The document discusses inhibition and induction of drug metabolism. Induction increases enzyme activity and intracellular enzyme concentration, while inhibition decreases enzyme activity. The cytochrome P450 system, specifically CYP3A4, metabolizes many drugs and its inhibition or induction can cause drug-drug interactions. Factors like genetic polymorphisms, disease, age, and gender can also affect biotransformation. Drug interactions are an important consideration in polypharmacy and when monitoring drug levels.

1. INHIBITION AND
INDUCTION OF DRUG
METABOLISM
INHIBITION OF BILIARY
Swarna Priya B
Pharm D 5th year

2. INTRODUCTION
The state of enzymatic systems involved in drug biotransformation
represents an important factor in pharmacokinetic and/or
pharmacodynamic variability. The changes in the state of enzymatic
systems may be qualitative and quantitative.
Qualitative changes are commonly due to impairments in the state of the
enzymatic systems, genetically pre-determined (enzymopathies).
Quantitative changes may evolve in two directions: either towards the
stimulation of enzyme activity (enzyme induction) or the reverse, a
reduction in enzyme activity (enzyme inhibition).
The pharmacological consequences of both phenomena are quantitative
and refer to the modification of intensity and/or duration of the
pharmacological effect of the drug, the modification of t1/2 and
biotransformation rate, the appearance of adverse reactions of
overdosing, and therapeutic inefficacy.

3. INDUCTION OF THE CYTOCHROME
P450 SYSTEM
Induction is defined as an increase in enzyme activity associated with an
increase in intracellular enzyme concentration.
Cytochrome P450 is a family of isozymes responsible for the
biotransformation of several drugs. Drug metabolism via the cytochrome
P450 system has emerged as an important determinant in the occurrence
of several drug interactions that can result in drug toxicities, reduced
pharmacological effect, and adverse drug reactions.
Recognizing whether the drugs involved act as enzyme substrates,
inducers, or inhibitors can prevent clinically significant interactions from
occurring.
Avoiding coadministration or anticipating potential problems and adjusting
a patient's drug regimen early in the course of therapy can provide optimal
response with minimal adverse effects.

4. CYP ENZYMES
Drug metabolism via the cytochrome P450 system has emerged as an
important determinant in the occurrence of several drug-drug
interactions.
A greater degree of interaction predictability has been achieved
through the identification of P450 isozymes and some of the drugs
that share them. Six different P450 isozymes—CYP1A2, CYP2C19,
CYP2C9, CYP2D6, CYP2E1, and CYP3A4—that play important roles in
drug metabolism have been identified.
Of these 6 isozymes, shared metabolism by the CYP3A4 isozyme has
resulted in several clinically significant drug-drug interactions.

5. FACTORS AFFECTING
BIOTRANSFORMATION
Genetic polymorphism
Disease
Age and
Gender

7. CYP ISOZYME INTERACTIONS
For CYP3A4-metabolized drugs that require periodic monitoring of
serum levels, the interaction of another CYP3A4- metabolized drug
can be controlled by dosage adjustments to maintain appropriate
levels of the monitored drug. Cyclosporine (CYA), tacrolimus, and
carbamazepine are all substrates of CYP3A4. Coadministration of
cyclosporine with a CYP3A4 inhibitor decreases an individual's CYA
dosage requirement.
Ketoconazole and diltiazem, purer entities of CYP3A4 inhibitors, have
been used successfully in this respect. Patients unable to obtain
therapeutic CYA levels with orally administered cyclosporine due to
inadequate absorption can been placed on either of these agents to
achieve this goal.

9. INDUCTION OF OTHER ENZYME
SYSTEMS
Naturally, since the phase II enzyme systems are involved in the
major routes of detoxication, there is much interest in the induction
of these systems, especially for cancer chemoprevention.
We refer especially to some of the phase II metabolising enzymes,
such as UDP-glucuronosyl transferase (UDPGT) and glutathione-S-
transferase (GST).
The induction of UDPGT and GST has been proven to be highly
dependent on the nature of the inducer under consideration, as well
as on the species variability.

11. INHIBITION OF THE CYTOCHROME
P450 SYSTEM
Inhibition of drug metabolism by pre- or co-administration of other
drugs or xenobiotics is a well-recognized phenomenon, with
pharmacological and toxicological effects, reflected by exacerbated
pharmacodynamic activity and adverse effects of relative overdosing
at the usual therapeutic doses.
In the context of the common practice of polypharmacy, another
topic of great interest arises, namely drug-drug interaction. The
other major interest in enzyme inhibition is based on a very
important sector of therapy, namely the selection of enzymes as
targets for drug action.

12. BASIC MECHANISM OF ENZYME
INHIBITION
1) Competitive inhibition
2) Non-competitive inhibition
3) Uncompetitive inhibition
4) Product inhibition
5) Transition-state analogues
6) Slow, tight-binding inhibitors
7) Mechanism-based enzyme inactivation
8) Inhibitors that generate reactive intermediates that can covalently
be attached to the enzyme.

13. INHIBITION OF BILIARY EXCRETION
Drugs are often conjugated and excreted in bile. Some drugs are
excreted in bile biotransformation. (Eg: water soluble drugs)
This excretion is mainly via transporters and possibility exists for
drug interaction with concomitant administration.
Conjugates such as glucoronides are often excreted in bile and
deconjugated in the intestinal tract and reabsorbed enterohepatic
circulation.
The co-administration of drugs which inhibits the co-transporter
involved in biliary excretion can reduce the biliary excretion of drug
which are substrates of the transporter, leading to elevated plasma
drug concentration.

14. CONCLUSION
The human cytochrome P450 enzyme system, and to some extent
phase II metabolizing enzymes, are susceptible either to induction or
inhibition mechanisms;
Sometimes, because of a too rapid biotransformation (direct
consequence of increased enzyme activity), mega-doses of drug are
required, which may not always be possible (e.g. for drugs with broad
therapeutic index); plasma levels are too rapidly achieved and the
clearance is also too rapid, so the drug has insufficient time to
display its pharmacological action;
Induction, by increasing enzyme activity, will result in decreased
metabolism of certain drugs, contributing to significant inter- and
intraindividual variations in drug efficacy and potential toxicity,
associated with drug-drug interactions;

15. CONCLUSION
As shown in the corresponding subsection, it is important to mention
that the clinical effects following alterations in drug efficacy are
dependent on several factors, including the extent of enzyme
induction, the relative importance of the enzyme in the multiple
pathways of metabolism, and on the therapeutic ratio of substrate
and metabolite;
Different inducers (drugs, or other compounds from food and the
environment) display substrate specificity for CYTP450 isoforms;
Prevalent inducing conditions in humans include smoking, alcohol
consumption and diet;
Elevated levels of specific CYP450 isoforms (1A and 2E1) may
contribute to increased risk of cancer; in particular, CYP2E1 may
contribute to alcohol-induced liver damage and acetaminophen
toxicity in alcohol consumers.

16. CONCLUSION
Inhibition of drug metabolism represents a subject of great interest
for several reasons. It can give rise to a decrease in drug
biotransformation, low plasma levels, decreased clearance (possibility
of overdosing at common, therapeutic doses) and increased risk in
the occurrence of drug-drug interactions. Besides decreasing the
therapeutic effect on one drug by concurrent administration of
another, it is unfortunately proven that some drug-drug interactions
may be even fatal;
Practical aspects of inhibition include an understanding of the
phenomenon at the molecular level, especially as it relates both to
such drug-drug interactions (prediction, avoidance or minimization
of the risks), as well as the utilization of enzymes as therapeutic
targets.

17. THANK YOU!