(C) Sir CED

1. Metabolic Changes
in Drugs
Chapter 3
Organic Medicinal and Pharmaceutical
Chemistry 12th Edition

2. Xenobiotics
O substances foreign to the body
O include environmental pollutants, food
additives, cosmetic chemicals,
agrochemicals, processed foods, and
DRUGS.
O substances entering the body are relatively
LIPOPHILIC (fat-loving or lipid soluble)

3. Xenobiotics
O If lipophilic drugs were not metabolized to
polar, readily excretable products, they
would remain indefinitely in the body,
eliciting their biological effects. Hence,
No Metabolism Accumulation Toxicity

4. Drug Metabolism
O Diagram (Refer to your notes)

5. Drug Metabolism
O conversion of lipophilic (hydrophobic)
compounds into hydrophilic (lipophobic)
derivatives that are readily eliminated in
urine or bile.

6. Drug Metabolism
O the formation of water-soluble metabolites
not only enhances drug elimination, but
also leads to compounds that are generally
pharmacologically inactive and relatively
nontoxic.

7. Drug Metabolism
O drug interactions are based on metabolic
processes
O Pharmacists: To understand why certain
drugs are contraindicated with other drugs

8. Drug Metabolism
PRODRUGS
O drugs biotransformed to pharmacologically
active metabolites
O usually, parent compound is inactive when
administered and must be metabolically
converted to a biologically active drug

9. Drug Metabolism
Inactive Parent
Compound Active Metabolite
O Sulindac (NSAID) O Sulfide Metabolite
Reduction

10. Drug Metabolism
Inactive Parent
Compound Active Metabolite
O Azathioprine
(Immunosuppresant)
O 6 – Mercapturine
Cleavage

11. Drug Metabolism
Inactive Parent
Compound Active Metabolite
O Acyclovir (Antiviral) O Acyclovir triphosphate
Phosphorylation

12. Drug Metabolism
Active Parent
Compound Active Metabolite
O Phenacetin
(Analgesic)
O Acetaminophen
O-dealkylation

13. Drug Metabolism
Active Parent
Compound Active Metabolite
O Imipramine
O Amitriptyline
(TCADs)
O Desipramine
O Nortriptyline
N-demethylation

14. Is drug metabolism a
detoxification process?

15. Sites of Biotransformation
LIVER
O most important organ in drug metabolism
INTESTINAL MUCOSA
O important site of metabolism for orally
administered drugs
KIDNEYS, LUNGS, ADRENAL GLANDS,
PLACENTA, BRAIN, SKIN
O substrate selective and more limited to
particular types of reaction

16. First Pass Effect
O phenomenon in drug metabolism whereby
the concentration of drug is greatly reduced
before it reaches the systemic circulation
O orally administered drugs that are
absorbed into the bloodstream through the
GI tract are susceptible for they must pass
through the liver before further distributed
into the system

17. Drugs Metabolized by the
First Pass Effect
OLidocaine
OIsoproterenol
ONitroglycerin
OSalicylamide
OPropranolol
OPropoxyphene
OPentazocine
OMeperidine
OMorphine

18. Role of Enzymes in
Biotransformation
Enzymes Reactions
Cytochrome P450s (CYP) C and O oxidation,
dealkylation
Flavin-containing
Monooxygenases (FMO)
N, S, and P oxidation
Epoxide hydrolases (mEH
and sEH)
Hydrolysis of epoxides
Alcohol dehydrogenases Reduction of alcohols
Aldehyde dehydrogenases Reduction of aldehydes

19. Role of Enzymes in
Biotransformation
Enzymes Reactions
Sulfotransferases (SULT) Addition of Sulfate
UDP-
glucoronosyltransferases
(UGT)
Addition of Glucoronic acid
Glutathione-S-transferases
(UST)
Addition of Glutathione
N-acetyltransferases (NAT) Addition of Acetyl group
Methyltransferases (MT) Addition of Methyl group

20. Reaction Cycle involving Cytochrome
p-450 in the oxidation of xenobiotics

21. Reaction Cycle involving Cytochrome
p-450 in the oxidation of xenobiotics
Steps involved:
1. Drug substrate binds to CYP450
2. CYP450-Drug complex is reduced by NADPH
3. Molecular oxygen (O2) binds to the reduced
CYP450-Drug complex
4. One atom of oxygen combines with the drug
substrate, the other atom forms water
5. Oxygen is reduced to an “activated” state
6. The enzyme complex dissociates to yield free
oxygenated drug metabolite

22. Pathways of Drug Metabolism
Phase I Reactions
O Oxidative reactions
O Reductive reactions
O Hydrolytic reactions
Phase II Reactions
O Glucuronic acid
conjugation
O Sulfate conjugation
O Amino acid conjugation
O Glutathione or
mercapturic acid
conjugation
O Acetylation
O Methylation

23. Phase I
Functionalization Reactions
O introduce functional polar groups (e.g., -OH,
-COOH, -NH2, -SH) into the compound to
produce a more water-soluble compound.
O may not produce sufficiently hydrophilic or
inactive metabolites.
O the functional group on the molecule
attached can undergo subsequent phase II
reactions.

24. Phase I
Functionalization Reactions
Direct Introduction of Functional Group
O Aromatic and Alipathic Hydroxylation

25. Phase I
Functionalization Reactions
Modification of Existing Functionalities
O Reduction
 RCOR/RCHO ROH (Alcohol)
 azo/nitro groups RNH2 (Amine)

26. Phase I
Functionalization Reactions
Modification of Existing Functionalities
O Oxidation
O ROH RCHO (Aldehyde)
O RCHO RCOOH (Carboxylic Acid)
O N, O, S -NH2, -OH, -SH

27. Phase I
Functionalization Reactions
Modification of Existing Functionalities
O Hydrolysis
O esters/amides RCOOH
ROH
RNH2

28. Phase II
Conjugation Reactions
O attaches small, polar, and ionizable
endogenous compounds (e.g. glucuronic
acid, sulfate, glycine, and other amino acids)
to the “handle” of phase I metabolites or
parent compounds to form water-soluble
CONJUGATED PRODUCTS – devoid of
pharmacological activity

29. Phase II
Conjugation Reactions
O Glucuronic acid conjugation
O Sulfate conjugation
O Amino acid conjugation (Glycine and
Glutamine)
O Glutathione or mercapturic acid conjugation
O Acetylation
O Methylation

30. Pathways of Drug Metabolism
In Conclusion,
Phase I and II reactions complement
one another in detoxifying and facilitating the
elimination of drugs and xenobiotics.
e.g. Δ1 – tetrahydrocannabinol (principal
psychoactive constituent of marijuana)

31. Pathways of Drug Metabolism
Refer to page 44
of the book

32. Factors Affecting
Drug Metabolism
Age Differences
O oxidative and conjugative capabilities:
Newborn vs. Adult
O oxidative metabolism of Tolbutamide is
lower in newborns: t1/2 40 hrs; adults: t1/2 8
hrs
O inability of babies to glucuronidate Bilirubin
leads to neonatal hyperbilirubinemia or
Kernicterus
O inability of babies to conjugate
Chloramphenicol results to Gray Baby
Syndrome

33. Factors Affecting
Drug Metabolism
Species and Strain Differences
O metabolism of drugs and foreign compounds
is species dependent
O Amphetamine
O Humans, Rabbits, Guinea Pigs –
undergoes oxidative deamination
O Rats – undergoes aromatic hydroxylation

34. Factors Affecting
Drug Metabolism
Species and Strain Differences
O Amphetamine
O Humans, Rabbits, Guinea Pigs – undergoes
oxidative deamination
O Rats – undergoes aromatic hydroxylation
O Cats – poor glucuronidation; good sulfation
O Pigs – poor sulfation; poor glucuronidation

35. Factors Affecting
Drug Metabolism
Species and Strain Differences
O even within the same species, individual
variations (strain differences) may result in
differences of specific metabolic pathways
O Acetylation
O Orientals and Eskimos – rapid acetylators
O Mediterrenean Jews and Egyptians – slow
acetylators

36. Factors Affecting
Drug Metabolism
Hereditary or Genetic Factors
O marked individual differences in the
metabolism of several drugs exist in humans

37. Factors Affecting
Drug Metabolism
Sex Differences
O species dependent
O significant in terms of drug-drug
interactions based on the drug’s metabolism
O e.g. Aspirin and Nicotine are metabolized
differently in men and women

38. Factors Affecting
Drug Metabolism
Enzyme Induction
O increased activity of drug metabolizing
enzymes
O increases the rate of drug metabolism and
decreases the duration of drug action
O e.g. Phenobarbital and Warfarin:
induction of phenobarbital increases the
metabolism of warfarin which decreases the
anticoagulant effect of the drug

39. Factors Affecting
Drug Metabolism
Enzyme Inhibition
O decreased activity of drug metabolizing
enzymes
O with decreased metabolism, the drug
accumulates, leading to prolonged drug
action and serious adverse effects
O e.g. grapefruit-drug interactions
Carbamazepine (Tegretol), Atorvastatin
(Lipitor), etc

40. Factors Affecting
Drug Metabolism
Miscellaneous Factors
O Dietary Factors
O protein-carbohydrate ratio
O indoles present in vegetables
O polycyclic aromatic hydrocarbons in
charcoal-broiled beef
O vitamins, minerals, starvation, malnutrition

41. Factors Affecting
Drug Metabolism
Miscellaneous Factors
O Physiological Factors
O state of the liver
O pregnancy
O hormonal disturbances