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Flashcards in Drug Metabolism Deck (39):

Why do drugs get metabolized?

The body needs a process to remove potentially harmful foreign chemicals or chemicals that aren't doing anything from accumulating.
Plants and some animals produce chemicals that could be toxic.
The body will generally remove all foreign chemical by a process known as metabolism or biotransformation


Where do drugs go?

There are many avenues by which drugs can be metabolized: liver (most important; e.g., first pass metabolism), secretions into the bile and elimination in feces, kidneys, lungs, intestinal gut flora (i.e., bacteria metabolize drugs), skin and other organs


What happens to hydrophilic drugs?

Very hydrophilic drugs will get excreted unchanged


What happens to lipophilic drugs?

Lipophilic drugs are usually metabolized (lipophilic drugs bind to proteins, distribute in the fatty tissue and tend to persist in the body longer than hydrophilic drugs)
They generally avoid excretion by the kidneys


What is the general goal of metabolism?

Chemically modify (metabolize) lipophilic drugs to increase their water solubility so that the metabolized drug can be excreted by the kidneys


What can metabolism do?

Metabolism can eliminate or reduce the activity of a drug, alter the activity of the drug, increase or decrease the potency of a drug, activate prodrugs (drugs that are designed to undergo metabolism in order for it to be fully active)


What happens in phase I metabolism?

A parent drug can be modified (oxidation, hydrolysis, reduction) into a modified drug


What happens in phase 2 metabolism?

A (modified) drug can undergo biosynthetic conjugation (glucuronidation, sulfation, glutathione acetylation) to become a drug conjugate


Are the phases of metabolism linear?

No, drug can be eliminated by:
No phases (excreted unchanged; hydrophilic drugs)
Phase I only
Phase I then Phase II
Phase II only
Phase I then Phase II then back to Phase I


What types of reactions happen in phase I metabolism?

Oxide formation
Alcohol oxidation


What are the most important phase I enzymes?

Cytochrome P450 family aka CYP enzymes


What are CYPs?

CYPs are heme proteins that require electrons and oxygen to function (electrons come from NADPH)
Oxygen is reduced while the drug is oxidized


Describe the CYP enzyme family

They are grouped by relatedness measured by amino acid similarity
There are at least 30 CYP enzymes, many found in the liver but also found throughout the boyd


How are CYPs designated?

CYP#letter# (e.g., CYP3A4)
The first number refers to the family (having >40% amino acid similarity)
The letter refers to the subfamily (having >59% amino acid similarity)
The second number refers to the gene/subtype of the sub family


CYPs are generally divided into two groups. What are the groups?

CYP1 through CYP4 are generally known as the drug metabolizing enzymes
CYP11, 17, 19 and 21 are the steroidogenic enzymes (they also participate in drug metabolism)


Name some important CYPs

CYP1A1 (found in the lung and placenta induced by smoke)
CYP1A2 (found in the liver induced by smoke metabolizes caffeine)
CYP2B6 (found in the liver and other tissues, induced by some anticonvulsants)
CYP2C8, 2C9, 2C18, 2C19 (found in the liver, metabolizes many drugs)
CYP2D6 (found in the liver and other tissues, metabolizes many drugs)
CYP2E1 (found in the liver, induced by alcohol)
CYP3A3, 3A4, 3A5 (one of the most abundant CYPs in the liver, one of the most important classes of CYPs for drug metabolism)
CYP4A11 (found in the liver and kidney, involved in fatty acid metabolism)


What are some CYP reactions?

Aliphatic hydroxylation
Aromatic hydroxylation
Alkene oxidation
N or S oxidation
N, O or S dealkylation
Nitro reduction (uncommon)
Oxidative dehalogenation


Where does aliphatic hydroxylation take place?

It happens on the next-to-last or penultimate carbon on an aliphatic chain
The chain has to be 2 or more carbons


What does the rate of aliphatic hydroxylation depend on?

The length of the chain; the longer the chain, the higher the rate


Where does aromatic hydroxylation take place?

If hydroxylation happens at all, its position of addition depends on R and its position in the ring. Electron donating R groups tend to increase hydroxylation and favour para-hydroxylation. Electron withdrawing R groups decrease hydroxylation


How can aromatic hydroxylation be eliminated?

By the addition of electron withdrawing substituents or halogens in the para position to R


What happens with regards to aromatic hydroxylation in fused aromatic ring systems?

Usually only one ring will be hydroxylated. Typically it is the ring with no electron withdrawing groups. Typically halogenated rings are also not hydroxylated


What happens more often: N oxidation or S oxidation?

S oxidation


What happens to epoxides?

Epoxides are very reactive and are hydrolyzed by epoxide hydrolase (EH). This process can also happen spontaneously.


What is a consequence of the reactivity of epoxides?

Epoxides are very reactive and can chemically modify proteins (e.g., protein alkylation). This is a potential source of toxicity produced by metobolism


What is a trans-diol?

If there is restricted rotation around a bond in an aromatic group, you get a trans diol. Otherwise you just get a idol


Can the formation of trans-diols be catalyzed?

Yes. Trans-diol formation can be catalyzed by epoxide hydrolase (EH) or can be non-enzymatic


Describe the active site of CYP enzymes

There is a heme group, with Fe in the centre. An oxygen finds to the iron and it is converted into a reactive form (active)


Describe CYP enzyme inhibitors

Some drugs are CYP inhibitors and many of these have imidazole groups that bind to the oxygen and inhibit the CYP enzymes. The azole antifungals are the most prominent example (ketoconazole, itraconazole, fluconazole).


Explain the importance of esterases and amidases

Esterases and amidases are not CYPs, but they preform hydrolysis reactions and are phase I enzymes. They are found throughout the body and in the blood
Prodrugs are often designed as esters or amides so that they are hydrolyzed by esterases and amidases to produce the active drug


Describe phase II enzymes

There are 6 important enzymes that transfer endogenous chemical to the drug.
They require: substrate (can be unmodified drug or drug modified by phase I), activated endogenous chemical (activated because it acts as a good leaving group for transfer of endogenous chemical to drug) and a functional group on the drug to modify


What are the 6 types of phase II conjugation?

Glucuronide conjugation (most important)
Glutathione conjugation
Sulfate conjugation
Amino acid conjugation


Describe glucuronide conjugation

Enzyme: UDP-glucuronosyl transferase (UGT)
Activated endogenous chemical: uridine diphosphate glucuronic acid (UDP-GA)
Target functional groups: OH (most common), SH, NH, COOH, R-NH-OH, R-S-OH
If the product is 350 Da, it is excreted in the feces


Describe glutathione conjugation

Enzyme: glutathione S transferase (GST)
Activated endogenous chemical: gamma-glutamyl-cystenyl-glycine (GSH) (exception to the general rule of activated substrate; it is not activated)
Target functional groups: any electrophile, carbonyls, substituted aromatic rings, double bonds
Mostly excreted in the feces


Describe glutathione S transferase

A tripeptide that is found in all tissues has a thiol group
Involved in scavenging reactive metabolites and free radicals
Toxic reactive metabolic intermediates of drugs are often detoxified by glutathione
Will work without GST but slower


Describe sulfate conjugation

Enzyme: sulfotransferase (ST)
Activated endogenous chemical: phosphoadenosine phosphosulfate (PAPS)
Target functional groups: OH, phenols, catachols, hydroxyl amines, hydroxysteroids (estradiol)
Excreted in the urine


Describe methylation

Enzyme: methyltransferase (MTase)
Activated endogenous chemical: S-adenosyl methionine (SAM)
Target functional groups: O, N, S
Excretion: urine or feces


Describe acetylation

Enzyme: acetyl transferase (AT; N-acetyl transferase are the most important but there is also O- and S-acetyl transferase) - decreases solubility
Activated endogenous chemical: acetyl co-enzyme A (Acetyl CoA)
Target functional groups: N, sometimes O or S
Mostly excreted in the urine


Describe amino acid conjugation

Enzyme: aminoacyl transferase (AA-T; most important is glycine)
Activated drug: Drug-CoA (exception: the drug is activated, usually through COOH, and you end up with a conjugated amino acid)
Target functional groups: COOH
Mostly excreted in the urine