3 Metabolism of Xenobiotics by the Liver Flashcards
Xenobiotics
- Xenobiotics are substances foreign to the host
- Many xenobiotics are non-polar and lipophilic
- Require modification to make them polar, water soluble and easier to excrete
- Non-natural molecules
Factors That Affect Absorption
- Lipophilicity versus hydrophilicity
- Relative concentration on the either side of the membrane
- High concentration of the xenobiotic and slow movement within the GIT favours absorption
- Association with food
- The ionisation of the xenobiotic, i.e. is it a salt
- Membrane proteins have +ve and –ve charged residues designed to repel xenobiotics
- Local pH controls: weak acids are absorbed in the stomach, whereas weak bases are absorbed in the SI
- Particle size, e.g. of the dosage form - slow release drugs may be contained in particles that are larger
pH in stomach and small intestine
stomach = 2, small intestine = 5
Aspects Which Affect Distribution
• Dynamics of distribution depend upon:
• Drug lipophilicity
• Lipoidality of the tissue
• Blood flow through the tissue
• Mass of the tissue
• Plasma/tissue concentration gradient
• All factors are affected by sex, age and health
• Women have less water (54 vs. 60%) and more
fat (28 vs. 18%) than men, so women absorb drugs better as more drugs associate strongly with fatty tissues
Metabolism
- The chemical modification of xenobiotics with the overall goal of ridding the body of the substance
- Occurs mainly in the liver
- During first pass effect there is extensive chemical transformation of lipophilic or heavy (MW >500) compounds
- The metabolite may have:
- Equal activity to the xenobiotic/drug
- No or a reduced activity
- Increased activity (prodrugs)
- Toxicity not observed in the parent molecule
Special Aspects of Excretion
- Lactation, passage of substances from mother
- Little excretion via faeces unless the GIT is diseased or e.g. the formulation of a drug is poor
- Volatile agents can be excreted via the lungs
- Passive re-absorption of lipid-soluble substances
- Entero-hepatic shunt:
- Glucuronic acid conjugates can be excreted in bile
- The -glucuronidase in the GIT will hydrolyse the carbohydrate conjugate
- Active xenobiotic may then be reabsorbed
Phase I Metabolism
- Phase I metabolic reactions create functional groups that place xenobiotics in a correct chemical state to be acted upon at Phase II
- Majority of Phase I reactions in hepatic microsomes employ cytochrome P450 (CYP) enzymes
Not all have to go through phase I they can go straight phase II.
Vast majority of Phase I are oxidations, and some reductions.
Cytochrome P450 (CYP) Enzymes found in
Gut, intestines, majority in the liver but some also in gut epithelia
Cytochrome P450 (CYP) Enzymes • Grouped based on..
- Grouped based on structural similarities
- CYP family has 40% sequence homology
- CYP subfamily has 55% sequence homology
- Individual enzymes within a subfamily denoted
- CYP2E1 has 40% homology with other CYP2s, at least 55% homology with other CYP2Es, but is distinct from CYP2E2, CYP2E3, etc
Overall reaction of CYP P450 enzymes
NADPH + H+ + O2 + SubstrateH →
NADP+ + H2O + SubstrateOH
Cytochrome P450 (CYP) Enzymes • Humans have..
- Humans have 18 families and 43 subfamilies of CYPs from 57 genes and 58 pseudogenes, CYP2 most represented
- CYP3A4 metabolises 50% of therapeutic drugs
- CYP2D6 metabolises ~20%
- CYP2C9 and CYP2C19 metabolise ~15%
- CYP1A2, CYP2A6, CYP2B6 and others ~15%
- A substrate may be processed by more that one isoform
- Genetic polymorphisms lead to individual metabolic profiles which can impact on chemotherapy of disease
Oxidations Not Catalysed By CYPs
- Aromatases
- Alcohol dehydrogenase and aldehyde oxidation
- Xanthine oxidase
- Amine oxidases
- Flavin-containing monooxygenase system
- Mainly in liver smooth endoplasmic reticulum
- Oxidizes compounds containing sulfur and nitrogen
- Uses NADH and NADPH as cofactors
- Multi-gene family, FMO3 is major human liver form
Reductive Metabolism
Reductive reactions are catalysed within the liver Require NADPH and are inhibited by O2
Phase II Metabolism
Making metabolites water soluble so we can excrete them
Some molecules go straight to phase II
Conjugation With Carbohydrates
- The most important Phase II pathway
- Major route is conjugation with -D-glucuronic acid
- UDP-glucuronic acid intermediate required
- UDP-glucuronosyltransferases (UGTs, cytosol)
- N-Glucuronidation: amines, amides, sulfonamides
- O-Glucoronidation: carboxylic acids, phenols, alcohols
- Products often excreted in the bile, possibility of enterohepatic recycling due to GIT enzymes
