cyp450 system

BY DR. SRIRAM.R

CYP 450 SYSTEM

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

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

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

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

(CONTD.)

Humans have 57 genes and more than

59 pseudogenes divided among 18 families of

cytochrome P450 genes and 44 subfamilies.

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.

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

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

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

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

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

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

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

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

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.

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.

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.

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.

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.

THE ENZYMES

„ 3A4

„„ 2D6

„„ 1A2

„„ 2C9

„„ 2C19

„„ 2E1

„„ 2B6

3A4

Notable Substrates

‹‹ alprazolam, triazolam

‹‹ aripiprazole

‹‹ carbamazepine

‹‹ methadone

‹‹ pimozide

‹‹ quetiapine

‹‹ risperidone

‹‹ tertiary amine TCAs (IMI, AMI, etc.)

‹‹ zolpidem/zaleplon

3A4

Notable inhibitors

‹‹ azole antifungals

‹‹ ciprofloxacin/norfloxacin

‹‹ fluoxetine/fluvoxamine

‹‹ grapefruit juice

‹‹ HIV protease inhibitors

‹‹ macrolide antibiotics (except azithromycin)

‹‹ methadone

‹‹ nefazodone

3A4

Notable inducers

‹‹ barbiturates


‹‹ modafinil

‹‹ oxcarbazepine

‹‹ phenobarbital

‹‹ phenytoin

‹‹ ritonavir

�� St. John’s wort

‹‹ topiramate

2D6

Notable substrates

‹‹ amphetamines amphetamines

‹‹ ß-blockers

�� codeine →morphine

‹‹ hydrocodone →hydromorphone

‹‹ phenothiazines

‹‹ TCAs

‹‹ tramadol

‹‹ venlafaxine

2D6

Notable inhibitors

‹‹ bupropion

‹‹ cimetidine

‹‹ duloxetine

‹‹ fluoxetine

‹‹ paroxetine

‹‹ quinidine

‹‹ ritonavir

‹‹ sertraline (>150 mg/d)

‹‹ TCAs

2D6

No known inducers – possibly dexamethasone

and/or rifampin

1A2

Notable substrates

‹‹ caffeine (and theophylline)

‹‹ clozapine

‹‹ cyclobenzaprine

‹‹ olanzapine

‹‹ probably several other typical antipsychotics

1A2

Notable inhibitors

‹‹ caffeine

‹‹ cimetidine

‹‹ fluoroquinolones

‹‹ fluvoxamine

‹‹ grapefruit juice

1A2

Notable inducers

‹‹Cruciferous vegetables (broccoli, brussels

sprouts, cauliflower)


‹‹ modafinil

‹‹ rifampin

‹‹ TOBACCO smoking

2C9

Notable substrates

‹‹ glipizide/glyburide

‹‹ phenytoin

‹‹ S-warfarin

THC

2C9

Notable inhibitors

‹‹ cimetidine

‹‹ fluconazole

‹‹ fluoxetine/fluvoxamine/paroxetine

‹‹ metronidazole

‹‹ modafinil

‹‹ ritonavir

‹‹ sulfamethoxazole

‹‹ valproate

2C9

Notable inducers



‹‹ phenytoin

‹‹ rifampin

2C19

Notable substrates

‹‹ diazepam

‹‹ phenytoin

‹‹ tertiary amine TCAs

2C19

Notable inhibitors


‹‹ cimetidine

‹‹ disulfiram

‹‹ fluoxetine

‹‹ fluvoxamine

‹‹ omeprazole

‹‹ sertraline

‹‹ ritonavir

‹‹ topiramate

2C19

Notable inducers (same as 2C9)



‹‹ phenytoin

‹‹ rifampin

2E1

Notable substrates

‹‹ acetaminophen

‹‹ ethanol

Notable inhibitors

‹‹ disulfiram

‹‹ isoniazid

2E1

Notable inducers

‹‹ chronic ethanol use

‹‹ isoniazid

‹‹ obesity

‹‹ retinoids

‹‹ tobacco smoking

2B6

Notable substrates

‹‹ bupropion

‹‹ cyclophosphamide/ifosfamide

‹‹ tamoxifen

2B6

Notable inhibitors

‹‹ fluoxetine

‹‹ fluvoxamine

‹‹ nefazodone

‹‹ paroxetine

‹‹ sertraline

2B6

Notable inducers


‹‹ phenytoin

‹‹ rifampin

THANK YOU

cyp450 system

Health & Medicine

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