1. Biotransformation refers to the chemical alteration of drugs in the body by enzymatic processes, primarily in the liver. This renders drugs more water-soluble and aids in their elimination. 2. Metabolism occurs in two phases - phase I involves oxidation, reduction, and hydrolysis reactions. Phase II involves conjugation reactions like glucuronidation that make drugs more polar and excretable. 3. Key enzymes involved in biotransformation include cytochrome P450 enzymes and UDP-glucuronosyl transferases. Metabolism can inactivate drugs, produce active metabolites, or sometimes toxic metabolites.

1. INTRODUCTION TO
BIOTRANSFORMATION OF DRUG
(EG METABOLISM OF PHENYTOIN AND
CODEINE )
PRESENTED BY
ADAM SHAHUL HAMEED
M.TECH COMPUTATIONAL BIOLOGY

2. INTRODUCTION
 Biotransformation means chemical alteration of the drug in the
body.
 Biotransformation is a major mechanism for drug elimination.
 Enzymatic processes in liver and other tissues that
modify the chemical structure of drugs render them more
water-soluble, increase their elimination, decrease their
half-life.
 Biotransformed metabolites are chemically different from the
parent molecule
 Metabolism makes the compound less lipid soluble and more
polar and thus hydrophilic.

3. TYPES OF METABOLIC TRANSFORMATION
There are two phases in the metabolism of drugs:-
 Phase 1 reaction. (Non synthetic phase).
 This involves a change in drug molecule. It involves oxidation,
reduction or hydrolysis. This may result in activation, change
or inactivation of drug.
 Phase II reaction. (Synthetic phase)
 It involves formation of conjugates with drug or its metabolites
formed in phase 1 reaction. The conjugate is formed with an
endogenous substance such as carbohydrates and amino
acids.

4. OXIDATION
 Loss of electrons M = M+ + e-
 Gain of oxygen R + O = RO
 Hydroxylation; Oxygenation at C,N and S atoms;N or O
dealkylation, oxidative deamination

5. CYTOCHROME P-450 MONOOXYGENASE
(MIXED FUNCTION OXIDASE)
 A large number of families (at least 18 in mammals) of
cytochrome P-450 (abbreviated “CYP”) enzymes exists
 Each member of which catalyzes the biotransformation of a
unique spectrum of drugs. some overlap in the substrate
specificities.
 This enzyme system is the one most frequently involved in
phase I reactions.

6. CYTOCHROME P-450 MONOOXYGENASE
(MIXED FUNCTION OXIDASE)
 Heme protein
 Terminal oxidase of the mixed-function oxidase (MFO)
electron-transfer system
 Located in the smooth endoplasmic reticulum of all
major organs and tissues
 Uses NADPH as a source of reducing equivalents

7. THE P450 GENE SUPERFAMILY
 Format of nomenclature:
CYPFamily/Subfamily/Gene
 The cytochrome P-450 families are referred to using an
arabic numeral, e.g., CYP1, CYP2, etc.
 Each family has a number of subfamilies denoted by an
upper case letter, e.g., CYP2A, CYP2B, etc.
 The individual enzymes within each subfamily are denoted
by another arabic numeral, e.g., CYP3A1, CYP3A2, etc.

8. Localization
 The primary location of cytochrome P-450 is the liver,
 Liver is the major organ of biotransformation
 Kidney, Lungs, testes, skin intestines are the secondary organ of
biotransformation.
 Other tissues, including:
 the adrenals
 ovaries and testis
 tissues involved in steroidogenesis and steroid metabolism.
 The enzyme's subcellular location is the endoplasmic reticulum.

9. Mechanism of reaction
In the overall reaction:
 the drug is oxidized
 oxygen is reduced to water.
 Reducing equivalents are provided by nicotinamide
adenine dinucleotide phosphate (NADPH), and
generation of this cofactor is coupled to cytochrome
 Most of the reactions of cytochromeP450 involve
the addition of a hydroxyl group to a compound
which may be represented as

10. REDUCTION
 Gain of electrons M+ + e- = M
 Loss of oxygen RO = R + O
 Gain of hydrogen R + H = RH

11. REDUCTION
 Nitro to amino group
NO2 NO HNOH HNH
 Chromium VI to Chromium III
Cr6+ + 3 e- Cr3+

13. CYCLIZATION AND DECYCLIZATION
Cyclization
This is formation of ring structure from a straight
chain compound, e.g. proguanil.
De cyclization
This is opening up of ring structure of the cyclic
drug molecule, e.g. barbiturates, phenytoin.

14. SYNTHETIC REACTIONS (PHASE 2 METABOLISM)
 These involve conjugation of the drug or its phase I
metabolite with an endogenous substrate, generally derived
from carbohydrate or amino acid, to form a polar highly
ionized organic acid, which is easily excreted in urine or bile
 Conjugation reactions have high energy requirement
 For conjugation to take place, a compound should have an
appropriate group or centre eg – COOH, -OH, -NH, or –SH.
 Conjugated metabolites are in variably less lipid soluble than their
parent compound

15. GLUCURONIDE CONJUGATION
 This is the most important synthetic reaction carried out by a group
of UDP-glucuronosyl transferases (UGTs).
 Compounds with a hydroxyl or carboxylic acid group are easily
conjugated with glucuronic acid which is derived from glucose.
 Examples are chloramphenicol, aspum, paracetamol, lorazepam,
morphine, metronidazole.
 Not only drugs but endogenous substrates like bilirubin, steroidal
hormones and thyroxine utilize this pathway.

16. Acetylation
 Compounds having amino or hydrazine residues are
conjugated with the help of acetyl coenzyme-A, e.g.
sulfonamides, isoniazid, PAS, hydralazine, clonazepam,
procainamide.
Methylation
 The amines and phenols can be methylated;
methionine and cysteine acting as methyl donors, e.g.
adrenaline, histamine, nicotinic acid, methyldopa,
captopril

17. SULFATE AND GLYCINE CONJUGATION
Sulfate conjugation
The phenolic compounds and steroids are
sulfated by sulfotransferases (SULTs).
e.g. chloramphenicol, methyldopa, adrenal and sex
steroids.
Glycine conjugation
Salicylates and other drugs having
carboxylic acid group are conjugated with glycine, but this
is not a major pathway of metabolism.

18. Glutathione conjugation:
 Forming a mercapturate is normally a minor pathway. However, it
serves to inactivate highly reactive quinone or epoxide intermediates
formed during metabolism of certain drugs, e.g. paracetamol.
 When large amount of such intermediates are formed (in poisoning
or after enzyme induction), glutathione supply falls short-toxic
adducts are formed with tissue constituents to tissue damage.
Ribonucleoside/nucleotide synthesis:
 This pathway is important for the activation of many purine and
pyrimidine antimetabolites used in cancer chemotherapy.

19. MICROSOMAL ENZYMES
 These are located on smooth endoplasmic reticulum
(a system or microtubules inside the cell), primarily in liver,
also in kidney, intestinal mucosa and lungs.
 The monooxygenases, cytochrome P 450, glucuronyl
transferase, etc. are microsomal enzymes.
They catalyse most of the oxidations, reductions, hydrolysis
and glucuronide conjugation
Microsomal enzymes are inducible by drugs, diet and other
agencies.

20. NONMICROSOMAL ENZYMES
 These are present in the cytoplasm and mitochondria of
hepatic cells as well as in other tissues including plasma
 The flavoprotein oxidases, esterases, amidases and
conjugases are nonmicrosomal enzymes.
Reactions catalysed are:
 Some oxidations and reductions, many hydrolytic
reactions and all conjugations except-glucuronidation.

21. 1. Cytochrome P-450
2. Alcohol
dehydrogenase
3. Deaminases
4. Esterases
5. Amidases
6. Epoxide hydratases
1. Glucuronyl transferase
(glucuronide conjugation)
2. Sulfotransferase (sulfate
conjugation)
3. Transacylases (amino acid
conjugation)
4. Acetylases
5. Ethylases
6. Methylases
7. Glutathione transferase.
Enzymes catalyzing phase I
biotransformation
Enzymes catalyzing phase II
biotransformation

22. HOFMANN ELIMINATION
 This refers to inactivation of the drug in the body fluids
by spontaneous molecular rearrangement without the
agency of any enzyme, e.g. atracurium.

23. RESULTS OF BIOTRANSFORMATION
 Production of metabolites that are more polar than the
parent drug
 Usually terminates the pharmacologic action of the
parent drug
 After phase I reactions, similar or different
pharmacologic activity, or toxicologic activity.

25. METABOLISM OF DRUG LEADS TO
 Inactivation of drug: The active drug is converted in to inactive
metabolites & excreted. Ex-lidocaine, ibuprofen. Also conversion of
phenytoin to p-hydroxy phenytoin.
 Active metabolites from equally active metabolites: The drug is
converted in to similar active metabolites. Ex- conversion of codeine in to
morphine, having similar activity.
 Active metabolites from inactive drug (prodrug): Some drugs given in
the form of inactive form which are made active by metabolism.
Ex- enalapril which activated in the form of enalaprilat, which is prodrug.

26. METABOLISM OF DRUG LEADS TO
 Conversion in to toxic substances: Xenobiotics metabolizing
enzymes are responsible for elimination of drug but may convert it in to
toxic metabolites.
 This occurs when the enzyme convert the drug in to unstable
intermediate which has affinity towards cellular component & causing
toxic effect.
 They have carcinogenic activity, when the electron deficient atom is
formed which reacted with DNA & RNA of the cell and causing
mutation of gene. Other ex- conversion of paracetamol to toxic
metabolite causing hepatic toxicity.

29. PHENYTOIN
EPILEPSY:
It is a Chronic medical condition produced by sudden
changes in the electrical function of the brain.

31. METABOLISM OF PHENYTOIN

32. Pharmacokinetics of phenytoin
 Well absorbed when given orally, however, it is also available as iv. (for
emergency)
 80-90% protein bound
 Induces liver enzymes (Very Important)
 Metabolized by the liver to inactive metabolite
 Metabolism shows saturation kinetics and hence t ½ increases as the dose
increased
 Excreted in urine as glucuronide conjugate
 Plasma t ½ approx. 20 hours
 Therapeutic plasma concentration 10-20 μg/ml (narrow)
 Dose 300-400 mg/day

33. CODEINE
 Codeine or 3methylmorphine (a naturally occurring
methylated morphine) is an opiate used for its
analgesic, antidiarrheal, antihypertensive, anxiolytic,
antidepressant, sedative and hypnotic properties.
 Codeine is used to treat mild to moderate pain and to
relieve cough.

34. METABOLISM OF CODEINE

35. METABOLISM OF CODEINE

36.  REFERENCE
1.Essential of medical Pharmacology by K.D Tripathi and
Jaypee page no 23 to 30
2.Biochemistry by U.Sathya narayana and U.Chakrapani.
3.Modern Pharmacology with Clinical applications by
Lipinncott (Sixth Edition )
4.Pharmacy Tutor www.pharmatutor.com
5.Wikipedia Biotransformation of Drug.
 My Sincere Thanks to SHRIKANTH (Comp Bio )