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