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)