Sue P450

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Here's FLockharts P450 chart.

You will have to make sure you understand the difference between

inducers, substrates and inhibitors.

http://medicine.iupui.edu/flockhart/table.htm

The following are definitions

a) The Cytochrome P450 SystemThe cytochrome P450 enzyme system

chemically oxidizes or reduces drugs

during the process of metabolism.

There are more than 25 human cytochrome P450 enzymes,

identified using a particular nomenclature. There are

4 major families, indicated by number, six major subfamilies,

indicated by letter, then individual enzymes within

a subfamily, also indicated by number.

For example, 3A4, 2D6, 2C19.

The origin of the name 'P450' lies in the

fact that these cytochromes absorb ultraviolet

light in the presence of carbon monoxide at a wavelength of 450 nm.

Other hepatic enzymes involved in drug clearance.

Besides the cytochrome P450 system, other enzymes

are also involved in metabolism. This includes

glucuronyl transferases, acetylases,

sulfotransferases and proteases.

c) What is a P450 substrate?

A P450 substrate is any drug that is

metabolised by one or more of the P450 enzymes

(also referred to as 'isoforms').

Most drugs are mainly metabolized by

a single P450 enzyme.

There are many P450 enzymes in humans.

Only a few of these enzymes are involved

in drug metabolism.

More than 50% of metabolised drugs

are substrates for the 3A4 enzyme.

This enzyme is by far the most important for antiretroviral drugs.

d) What is a P450 inhibitor?

A P450 inhibitor is any drug that inhibits

the metabolism of a P450 substrate.

This occurs because the drug reduces

the amount/activity of the P450 enzyme,

which leads to inhibition of metabolism.

Like most enzymatic inhibition, this

process is almost always competitive

and reversible. In other words,

as soon as the inhibitor is gone,

metabolism is back to normal.

Like all enzyme inhibitors,

some P450 inhibitors are strong (potent)

inhibitors, and others are poor (weak).

For example,

the approved HIV protease

inhibitors are all cytochrome

P450 3A4 enzyme inhibitors. However,

ritonavir is a potent inhibitor,

amprenavir, indinavir and nelfinavir

are moderate inhibitors, and saquinavir

is a weak inhibitor.A drug does not have

to be a P450 substrate to be an inhibitor.

For example, fluconazole is a moderate to

weak P450 inhibitor, but is not a P450 substrate

- it is primarily cleared renally.

e) What is a P450 inducer?

A P450 inducer increases the amount of the P450 enzyme.

It does this by binding directly to elements

in the DNA that regulate expression of the gene.

By doing this, inducers cause an increase in

transcription of the P450 gene and thus increase

the amount of enzyme produced. An increase in the

amount of enzyme produced implies a more rapid rate

of metabolism of drugs that are substrates for that

enzyme.Unlike inhibition, induction persists for

several days, even after stopping administration

of the inducing drug. This is because the enzymes

which have been induced persist for several days

following induction.Inducers can turn on (activate)

many genes at once. Thus, an inducer like ritonavir

can increase the amount of not only P450 3A4 and 2D6,

but also the amount of glucuronyl transferase.

This is the reason why ritonavir and nelfinavir

reduce concentrations of glucuronyl transferase

substrates like zidovudine, as well as P450

substrates like ethinyl estradiol.

Some drugs are potent inducers,

while others are moderate or weak inducers.

Rifampin and phenobarbital are two of

the most potent inducers. Ritonavir,

nelfinavir, efavirenz and nevirapine

are moderate P450 inducers