Cytochrome P450 and Drug (Xenobiotic) Metabolism
TF - Drug Metabolism using CYP3A4 also Occurs Outside the Liver?
True CYP3A4 expression in small intestinal mucosa
Define Induction of Drug Metabolism
• The process by which exposure to a stimulus increases the expression of a drug metabolising enzyme or enzymes - transcriptional phenomenon - evolved as an adaptive process to defend an organism from the environment - Increase in enzyme expression can be huge: 50- to 100-fold increases not uncommon - Common source of drug interactions
Describe the 2 phases of Biotransformation
- Phase 1 Alter molecule's structure/reactivity • Mainly cytochrome P450 - Phase 2 Conjugation to endogenous molecule • Mainly transferases: glucuronidation,sulphation, etc
how does the body cope with diversity of xenobiotics present in the environment?
Enzymes have multiple substrates
3 things that make P450 a gene super family
-Many genes encoding many P450 enzymes -Each enzymes recognizes a distinct range of substrates (substantial overlap) -Genetic variation common (Pharmacogenetics)
Give some examples of High Clearance Drugs
-alprenolol -glyceryl trinitrate -propranolol -lignocaine -morphine
Give some examples of Intermediate clearance drugs
-desipramine -nortriptyline -quinidine -paracetamol
Give some examples of Low Clearance Drugs
-warfarin -tolbutamide -theophylline -diazepam -phenytoin -carbamazepine
For an orally administered drug, Bioavailability depends on: 2 things
1. Fraction of drug absorbed by the gut 2. ʻFirst Passʼ metabolism by the liver
What is another word for Metabolism?
Biotransformation
CYP Induction: Examples
CYP1A - polyaromatic hydrocarbons CYP2B - phenobarbitone CYP2E - ethanol CYP3A - anticonvulsants, rifampicin
Name the CYP required in Paracetamol or Ethanol metabolism according to Standardized nomenclature
CYP2E1 2= Family E= Subfamily 1 = Member
What are Endobiotics? Give 2 examples
Chemical substances produced by the body to accomplish a variety of tasks - Steroid hormones - act as signaling molecules - Bile acids - an elimination pathway for cholesterol and necessary for fat digestion
What kind of proteins are Cytochrome P450s?
Haemoproteins (iron containing) -Major enzymes of Phase 1 metabolism
Why Can Some Xenobiotics and Endobiotics be Dangerous?
Lipophilic chemicals easily permeate lipid cell membranes and accumulate within cells
How does Simvastatin affect the plasma concentrations of other drugs metabolised by CYP3A4?
Simvastatin is metabolised by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolised by CYP3A4
Potent inhibitors of CYP3A4 such as Itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors and nefazodone increase risk of what by reducing the elimination of simvastatin?
Myopathy (muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness)
What is the most important reaction type in Phase 1 reactions?
Oxidation - Cytochrome P450s the most important oxidative system
How Can Cells Cope with Toxic Molecules? 3 phases
Oxidative Metabolism (e.g., CYP enzymes) = Phase I Conjugative Metabolism (Transferases) = Phase II Transport = Phase III e.g., ABC transporters
Are Endobiotics toxic?
Potentially toxic and must be maintained within strict concentration ranges
Basic Cytochrome P450 reaction
RH+O2 +NADPH+H+ → R-OH+H2O+NADP
2 main mechanisms of Inhibition of P450-Mediated Metabolism
Reversible - inhibitor competes with drug for P450 - imidazole antimycotics (ketoconazole) - fluoroquinolone antibiotics (ciprofloxacin) - Cimetidine - diltiazem metabolites Metabolite intermediate complexation (mechanism-based inhibitors) - metabolites of inhibitor sequester P450 in an inactive form
Define Bioavailability
The fraction of a drug reaching the systemic circulation intact
What is the Purpose of Metabolism?
To render compounds more water soluble for elimination in: - Urine - Bile
Summary
Well conserved mechanisms exists to metabolize xenobiotics: • Metabolism can be divided into 2 types - Phase 1 or alteration of structure - Phase 2 or conjugation reaction! •A xenobiotic may be metabolised by several enzymes •A single enzyme may be capable of metabolising many xenobiotics •A number of variables determine the rate of metabolism (e.g., hepatic blood flow, intrinsic clearance and protein binding) •Induction or inhibition of metabolism may give rise to significant drug interactions
What are Xenobiotics? Give 3 examples
foreign chemical substances - Drugs - Herbal remedies - Compounds contained in food - Environmental pollutants - Poisons and industrial chemicals
What are conjugation reactions catalyzed by? What are some examples
transferases • Glucuronidation - catalysed by UDP-glucuronosyltransferases • Glutathione Conjugation - catalysed by glutathione-S-transferases • Sulphation - catalysed by sulphotransferases • Amino-acid Conjugation
What Determines the Rate of Liver Drug Metabolism?
• Intrinsic clearance - The affinity of liver enzymes for the drug • Liver blood flow - Determines the rate at which drug is delivered to the liver • Binding to plasma proteins - Only free drug can diffuse into liver cells
Metabolism can give rise to 4 outcomes. What are they
• Less active compounds - Codeine → Codeine glucuronide • More active compounds (bio-activation) - Codeine → Morphine • Less toxic compounds - NAPQI → NAPQI-GSH • More toxic compounds - Paracetamol → NAPQI
Where Does Metabolism Take Place?
• Liver - predominant metabolising organ for both phase I and phase II metabolism • Gut - alcohol dehydrogenase in stomach, cytochrome P450 in small intestine • Circulation - plasma cholinesterases, proteases • Other tissues - Lung, kidneys, brain, skin (less known about these sites)
