Drug Metabolism and Excretion

Dr Claire Garden

c.garden@napier.ac.uk

By the end of this lecture you should be able to:

• Define ‘pharmacokinetics’ and ‘pharmacodynamics’

• Define ‘elimination’, ‘metabolism’ and ‘excretion’ • Describe the main pathways of drug metabolism

and excretion • Summarise phase I and II metabolism • Explain factors affecting drug elimination and

excretion • Give examples of drugs with pharmacologically

active metabolites

Pharmacokinetics and Pharmacodynamics

• Pharmacokinetics is what the body does to a drug

– i.e. the time taken for a drug to reach different areas of the body: ADME

• Pharmacodynamics is what the drug does to the body

– i.e. interaction with the receptor to cause and effect

Drug Elimination

• Elimination is the irreversible loss of drug from the body

• Requires metabolism and excretion of the drug

– Metabolism converts the drug into another molecule (metabolite) using enzymic reactions

– Excretion is the physical removal of the drug/ metabolite from the body

Metabolism

• Required to detoxify drugs and other toxic substances – E.g. plant alkaloids

• Required for elimination of a drug – Lipophilic substances not well eliminated by kidney so

need to be metabolised first – Polar substances are often excreted in urine unchanged

• Sometimes required for a drug to become active • Mostly hepatic • Occurs in two phases

– Phase I results in more chemically reactive metabolites – Phase II inactivates the metabolite via conjugation

First-Pass Metabolism

• Occurs in the liver or gut – Even if drug well absorbed from gut

• Depends upon route of administration – Much higher doses are required orally

– Differs between individuals

• Affects the amount of drug reaching the systemic circulation – Less than the dose

– So reduces bioavailability

Two Phases of Metabolism

Phase I Metabolism

• Introduction of a reactive group – E.g. OH

– Functionalisation

• Metabolite may be more toxic than the parent drug – E.g. paracetamol

• Cytochrome P450 is very important (CYP system) – Embedded in SER = microsomal

– There are some extra-hepatic P450 enzymes but don’t need to consider these here

P450 Monooxygenase System

• Superfamily of 74 haem proteins

• CYP#letter – CYP1-3 are involved in hepatic drug metabolism

• Each has a different amino acid sequence, sensitivity to inducing agents and inhibitors and specificity of substrate – Substrate specificity can overlap such that two enzymes in

the family are responsible for metabolising a drug

– You can find a list of different CYP enzymes and their drug substrates here: http://medicine.iupui.edu/clinpharm/ddis/main-table/

Phase I Reaction

• DH →DOH

• Requires P450 enzyme, O2, NADPH and NADPH-P450 reductase

P450 Monooxygenase

P450 and Biological Variation

• Species differences require that animal models are selected carefully

• Major inter-individual variation in humans – E.g. genetic polymorphisms

• Dietary and environmental factors contain inducers and inhibitors of these enzymes – Grapefruit juice inhibits and brussels sprouts induce!

– See here for a list http://medicine.iupui.edu/clinpharm/ddis/clinical-table/

– Drugs may also act on this enzyme

– E.g. ketoconazole inhibits CYP3A4

– Causes drug interactions

P450-Independent Phase I Metabolism

• Not all phase I metabolism requires CYP-mediated oxidation – E.g. alcohol uses alcohol dehydrogenase (soluble,

cytoplasmic) + CYP2E1

– Other enzymes include xanthine oxidase and monoamine oxidase

• CYP are also capable of reduction reactions e.g. warfarin metabolism by CYP2A6

• Hydrolysis may occur in plasma

Phase II Metabolism

• Conjugation of a small group to a reactive group on the drug – Sometimes provided by phase I metabolism

– E.g. hydroxyl, thiol or amino group

• Inactivates drug

• Reduces lipid solubility

• Includes the addition of glutathione, glucuronyl, sulphate, methyl, acetyl, and glycyl groups.

• Mostly occur in the liver

Drug Excretion

• Metabolites are usually cleared more quickly than the parent drug

• Main routes that drugs leave the body via: – Kidneys

• Unchanged or polar metabolites • Rates vary

– Hepatobiliary system • Increasingly important in patients with poor kidney function

– Lungs • Highly volatile substances

– Secretions • Milk or sweat

The Enterohepatic Circulation

• Glucuronide conjugates concentrated in bile

• Excreted into the gut

• Glucuronide is hydrolysed by gut enzymes

• Drug becomes active again

• Drug is reabsorbed and the cycle begins again

– Prolongs drug action

– Can account for <1/5th total drug

– E.g. morphine

Renal Excretion: Glomerular filtration

• 20kDa cut-off for filtration into the glomerulus

– Albumin is too large

• Therefore only unbound drugs able to pass through

• Only 20% blood passes into glomerulus, the rest is in the capillaries surrounding the tubules

Renal Excretion: Tubular Secretion

• Enter tubules via non-selective carriers for acidic drugs/ organic bases

• Drugs can compete for the same transporter, e.g. probenecid can prevent tubular secretion of penicillin

• Tubular secretion is the most effective means of drug elimination

• Drugs may also diffuse across the tubule – Polar drugs

– Some drugs are not metabolised and are excreted in this way, so rate of elimination determines duration of action

The Kidney

Drug Interactions

• Can occur via pharmacodynamic or pharmacokinetic mechanisms

• E.g. of pharmacodynamic drug interactions are non-competitive and physiological antagonists

• Pharmacokinetic interactions occur where one drug alters the ADME profile of another – E.g. morphine slows gastric emptying and will therefore

slow GI absorption – E.g. over 200 drugs induce enzymes and can alter

metabolism of other drugs

• Tolerance may be pharmacodynamic or pharmacokinetic – Via receptor desensitisation or enzyme induction

Manipulating Metabolism

• Some drugs must be metabolised in order to become active – These are prodrugs

– E.g. enalapril

• Some drugs have active metabolites – E.g. salycilic acid is the metabolite of aspirin. Has

anti-inflammatory but not antiplatelet activity

– E.g. Tamoxifen is metabolised into Endoxifen (100x more effective) by CYP2D6

Summary

References

Rang, H.P. Dale, M.M. Ritter, J.M. And Flower, R.J. (2007) Drug Elimination and Clearance in: Pharmacology, 6th Ed. London: Churchill Livingstone

Future Work

• Read the exam article available on Moodle

• Write a series of questions based on the article

– You can share these with your classmates

• Read articles to help you answer these questions