2. INTRO
The cytochrome P450 is a superfamily of mono-
oxygenases
Heme-containing enzymes OR hemoproteins
Officially abbreviated as CYP
Is a large and diverse group of enzymes that
catalyze the oxidation of organic substances
They absorb light at a wavelength of 450 nm
3.
4.
5. INTRO (CONTD.)
The substrates of CYP enzymes include –
1. lipids and steroidal hormones
2. Xenobiotics such as drugs and toxic chemicals
CYPs are the major enzymes involved in drug
metabolism and bioactivation, accounting for
about 75% of the total number of different
metabolic reactions
6. SITE
Present throughout the body
Act primarily in the ER of the hepatocytes and
the cells of the intestine
Conditions that cause viral hepatitis or cirrhosis
will affect the efficiency of drug metabolism by
the CYP enzymes
7. P450 IN HUMANS
Human CYPs are primarily membrane-
associated proteins located either in the inner
membrane of mitochondria or in the endoplasmic
reticulum of cells
Some CYPs metabolize only one (or a very few)
substrates, such as CYP19 (aromatase), while
others may metabolize multiple substrates
8. (CONTD.)
Humans have 57 genes and more than
59 pseudogenes divided among 18 families of
cytochrome P450 genes and 44 subfamilies.
9.
10. DRUG METABOLISM
CYP enzymes account for 75% of drug
metabolism
Most drugs undergo deactivation by CYPs, either
directly or by facilitated excretion from the body.
Also, many substances are bioactivated by CYPs
to form their active compounds.
11. DRUG INTERACTION
Many drugs may increase or decrease the activity
of various CYP isozymes
Inducing the biosynthesis of an isozyme (enzyme
induction)
Directly inhibiting the activity of the CYP
(enzyme inhibition)
This is a major source of adverse drug
interactions
12. If one drug inhibits the CYP-mediated metabolism
of another drug, the second drug may accumulate
within the body to toxic levels
Hence, these drug interactions may necessitate
dosage adjustments or choosing drugs that do not
interact with the CYP system
Drug interactions are especially important when
using drugs of vital importance to the patient, drugs
with important side-effects and drugs with small
therapeutic windows
13. 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
14. THERAPEUTIC IMPLICATIONS OF INDUCTION
Most drugs can exhibit decreased efficacy due to
rapid metabolism
but drugs with active metabolites can display
increased drug effect and/or toxicity due to
enzyme induction
Dosing rates may need to be increased to
maintain effective plasma concentrations
15. CONSEQUENCES OF INHIBITION
Increase in the plasma concentration of
parent drug
Reduction in metabolite concentration
Exaggerated and prolonged pharmacological
effects
Increased liklihood of drug-induced toxicity
16. 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 predicting and understanding
inhibition
17. GENETIC VARIATION AND ITS IMPLICATION
Wide variability in the response to drugs
between 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
18. CYP2D6 is extensively studied, the gene for CYP2D6 is
highly polymorphic
It’s expression leads to 3 phenotypes (phenotype is the
expression of genetic make-up)
Extensive metabolizers (EMs) have functional enzyme
activity
Intermediate metabolizers (IMs) have diminished enzyme
activity
Poor metabolizers (PMs) have little or no activity
5-10% of Caucasians and 1-2% of Asians exhibit the PM
phenotype
19. CONCEPTS
Substrate - An agent that is metabolized by an
enzyme into a metabolic end product and eventually
excreted
Inhibitor - An agent which interferes with the
ability of a given enzyme to metabolize a given
substrate (Competitive or allosteric). This leads to
RAPID increase in levels of the substrate.
Inducer - An agent which causes an increase in the
production of the enzyme(s) responsible for
metabolizing a given substrate. Leads to GRADUAL
(1-3 weeks) decrease in blood level of substrate.
20. DRUG-DRUG INTERACTION PATTERNS
‹Pattern 1 - An inhibitor is added to a substrate.
Example: Paroxetine is added to nortriptyline,
leading to an increase in the nortriptyline blood
level.
Pattern 2 - A substrate is added to an inhibitor.
Example: Nortriptyline is added to paroxetine,
leading to a higher than expected blood level of
nortriptyline at a given dose.
21. Pattern 3 : An inducer is added to a substrate.
Example: Carbamazepine is added to haloperidol,
leading to a decrease in the haloperidol blood
level.
Pattern 4: A substrate is added to an inducer.
••Example: Haloperidol is added to carbamazepine
leading to a lower than expected blood level of
haloperidol at a given dose.
22. Pattern 5 : Reversal of inhibition.
An inhibitor and a substrate have been stably co--
administered and then the inhibitor is
discontinued.
Example: Cimetidine is discontinued in the
presence of nortriptyline, leading to a decrease in
the nortriptyline blood level.
23. Pattern 6 : Reversal of induction.
An inducer and a substrate have been stably co-
administered and then the inducer is discontinued••
Example: A patient on clozapine abruptly
discontinues smoking, leading to an increase in
the clozapine blood level.
