531 Lec 11-13

Xenobiotic Metabolism

Xenobiotic Metabolism

•Xenobiotics are molecules that are foreign to life- cannot be utilized for energy or as metabolism building blocks

•Drug metabolism is a subset of xenobiotic metabolism

Ex: Pharmaceuticals, Recreational drugs, dieatary supplements, food additives

Why are Lipophilic xenobiotics are a problem?

they do not partition into teh aqueous compartments and bind in hydrophobic parts of the cells and tissue

Accumulation of lipophilic molecules leads to toxicity

Drug Disposition

Description of the absorption, distribution, metabolism, excretion as well as the pharmacokinetics of a drug in an animal or human

ADME(T)

Absorption, Distribution, Metabolism, Excretion, (Toxicity)

Pharmacokinetics

The mechanism and rate at which the drug is absorbed, distributed and excreted in an animal or human

Phase I  Drug Metabolism

Biotransformation- oxidation, reducation, hydrolysis reactions that create a chemical handle (hydroxyl, carboxylic acid, amine) for conjugating ionized group

•Oxidation of alkanes, arenes, aldehydes, dealkylation, dehalogenation

•Hydrolysis of esters, amides, epoxides

•Reducation of ketones, aldehydes

Phase II Drug Metabolism

Conjugation- addition of polar, charged group to increase water solubility for clearance or an addition reaction for detoxification

•Conjugation- sulfation , glucuronidation , amino acid conjugation

•Acetylation of amines to give amides

•Methylation of amines and phenols

•Alkylation of glutathione- reaction with electrophiles

Location of Drug metabolism

•Metabolism enzymes are concentrated in the liver and cells lining the GI tract

•First pass metabolism: phenomenon which occurs whenever the drug is administered orally, enters the liver, and suffers extensive biotransformation to such an extent that the bioavailability is drastically reduced

Transport proteins

•Solute Carrier proteins (SLCs): import into cell

→OATP, OCT

ABCs

export molecules out of cell

→MDR1/ ABC1/ Pgp major efflux pump in human cells

→Lower bioavailability drugs are substrates for efflux pumps

Grapefruit juice causes..

too much drug in your body

blocks CYP3A4

Why are some drugs only effective for a subset of the population and can be

dangerous for another subset?

•Some people need higher doses because there body metabolizes that drug ata higher rate: Extensive metabolizers

•Some people need smaller doses becuase their body doesnt metabolize the drug well leading to toxicity : Poor metabolizers

Bimodal population profile

Cytochromes P450 (CYP450)

•Family of related mixed function monooxygenases

•Incorporate a heme iron activated oxygen species that is a powerful oxidant able to oxidize unactivated CH bonds and variety of other functionality

•Located in the membranes of the endoplasmic reticulum- major source of degradation of small molecule drugs and other lipophilic xenobiotics

•Lab preps involve grinding liver and centrifugation to give microsomes: membrane containing enzyme preparations

•Originally evolved for lipid/hormone biosynthesis

•Most important enzymes in drug metabolism

Do many P450 catalyzed rxns do follow michaelis menton kinetics?

No →Maybe bc active sites are conformationally ambiguous and may bind multiple substrates leading to complex kinetics

How does the substrate find the active site?

•CYP3A4 has 3 major conformations with limited access

CYP1 family has 3 genes:

•CYP1A1

•CYP1A2

•CYP1B1

CYP2 family contains…

16 genes across 13 subfamilies

CYP3 family has 4 genes in one subfamily

CYP3A4,5,7 and 43

CYP1A1

historically called Aryl Hydrocarbon Hydroxylase oxidizes planar polycyclic aromatic hydrocarbons (PAHs) induced by dioxin, benzo[a]pyrene, PCBs, cigarette smoke

CYP1A2

oxidizes aromatic nitrogen containing compounds such as caffeine, imipramine, acetaminophen

CYP2C9/19

related isoforms that metabolize a wide range of prescribed drugs including warfarin, ibuprofen, phenytoin, omeprazole, and others

CYP2D6

also metabolizes a wide variety of structurally diverse drugs, especially in the antidepressant and antipsychotic drug classes. Also know for showing the largest genetic diversity in activity in humans. Not known to be induced in humans.

CYP2E1

small active site restricts substrates to smal molecules such as ethanol, styrene, acetaminophen, halogenated hydrocarbons and general anesthetics. Is induced by ethanol

CYP3A4/5

most abundant CYP450 isoform which metabolizes the most prescribed drugs. Especially important for bioavailability due to its abundance in cells lining the GI tract. Can be induced by a wide variety of drugs and is potently inhibited by ketoconazole and erythromycin.

Poor metabolizer

little or no CYP2D6 function

Intermediate metabolizers

Metabolize somewhere between the poor and extensive metabolizers

Extensive metabolizer

Normal CYP2D6 function

Ultrarapid metabolzier

Multiple copies of the CYP2D6 gene, greater than normal CYP2D6 function