid solubility (lipophilic) to be absorbed.
 If highly lipid soluble will not be eliminated from the body.
 To be excreted in the urine (major excretion site) a drug has to be polar enough to
dissolve in water.
 Other excretion sites are sweat, saliva, bile etc…
 The introduction of small polar groups into the molecule ( metabolism):
A-ends pharmacological activity (alters fitting in the receptor) (Key & lock)
B-ends toxicity (detoxification)
C-increases polarity and water solubility (elimination).

 In general metabolism means detoxification

Exceptions:

A-Inactive drug (mostly a pro-drug) by metabolism will produce active drug ( bio-activation)
e.g. prontosil.

B- metabolism of the active drug (imipramine) gives the active metabolite (desipramine).

C-Some drugs give toxic metabolites e.g. chloarmphenicol.

Sites of drug metabolism

 divided into hepatic and extra hepatic:

1. Hepatic metabolism in the liver (major site of metabolism) for the following reasons:
i- Rich in almost all drug-metabolizing enzymes
ii-A well-perfused organ i.e easy access to the metabolizing enzymes.
iii-Orally administered drugs will all pass through the liver before reaching systemic

1
 circulation thus extensively metabolised (first pass effect)  the extent of metabolism
may affect the bio-availability (Lidocain and nitroglycerine)
2. Extra hepatic metabolism:  overall metabolism in tissues other than the liver.
i-Intestine:
a- estrases and lipases are abundant in intestinal wall leading to the hydrolysis of many
ester pro-drugs.
b-Intestinal b-glucuronidase enzyme hydrolyzes glucuronide conjugates the product
will be reabsorbed into the blood stream (enterohepatic circulation or recycling) thus
the drug stays longer in the body (affect duration of action).
c- Bacterial flora present in the intestine and colon also contribute to the overall drug
metabolism.
ii-Kidney, lungs, adrenal glands, placenta, brain etc….

Phase I (Functionalization Reactions):

 Introduces a polar functional group e.g. OH, COOH, NH2, SH, into drug molecule
a- direct introduction of the functional group (e.g. aromatic & aliphatic hydroxylation)
b- modifying existing functionalities (e.g. reduction of ketones & aldehydes to
alcohols, oxidation of alcohols to acids, hydrolysis of esters & amides to yield COOH,
OH , NH groups, reduction of azo & nitro compounds to give NH2).
 Generally provides a functional group in the molecule in preparation for phase II
reactions.
 Product may be polar enough to be excreted.

Phase II (Conjugation Reactions):

 Attaches a small, polar& ionizable endogenous compounds such as glucuronic acid,

sulfate, glycine and other amino acids to the functional group"handle" of phase I
metabolites to produce water soluble conjugates.
 Conjugated metabolites are readily excreted in the urine and generally devoid of
pharmacological activity and toxicity.
 Compounds with existing functional groups may go directly to phase II.
 Drugs which are already hydrophilic are largely excreted unchanged.

2
PHASE I (FUNCTIONALIZATION REACTIONS):

1-OXIDATION REACTIONS

 Requires molecular oxygen + reducing agent NADPH (reduced form of nicotinamide

adenosine dinucleotide phosphate).

According to the following equation:

RH +NADPH+ O2+ H+ = ROH+ NADP+ +H2O

 The enzyme systems involved is called mixed function oxidases or monooxygenases.

Composed of :
a-Cytochrome P-450 (heme-protein). Transfers an oxygen atom to the substrate (RH)
through the activation of  molecularoxygen, introducing one oxygen atom into drug
molecule & reduction of other to water
b-NADPH- dependent cytochrome P-450 reductase.
c- NADH- linked cytochrome p450.
a + b + cofactors NADPH& NADH provide reducing equivalents (electrons).

 Cytochrome P450 is present in high concentration in liver. Also present in other

tissues e.g kdney
 The name cytochrome P-450 is due to the reduced (Fe2+) form enzyme – substrate
complex binding with carbon monoxide giving a complex with UV-absorption maximum
at 450 nm.

Types of oxidation reactions catalyzed by Cytochrome P450

1-Oxidation of aromatic moieties (aromatic hydroxylation):

 Oxidation of aromatic compounds (arenes) by mixed function oxidase enzymes to

phenolic metabolites (arenols) through epoxide intermediate (arene oxide).
 Aromatic oxidation is a  major pathway in human.

Rules for hydroxylation aromatic rings

 Para hydroxylation usually predominates (preferred) ( less sterically hindered) e.g.

phenobarbital.

e.g.phenobarbital

Sometimes ortho oxidation may take place.

3
  If two identical aromatic rings are present, oxidation of only one ring e.g..
phenybutazone

phenylbutazone

Chlorpromazine

Diazepam

2-Oxidation of olefins:

 Olefinic carbon–carbon will produce epoxides (more stable than arene oxide)
 The epoxide is susceptible to enzymatic hydration by epoxide hydras giving the1, 2-
dihydrodiols.

example is the oxidation of chlorpromazine (above) into diole metabolite through

the stable active epoxide intermediate which contributes to the overall activity of the drug.

4
similarly, secobarbital (above) is metabolized to diol metabolite through the formation of the
epoxide.

3- Oxidation at benzyllic carbon atoms:

 Carbon atoms attached to aromatic rings (benzyllic) oxidation produces alcohols

(carbinol) ) metabolite.
 Primary alcohols metabolites are further oxidized to aldehydes and carboxylic acids
(CH2OH→CHO→COOH). Eg. tolbutamide.

4- Oxidation at allylic carbon atoms:

 Commonly observed in drug metabolism

Tolbutamide........................................ THC(tetrahydrocannabinol)

5-Oxidation at carbon atoms alpha to carbonyl and imines:

benzodiazepines an important class of drugs undergo oxidation to 3-hydroxyl metabolite

5
6-Oxidation at aliphatic and alicyclic carbon atoms:

 Oxidation at the terminal carbon

 ω -1 also called penultimate carbon atom (carbon next to the last carbon)
 The alcohol metabolites undergoes further oxidation giving aldehydes and ketones or
carboxylic acid. e.g. anticonvulsant valproic acid

valproic acid

secobarbital

Phenylbutazone

7-Oxidation involving carbon-heteroatom systems:

 Nitrogen, oxygen & sulfer.

 Two types of biotransformation reaction
 1-Hydroxylation of the α-carbon atom attached directly to the heteroatom (N, O, S)
giving an unstable intermediate which decomposes leading to the break of the carbon-
heteroatom bond thus causing Oxidative N-, O-, and S-dealkylation and oxidative
deamination.

The presence of a- hydrogen is a must

6
  2-Hydroxylation or oxidation of the heteroatom (N, S only) → N-hydroxylation, N-
oxide formation, sulfoxidation and sulphone formation.

a-Oxidation involving carbon–nitrogen systems

I-Oxidation of tertiary aliphatic and alicyclic amines:

 Two types of oxidation reactions.

 Catalyzed by Cytochrome P450

i-Oxidation of the carbon atom α to the nitrogen:

oxidation reaction leading to the elimination of alkyl groups (especially methyl groups).
oxidative N-dealkylation.

carbinolamine

 α-carbon hydroxylation gives unstable carbinolamine intermediate which undergoes

spontaneous heterolytic cleavage of the C-N bond giving secondary amine + carbonyl
moiety.

 rules which govern the N-dealkylation reactions:

1-small alkyl groups e.g. methyl, ethyl and isopropyl are removed rapidly

2- α-carbon involved has to be attached to a hydrogen atom.

3-The removal of first alkyl gp from tertiary amines is faster than second alkyl gp.

4- In tertiary amines with different substituents smaller alkyl group is more rapidly
removed.e.g. benzphetamine.

7
5- Bisdealkylation of tertiary amines will give primary aliphatic amine which will lead to
further oxidation as shown later.
6-Alicyclic tertiary amines undergo oxidative N-dealkylation. e.g. meperidine .

7-carbon α to an alicyclic nitrogen will undergo hydroxylation giving lactam metabolite. e.g.
nicotine (below).

8-Dealkylation of tertiary amines is faster than secondary.

b- Oxidation of the nitrogen gives N-oxide which may undergo reduction by reductase to give
tertiary amine again.

 N-oxide metabolite may possess pharmacological activity. e.g. imipramine oxidized to

active N-oxide

 N- oxidation is a minor metabolic pathway.

 Dealkylation more predominant.

II-  Secondary aliphatic and alicyclic amines:

8
  The secondary amine may be parent drug or metabolite which will undergo metabolism
by

 a- oxidation of the carbon α to the nitrogen  giving.

i-N-dealkylation through carbinolamine intermediate giving primary amine metabolite.

propranolol..................Carbinolamine..........pri
mary.........ketone

ii-Oxidative deamination:

 similar to N-dealkylation.
 larger bulk of the molecule will be eliminated as a carbonyl metabolit.
 smaller bulk is removed as a small amine moiety.
 The mechanism is again through α-carbon
hydroxylation giving carbinolamine intermediate leading to carbon-nitrogen cleavage
and the formation of carbonyl + amine.

as shown below:

9
  Both reactions possible dealkylation first then deamination is more favourable.
 Secondary amines will undergo N-dealkylation before deamination.
 direct deamination of secondary amines takes place.
 propranolol has two α- carbon atoms which contain H (both subject to hydroxylation)
leading to two possibilities :

A- N-Dealkylation followed by elimination of acetone moiety giving primary amine metabolite

then deamination giving carbonyl metabolite.

OR
B-Direct dealkylation → elimination of isopropylamine → aldehyde metabolit.

Secondary alicyclic amines undergo α hydroxylation giving lactam metabolite e.g.

phenmetrazine (shown below).

10
b-Oxidation of the nitrogen atom:

 Results inseveral oxygenated products.

 N-Hydroxylation will give the corresponding N-hydroxylamine metabolites which will

undergo further oxidation (spontaneously or enzymatically) giving nitrone derivatives.

Example is N-benzylampheatmine sahown below).

III-Primary aliphatic amines:

 Parent drug or metabolite (Dealkylation of primary amine or bis dealkylation of

secondary amine) will undergo
a- Oxidation of the carbon α to the nitrogen leading to oxidative
deamination (catalized by mixed function oxidases).

Endogenous primary amines e.g. dopamine, nor epinephrine → oxidative deamination

(monoamine oxidases (MAO))  inactivation.
b- Oxidation of the nitrogen atom leading to formation of N-hydroxyl amine (chemically
unstable) which undergoes spontaneous or enzymatic oxidation giving nitroso and nitro
derivatives.

Structural features of the α- substituent will determine which oxidation will take place that
of the carbon or the nitrogen.
E.g. in phenteramine the Oxidation of Nitrogen inevitableas shown below:

11
  normally if α-carbon contains a H then either oxidation of N to give N oxide or
Oxidation of C to give deamination as shown

Dealkylation is a more common pathway than N-oxidation in human

IV-Oxidation of aromatic amines and heterocyclic nitrogen compounds

1-For tertiary aromatic amines: N-dealkylation and N-oxidation e.g. N,N-dimethylaniline.

2-Secondary aromatic amines:

1. N-dealkylation →primary amine or N-hydroxylation to give nitrone e.g. N-methyl-4-

aminoazobenzene.

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3- Primary aromatic amines:

 more common in drug

 Can be formed from metabolism of other compounds.
 Will be N-hydroxylated giving N-hydroxylamine which is further oxidized to the
nitroso then nitro derivatives.
 Nitrogen atoms in aromatic heterocyclic moieties undergo N-oxidation (minor extent)

c-Oxidation of carbon-sulfur system

 Three types of oxidative metabolic reactions.

1......Cleavage of carbon-sulfur bonds (S-Dealkylation).

similar to O- and N- dealkylation reactions (α-carbon hydroxylation} + (α-hydrogen

atom).

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2.......Desulfuration:
oxidative conversion of carbon-Sulfur double bonds (C=S) to carbon-oxygen double bond
(C=O).

3.......Oxidation of the sulfer or  S-Oxidation.

 Common metabolic pathway.

 Major metabolic pathways for several phenothiazines.

 Thioridazine (Mellaril) undergoes S-

oxidation (2- methylthio group) giving
the active sulfoxide metabolite
mesoridazine twice as active an
antipsychotic thus was synthesized and
introduced in the market as sentril.
Further S-oxidation will produce sulfones (-SO2-).

Oxidation of alcohols and aldehydes

non-microsomal

 Alcoholic metabolites produced by microsomal oxidation will undergo phase Π

conjugation or will be oxidized. Primary alcohols will give aldehydes and secondary
alcohols will give ketones.
 Catalyzed by a non-microsomal enzyme alcohol dehydrogenase in the liver and
other tissues and requires NAD+ or NADP+ as coenzyme.
 Reversible i.e. if not immediately oxidized will be reduced to the alcohol again by
alcohol dehydrogenase.
 Aldehyde produced from primary alcohol drug or from the deamination aliphatic
amines will be further oxidized to the corresponding carboxylic acids catalyzed
by aldehyde dehydrogenase enzymes e.g. aldehyde oxidase and xanthine oxidase.
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  As mentioned before cyclic amines give lactam metabolites.

First oxidized by  microsomal oxidation  of ring carbon α- to the nitrogen giving
carbinolamine intermediate then carbinolamine will be oxidized tocarbonyl moiety by  non
microsomal alcohol dehydrogenase.

2-Reductive reactions

i-Reduction of aldehydes and ketones:

 The aldehyde or keton may be parent drugs or metabolits (oxidative deamination of

primary and secondary amines) will undergo reductive metabolic reactions.
 Reduction is  not a major metabolic pathway for aldehydes since the undergo rapid
oxidation to carboxylic acids.
 Ketones are not easily oxidized so they undergo reduction to secondary alcohols then
are conjugated to glucuronic acid and are excreted in urine.
 The reduction is catalyzed by enzymes called aldo-keto reductases (nammely alcohol
dehydrogenase) undergo bioreduction of aldehydes and ketones.
 In liver and other tissues and require NADPH as cofactor.
 The same enzyme undergoes both the oxidation and the reduction reactions e.g.
alcohol dehydrogenase.
 Bioreduction of aldehydes to alcohols is not common, a known example.

 Reduction of ketones will produce asymmetric center i.e. two possible isomers
( formation of one isomer more favorable).
 The preferable production of one stereoisomer over the other is called product
stereoselectivity.

ii-Reduction of azo and nitro compounds:

 Leads to formation of primary amines.

 Aromatic nitro compounds are reduced initially to the nitroso and hydroxylamine
intermediates.
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  Another example is Clonazepam reduction of the aromatic nitro group to amino.

 Performed by NADPH-dependant microsomal and nitro reductase enzymes in the liver

and bacterial reducrases in intestine.
 Clonazepam and nitrazepam are metabolized extensively by reduction of the nitro
group to give the 7-amino metabolite in human.

 Most famous example is metabolic redcution of azo drugs e.g. sulphamidochyrosidine

(prontosil) to give sulfanilamide (liver). This lead to discovery of sulfonamides as
antibacterial. (structures before).
 Bacterial reductase in the intestine also undergo reduction of nitro compounds ehich
are excreted in the bile.
 Bacterial reductases also contributeto the reduction of azo drugs (poorly absorbed)
e.g. sulfasalazine (in ulcerative colitis) (poorly absorbed) undergoes reductive cleavage
of the azo linkage in the colon producing Sulfapyridine and 5-aminosalicylic acid in thus
becomes active.

iii-Miscellaneous reductions :

 Reduction of sulfoxides (limited extent)

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  More common is the oxidation of sulfoxides to sulfone (i.e. the opposit reaction).
 Sulindac (anti-inflammatory) will undergo reduction to give sulfide metabolite (active
and is responsible for the overall anti-inflammatory activity of the parent drug.
 Sulfone metabolite have little anti-inflammatory activity.

3-Hydrolytic reactions

1-Hydrolysis of esters:

 Catalyzed by esterasesin the liver, kidney and intestine.

 Hydrolysis is major metabolic pathway for esters (ease of hydrolysis of the ester
linkage).
 Hydrolysis of esters will produce alcohol and acid functional groups which will undergo
conjugation.
 Hydrolysis → pharmacologically active metabolites.

 P-chlorophenoxyisobutyric acid is a major metabolite and is responsible for

hypolipidimic effect of the drug.
 The ease of hydrolysis of esters and the presence of estrases in many tissues and
plasma leds to the use of ester derivatives as prodrugs to overcome side effects
(bitter taste, poor absorption, and poor solubility irritation at site of injection).
 Once inside is biotransformed to the active drugs.
 A famous example is the antibiotic chloramphenicol ( bitter taste).
 Palmitate ester will mask the taste in pediatric preparations.
 Upon oral administration intestinal estrases and lipases will undergo hydrolyis
liberating active chloramphenicol.

17
2-Hydrolysis of amides:

 Microsomal amidases and deacylases will produce carboxylic acid + amine metabolites.
 Hydrolyis of amides is slowler than ester hydrolysis.

Hydrolysis of procainamide is much slower than procain (ester) (cannot be administered

orally).

 Another example is the hydrolysis of the amide linkage in.

 Another example is indomethacine.

PHASE II (CONJUGATION REACTIONS)

 Capable of converting parent xenobiotics or phase I metabolites into polar and water
soluble products.
 Conjugated products are relatively excretable, biologically inactive and non toxic.
 Some phase II reactions such as methylation and acetylation only terminate the
pharmacological activity.but does not not increase solubility.

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  Phase II reactions is the truly detoxifying pathway in drug metabolism (few
exceptions).

Drug + Conjugating Agent → Conjugating Product

 The conjugated agent (e.g. glucuronic acid, sulfate, methyl & acetyl) is activated
to give coenzyme with the appropriate transferase enzyme leads to the attachment to
the accepting substrate.
 In case of glycine and glutamine → substrate is initially activated.
 Glutathione does not require initial formation of an activated coenzyme or substrate.

I- Glucuronic acid conjugation

 Most common conjugative pathway in drug metabolism

1. Readily available supply of D- glucuronic acid in the body (from D- glucose).

2. A large number of functional groups can combine enzymatically with glucuronic acid
e.g. hydroxyl groups (phenols, alcohols, enols, N-hydroxylamines, N-
hydroxylamides) carboxyl groups (aryl acids, arylalkyl acids). nitrogen
groups (arylamines, alkylamines, amides, sulfonamides, tertiary amines) sulfhydryl
groups.
3. The conjugated products are water soluble and are eliminated very fast.

 Involves two steps

a-Synthesis of the activated coenzyme, uridine-5'-diphospho –α-D- glucuronic
acid (UDPGA).
b-Transfer of glucuronyl group from UDPGA to an appropriate substrate.
catalyzed by microsomal enzymes called UDP-glucuronyltransferases.

α-D-Glucose will be transformed to α-D-Glucose-1-phosphate which is then converted

to  Uridine-5'-diphospho-α-D-glucose (UDPG)  then by UDP-Glucoronyl-transferase will
produce-B-Glucoronide.

II- Sulfate conjugation

 The amount of sulfate available is limited.

 Utilized to conjugate endogenous compounds e.g. steroids, catecholamines, and
thyroxin.
 Phenols and alcohols, aromatic amines, and N- hydroxyl compounds can combine
enzymatically with sulfate.
 The sulfate conjugation process involves:
a-Activation of inorganic sulfate into the coenzyme 3-phosphoadenosine -5'-
phosphosulfate (PAPS).

19
 b-Sulfate group by sulfotransferases (in liver, kidney and intestine) is transferred to
the substrate.

III-Conjugation with glycine, glutamine and other amino acids

 Availability of amino limited acids in the body.

 Glycine and  glutamine are conjugated to carboxylic acids (aromatic acids and arylalkyl
acids).
 Glycine and glutamine are not activated to coenzymes. the carboxylic acid substrate is
activated.
 The conjugation process involves:
a-The carboxylic substrate in presence of ATP and coenzyme A is converted to acyl
coenzyme A complex
b- Acyl coenzyme A complex react with glycine or glutamine in presence of N- acyl
transferase enzymes is transferred onto glycine or glutamine causing
acylation(conjugation).

IV- Glutathione or mercapturic acid conjugation.

 Covalent interaction of electrophilic metabolites with cellular nucleophiles causes

toxicity.
 Glutathione conjugation (nucleophilic sulfhydryl group) is a pathway to detoxifiy
chemically reactive electrophilic compounds.
 No initial formation of an activated coenzyme or substrate is required.
 The inherent reactivity of the nucleophilic GSH towards an electrophilic substrate will
sufficient driving force to cause conjugation.

 The conjugation process involves:

1. The substrate conjugates with glutathione (γ- glutamylcysteinylglycine) by enzymes

known as glutathione S- transferases gives (glutathione adduct).
2. Glutathione adduct undergoes sequential enzymatic cleavage of two amino acids
(glutamic acid and glycine).
3. N- Acetylation of the S- substituted cysteine residue will produce mercapturic acid.

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V-Acetylation

 Important metabolic route for drugs containing primary amino groups (e.g. primary
aromatic amines sulfonamides, hydrazines, hydrazides, and primary aliphatic
amines).
 The produc is inactive and non toxic but water solubility is not enhanced.
 The conjugation process involves:

1. Formation of Acetylcoenzyme A conjugating agent (active form).

2. Transfer of the acetyl group from accetyl coenzyme A to the accepting amino
substrate by N- acetyltransferases enzyme.

VI-Methylation

 Methylation does notproduce polar or water soluble metabolites except when it

produces ammonium derivative.
 Methylated products are mostly pharmacologically inactive.
 Methylation plays an important role in the biosynthesis of many endogenous
compounds (e.g. epinephrine) in addition to the inactivation of physiologically active
biogenic amines (e.g. norepinpherine, serotonin and histamine).
 Groups which under go methylation are: catechols, phenols, amines, N-heterocyclic and
thiol compounds.
 The conjugation process involves:

1. The methyl group is converted into its active form (S- adenosylmethionine (SAM)).
2. The activated methyl group is transferred onto accepting substrate by
methyltransferases
enzyme.

FACTORS AFFECTING DRUG METABOLISM

 A drug is not metabolized by a single metabolic pathway.

 A single drug may be metabolized by different phase I and phase II metabolic
pathways giving several metabolites from the same parent drug.
 Relative amount of metabolites depends on the concentration and the activity of the
enzymes metabolizing them.

The following factors may affect the metabolic rate of the drug:

1.Age-related differences:
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  Newborn suffer from underdevelopment or deficiency of oxidative and conjugative
enzymes leading to reduction of metabolic capacity. e.g.oxidative (cytochrome P-450)
metabolism of tolbutamide is reduced in newborn leading to increased t ½ (40 hours Vs
8 hours in adults).
 Glucuronyltransferase activity reductuin leading to the reduction inchloramphenicol
conjugation with glucuronic causing the accumulation of toxic levels of the drug
causing gray baby syndrome.
 Elderly patients show evidence of inefficientdrug metabolism due to compromised liver
functions.

2-Genetic or hereditary Factors:

 There are differences in the rate of metabolism observed of some drugs in hum.
 Acetylation shows rate differences in human e.g. procainamide undergoes conjugation
of amino groups with acetyl group.
 Marked difference among individuals in the rate of acetylation of these drugs leads to
it's being either slowly or rapidly metabolized (bimodal distribution).
 Rapid acetylators (have more acetyl transferase in their liver).
 The rate of acetylation affects the therapeutic response and toxicity of these drugs.
 Rapid acetylators undergo fast elimination leading to inadequate therapeutic response
to the drug.
 Slow acetylators are subject to toxicity due to accumulation of the drug.

3-Species differences:

 A particular drug may be metabolized differently by different species.

 Strain differences in metabolism may also take place e.g. oxidative deamination or
aromatic hydroxylationare two metabolic pathways of amphetamine.
 In human, guinea pig and rabbit oxidative deamination predominates.
 In rats aromatic hydroxylation is the predominates.
 There is also some difference due to presence or absence of the particular
transferase enzyme e.g. cats lack glucuronyl transferase while pigs lack
sulfotransferase enzyme and thus unable to conjugate phenols .

4-Sex differences:

 Sex differences is species dependent.

 Rabbits and mice do not show sex differences in human there arevery few reports of
sex differences in metabolism e.g. the metabolism of nicotine and aspirin seem to
differ between men and women.

5-Enzyme induction:
22
  Exposure to certain drugs leads to markedly increased activity of hepatic microsomal
enzymes e.g. cytochrome P450 (enzyme induction), E.g pesticides and polycyclic
aromatic hydrocarbons and other environmental pollutants.
 Due to the increase in the synthesis of more enzymes in the liver.
 Enzyme induction leads to increase in the rate of metabolism of drugs including the
the those drugs that induced the enzyme activity in the first place.
 Drug induction leads to serious drug interaction if a known enzyme-inducing drug is
coadministered with one or two drugs which are known to be largely metabolized by
liver enzymes.
 This will lead to marked decrease in the bioavailability of the drugs leading to
decrease in activity.
 Coadministration of warfarine (anticoagulant) ((largely eliminated through liver
metabolism)) and the hypnotic phenobarbitone (efficient enzyme enducer) leads to
marked decrease in anticoagulant activity of warfarine.
 Dosage readjustment of warfarin is very important when it is coadministered with
phenobarbital and also when the patient suddenly stops taking the barbiturate.
 Poycyclic hydrocarbons e.g. benzo[α] pyrine and environmental pollutants e.g.
polychlorinated biphenyls induce certain oxidative pathways and consequently the
metabolism of drugs.
 Enzyme induction increases toxicity of some drugs by increasing the production of a
certain chemically reactive metabolite. E.g oxidation of acetophenone → reactive
imidoquinones is catalyzed by phenobarbital-inducible form of cytochrome P450
enzymes in rats.
 Phenobarbital pretreatment leads to in vivo hepatotoxicity and covalent binding of
phenacetine.

6-Enzyme inhibition:

 Certain drugs are capable of inhibiting drug metabolizing enzymes.

 Through substrate competition, inhibition of protein synthesis, inactivation of drug-
metabolizing enzyme and hepatotoxicity leads to impairment of drug metabolism
causing accumulation of the drug in the body.
 Phenylbutazone stereoselectively inhibits the metabolism of the more potent (S)(-)-
enantiomer of warfarine.This explains the increased hypoprothrombinemia and
hemorrhaging in patients taking both warfarine and phenylbutazone.

7-Miscellaneous factors affecting drug metabolism:

 Dietary factors e.g. protein/carbohydrate ratio, indoles present in some vegetables

e.g. cabbage, vitamins and minerals, starvation and malnutrition will all influence drug
metabolism.
 Physiologic state of the liver (Hepatic cancer, cirrhosis, hepatitis).
 Pregnancy, hormonal disturbances (thyroxin, steroids).
 Circadian rhythm may all influence the metabolism of drugs.

23
 Summary

Phase I

*Cytochrome P450 looks for sites most electron rich and least sterically hindered.
So aromatic rings with electron withdrawing groups (Halogens, Nitro, carboxylic acid etc..)
are not oxidized.
*The same drug can be oxidized at different sites.

so when looking at a drug we look for

1-Aromatic (benzene ring) → para hydroxylation.

(R is the rest of the molecule)

2-Olifin (double bond) → diol

24
3- Methyl group attached to benzene (benzylic carbon) → alcohol

4-Methyl group attached to C=C (allylic carbon) → alcohol.

5-Carbon next to carbonyl and imin (benzodiazepine) → secondary alcohol

6-long chain → oxidation of ω (terminal) carbon or ω -1 (carbon before the terminal)

...........................→ alcohol

7-Alicyclic (saturated ring) → alcohol on para position .

8-Tertiary or secondary aliphatic amine → removal of a methyl group to give amine

.......(make sure to remove the smaller group)
.......(called oxidative dealkylation)
.......(make sure the alkyl group removed has H on it )
25
.......(if the other group is small will be removed in a second step)

9-Tertiary nitrogen (nitrogen with no hydrogen on it) → N-oxide.

10-Primary amine (R-CH2-NH2) → NH3 (amonia) + R-CHO (carbonyl)

.........(oxidative deamination)
.........(make sure the carbon next to N has H on it)

or

........R- NH2 → R-NO2 (nitro).

11-An OCH3 group R-OCH3 → R-OH (alcohol)+ HCHO

12-An (R-S-CH3) → removal of CH3 → R-SH + HCHO

..........the carbon removed should have H

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or

..............→ Oxidation of the sulfur → Sulfoxide or sulfone.

13-A Sulfur attached to a carbon with double bond C=S → C=O (oxidative desufuration).

14- R-CH2OH (alcohol) → R-CHO (aldehyde) → R-COOH (acid).

15- R-COOCH2R' (ester) → RCOOH (acid)+ R'-CH2OH (alcohol).

16-R-HNCO-R' (amide) → R-NH2 (amine) + R-'COOH (acid)

all the functional groups produced above (aromatic OH ; NH2 ; C=O ; COOH ; SO2 ;
NO2 ; SH etc...) will be conjugated in phase II.
*If a drug has a functional group before metbolism e.g. OH or COOH or aromatic NH2 etc..
It can go directly to phase II and conjugates this functional group to a conjugating agent
(mostly glucoronic acid)
*Aromatic amines are famous for conjugation to Acetyl group.

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