DRUG METABOLISM

Objectives

Describe about the drug

metabolism

Differentiate and understand

the Phase I and II metabolism.
• Renal excretion plays pivotal role in
terminating the biologic activity of some
drugs, particularly those that have small
molecular volumes or possess polar
characteristics, such as functional groups
that are fully ionized at physiologic pH.
• Pharmacologically active organic molecules
are lipophilic, remain unionized or only
partially ionized at physiologic pH;
• Readily reabsorbed from the glomerular filtrate
in the nephron.
• Certain lipophilic compounds are strongly bound
to plasma proteins and may not be readily filtered
at glomerulus.
• So, most drugs have a prolonged duration of
action if termination of their action depended
solely on renal excretion.
• An alternative process leading to
termination or alteration of biologic activity
Metabolism.
Transformation of Xenobiotics by Biological
Systems
 Phase I reactions
• Convert parent drug to a more polar
metabolite by introducing or unmasking a
functional group (–OH, –NH2, –SH)
• Often these metabolites are inactive,
although in some instances activity is
only modified or even enhanced
• If phase I metabolites are sufficiently
polar, they may be readily excreted.
Phase II metabolism
• Many phase I products are not eliminated
rapidly and undergo subsequent reaction in
which endogenous substrate such as
glucuronic acid, sulfuric acid, acetic acid,
or an amino acid combines with newly
incorporated functional group to form a
highly polar conjugate.
• Conjugation.
 WHERE DO DRUG
BIOTRANSFORMATIONS OCCUR?
• Principal organ………….
• Gastrointestinal tract, lungs, skin, kidneys,
brain
• After oral administration: many drugs:
…………effect
• Intestine: clonazepam
• Gastric acid (penicillin)
• Although drug
biotransformation in vivo can
occur by spontaneous, non-
catalyzed chemical reactions,
most transformations catalyzed
by specific cellular enzymes.
• Endoplasmic reticulum,
mitochondria, cytosol,
lysosomes, nuclear envelope
plasma membrane
 Liver enzymes
• Oxidation-reduction process, two
microsomal enzymes play a key role.
• NADPH cytochrome P450 oxidoreductase
and cytochrome P450
• CYP1A2, CYP2A6, CYP2B6, CYP2C9,
CYP2D6, CYP2E1, and CYP3A4: most
important forms
• More than 50% drugs: CYP3A4
 Phase I Metabolism

R ROH R RCOOH

R RSH R RNH2
Phase I Reactions

OXIDATION
REDUCTION
HYDROLYSIS
Aliphatic Oxidation
 Aromatic Hydroxylation

acetanilid p-hydroxyacetanilid
N-Dealkylation
O-Dealkylation
S-Demethylation
Oxidative Deamination
S-Oxidation
N-Oxidation
N-Hydroxylation
Desulfuration
Reduction
 Nitro Reduction
NITRO REDUCTION

RNO2 RNH2

MICROSOMES AND CYTOSOL

Nitro Reduction
AZO REDUCTION
Azo Reduction

RN=NR' RNH2 + R'NH2

MICROSOMES AND CYTOSOL

 Amide Hydrolysis
AMIDE HYDROLYSIS

RCONR'R" RCOOH+ HNR'R"

MICROSOMES AND CYTOSOL

 Ester
ESTER Hydrolysis
HYDROLYSIS

RCOOR' RCOOH + R'OH

MICROSOMES AND CYTOSOL

PHASE II METABOLIC PATHWAYS
 Phase II Metabolism
A molecule endogenous to the body
donates a portion of itself to the foreign
molecule

D+ENDOX DX+ENDO
 Glucuronidation
Methylation
Sulfation
Glycine conjugation
Glutathione conjugation
Acetylation
 Uridine-5’--D-glucuronic
Acid

The microsomal enzyme glucuronyl transferase conducts the donation of

glucuronic acid from the endogenously synthesized UDPGA to various
substrates to form glucuronide conjugates. morphine and acetaminophen.
 UDP--D-Glucuronsyltransferase

• Is also called glucuronyl transferase

• A microsomal enzyme
• Products are called glucuronides
• Glucuronides formed
– RN-G; RO-G; RCOO-G; RS-G;
RC-G
 Glucuronidation of Benzoic Acid

UGT= UDP--D-Glucuronsyltransferase
 Sulfate Conjugation

PAP: 3’-phosphoadenosine- 5’-phosphate

 S-Adenosylmethionine

Cytosolic enzymes such as catechol-O-methyl transferase (COMT)

and phenylethanolamine-N-methyl transferase (PNMT) conducts
the donation of the methyl group from the endogenously
synthesized SAM to various substrates to form methylated
conjugates
 Methyltransferases
• A family of soluble enzymes that
conducts
– N-methylation; N-CH3
– O-methylation; O-CH3
– S-methylation; S-CH3
• S-adenosylmethionine (SAM)is the
endogenous donor molecule.
 Maintenance dose
• Drugs are administered in such a way as to
maintain a steady state of drug in the body,
i.e, just enough drug is given in each dose to
replace the drug eliminated since the
preceding dose.
 Plasma Protein Binding
• Acidic drugs generally bind to plasma
albumin and basic drugs to alpha1 acid
glycoprotein.
 Implications
1. Highly plasma protein bound drugs are largely
restricted to vascular compartment.

2. The bound fraction is not available for action.

3. High degree of protein binding generally

makes drug long acting.

4. Plasma concentrations of drug: bound as well

as free drug.
• Listen
• One person at a time
• Active participation
• Discussion during activity only
• Any questions, ask immediately
• No question is wrong, no question is superb
• Group: discussion leader, time keeper,
recorder, presenter
• Listen
 How to learn?
No rote learning

Understand

Knowing topic beforehand

Going through topic after class

Any queries, doubts; solve immediately (peers, references,

facilitator)
 Enzyme Induction
Some of the chemically
dissimilar P450 substrate By enhancing rate of
drugs, on repeated synthesis or reducing
administration, induce rate of degradation
P450 expression

Accelerated substrate
metabolism decrease in
the pharmacologic action
of inducer and also of
co-administered drugs.
• Smoke, charcoal-
broiled meat, other
organic pyrolysis
products, cruciferous
vegetables, and the
proton pump
inhibitor,
omeprazole: CYP1A
• CYP3A: phenytoin,
dexamethasone,
rifampin, mifepristone,
phenobarbital, St.
John’s wort
 Enzyme Inhibitors
• Cimetidine, Erythromycin, fluconazole,
grapefruit juice,
• Indinavir, Ritonavir, saquinavir,
telaprevir,
• Diltiazem, Verapamil
• Itraconazole, ketoconazole,
voriconazole
First order (exponential)
kinetics)
Rate of
elimination
directly
proportional to
drug
concentration

Constant fraction
of drug present
in body is
CL remains eliminated in unit
constant time.
 Zero Order Kinetics
• Rate of elimination remains constant
irrespective of drug concentration
• CL decreases with increase in
concentration
• Constant amount of drug is eliminated
in unit time, e.g. ethyl alcohol.
• Kinetics changes from first order to
zero order at higher doses:
phenytoin, tolbutamide,
theophylline, warfarin: Clinical
Implication
 Plateau principle
• When constant dose of a drug repeated before
expiry of 4 half-lives , achieves higher peak
concentration, as some remnant of previous
dose will be present.
• Continues with every dose until progressively
increasing rate of elimination balances amount
administered
• So, plasma concentration plateaus and
fluctuates about an average steady-state level.
• An 85-year-old, 60-kg woman
with a decreased creatinine
clearence has atrial fibrillation. A
decision has been made to use
digoxin to control the rapid heart
rate. The target concentration of
digoxin for the treatment of atrial
fibrillation is 1 ng/mL.
 Effects on:
• Volume of distribution
• Renal clearance
• Half life
• Bioavailability
• Target concentration: when will
it be reached?
• A drug with a high Vd has a propensity to
leave the plasma and enter the extravascular
compartments of the body, meaning that a
higher dose of a drug is required to achieve a
given plasma concentration. (High Vd -> More
distribution to other tissue)
• Conversely, a drug with a low Vd has a
propensity to remain in the plasma meaning a
lower dose of a drug is required to achieve a
given plasma concentration. (Low Vd -> Less
distribution to other tissue)
• For example, patients with chronic renal
failure have both decreased renal clearance
of digoxin and a decreased volume of
distribution; the increase in digoxin half-life
is not as great as might be expected based
on the change in renal function.
• The decrease in volume of distribution is
due to the decreased renal and skeletal
muscle mass and consequent decreased
tissue binding of digoxin to Na+/K+-
ATPase.
• Only 70% of a dose of digoxin reaches the
systemic circulation after oral
administration, mainly due to lack of
absorption from the gut.