Metabolism / Excretion

What is Biotransformation of a drug

Drug Metabolism - The process whereby drugs in the body undergo transformations catalyzed by Enzymes

Drug Elimination

The irreversible loss of drug from the body

3 Main routes of Drug Elimination

Kidney

Hepatobiliary System

Lungs

In drug metabolism how can drugs be changed 

What is First-Pass Metabolism

• a.k.a. Presystemic Metabolism

• Drug metabolised (Concentration Decreased) before it reaches Systemic Circulation and, ultimately, target

• The drug is absorbed from the GI tract and passes via the portal vein into the liver where some drugs are metabolised.

First pass metabolism can occur in what organs

the gut, liver and the lung

What would be broken down by first pass metabolism in the gut (2 examples)

benzylpenicillin

insulin

What would be broken down by first pass metabolism in the liver (2 examples)

Lignocaine

Glyceryl Trinitrate (GTN)

What alternative routes of administration can be used to avoid the first pass effect

Alternative routes of administration = intravenous, intramuscular & sublingual avoid the first-pass effect

How does metabolism in the liver work? What structures & enzymes?

Enzymes: Hepatic Microsomal Enzyme System

There are 2 main phases of drug metabolism. What is the purpose of both

There are 2 main phases of drug metabolism. What is the process of both

What reactions occur in phase 1 of metabolism

• Oxidation

• Reduction

• Hydrolysis

(functionalisation reactions)

What enzymes are responsible for phase 1 metabolism of drugs

Cytochrome P450 (CYP450) enzymes

Most utilised forms of Cytochrome P450 (CYP450) for phase 1 metabolism

• CYP3A4

• CYP2D6

Function of Cytochrome P450 (CYP450) enzymes in phase 1 metabolism

Converts Non-Polar Drugs to Polar Drugs (i.e. lipophilic → hydrophillic)

CYP1 function

Primarily metabolize carcinogens, some drugs as well

CYP2 function

Metabolize many important drugs

CYP3 function

Most abundant family in human liver, metabolize many important drugs (60%)

Name 4 Factors affecting CYP450 Activity

Polymorphisms most often occur in what form of CYP450 enzymes

Most commonly occur with CYP2D6

Consequences of polymorphisms of CYP450 enzymes

Alter rate of metabolism - Can Increase or Decrease rate of Metabolism

Function of enzyme inducers

Cause Enzyme to Work Faster

What 2 ways can enzyme inhibitors effect enzymes

• Inhibit action of the Enzyme

• Propagate Drug Effect

Name 7 enzyme inducers

SCRAP GP

Name 12 Enzyme Inhibitors

SICKFACES.COM

Warfarin is metabolised by what

Metabolised by CYP450 (CYP1A2 / CYP3A4) (1, 2, 3, 4)

What effect would ciprofloxacin have on warfarin action

Raise warfarin levels - increase anticoagulant ability

What happens to CYP450 enzyme activity in liver dysfunction?

CYP450 enzyme efficacy decreases, leading to slower drug metabolism.

How does reduced CYP450 function affect drug levels?

It causes increased plasma drug concentrations and a higher risk of toxicity.

How does age affect enzyme function

Neonates / Elderly have Decreased Enzyme Function

Steps of ethanol metabolism & enzymes involved & location

Two Oxidative Steps involved:

• Dehydrogenation (Oxidation) from Alcohol to Acetaldehyde (Alcohol Dehydrogenase)

• Second Oxidative Step: Acetaldehyde → Acetate (Aldehyde Dehydrogenase)

• Acetate then released to blood for subsequent oxidation to CO2 by other tissues

Disulfiram / Antbuse use

Alcohol Cessation

Disulfiram / Antbuse is soluble in what (lipid/water)

Highly lipid soluble

Disulfiram / Antbuse bioavailability %

80%

Disulfiram / Antbuse accumulates where

in tissue

Disulfiram / Antbuse mechanism of action

Irreversible inhibits Oxidation of Acetaldehyde to Acetate

Competes with CoFactor: Nicotinamide Adenine Dinucleotide (NAD) for binding sitse on ADLH

Disulfiram / Antbuse consequence of MOA

Prevents oxidation of Acetaldehyde

Propagates the unpleasant side effects of Acetaldehyde

What can occur as a result of an aldehyde dehydrogenase mutation

Metabolise Ethanol more quickly

or 

Metabolise Acetaldehyde less efficiently

• Accumulation of Acetaldehyde → Vasodilation → Facial Erythema

Give 5 examples of phase II conjugation reactions

Methylation (Methyl Transferases)

• Acetylation (Acetyl Transferases)

• Sulfation

• Glutathione Conjugation

• Glucuronidation

Fill in this for phase II reactions

Glucuronidation is one of the phase II Conjugation Reactions. Name 3 drugs associated with it

Acetaminophen (Paracetamol), Morphine, Oxazepam

Glucuronidation is one of the phase II Conjugation Reactions. Name the enzyme associated with it

UDP-Glucuronyl Transferases

Glucuronidation is one of the phase II Conjugation Reactions. Name the substrate associated with it

Uridine Diphophate

Glucuronidation is one of the phase II Conjugation Reactions. Name the product associated with it

Uridine 5’-Diphosphate

(Catalyses the transfer of Glucuronic acid from the cofactor UDP-G A to a substrate to form β-d-glucopyranosiduronic acids (glucuronides), metabolites that are sensitive to cleavage by β- glucuronidase)

Prodrug

inactive compounds that are metabolised into their active, therapeutic forms

Tamoxifen is the prodrug of ______ which is _____x more active than it

4-hydroxytamoxifen

30-40x

Morphine (CYP2D6) prodrug

Codeine → Morphine (CYP2D6)

enalprilat prodrug

Enalapril → enalprilat

prednisolone prodrug

Prednisone → prednisolone

5-ASA prodrug

Sulfasalazine → 5-ASA (5-aminosalicylic acid)

The conversion of Sulfasalazine → 5-ASA has what effect on its action

It allows it to have site specific action

Give an example of a drug that when metabolised can produce toxic metabolites

Paracetamol (acetaminophen)

Use for Sulphasalazine

treat inflammatory conditions of the gut and joints

What percentage of the Active Metabolite: Sulphasalazine reaches the colon

Approx 90%

What happens the Active Metabolite: Sulphasalazine when it reaches the colon

(metabolised by? produces?)

Metabolised by GI Bacteria

Product: Sulfapyridine and Mesalazine

T/F: Sulphasalazine exerts it’s therapeutic effect locally

True

Codeine (3-methoxymorphine) undergoes what process by CYP2D6 to produce morphine

Codeine (3-methoxymorphine) undergoes demethylation by CYP2D6 to produce morphine

codeine has what % the analgesic potency of morphine

20%

What % of the population have codeine resistance

10%

What causes codeine resistance

absence of Demethylating Enzyme that converts it to Morphine

Codeine is often given in combination with what

Often combined with paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) in proprietary analgesic preparations

(• Synergistic effect

• Potential for safety concerns)

Name 2 phase II reactions that break down paracetamol

(enzyme & product)

Explain the minor pathway that leads to a toxic metabolite of paracetamol (& name that toxic metabolite)

Paracetamol  —(P450 system)→  NAPQI (toxic)  —(Glutathione transferase)→  Glutathione conjugate

how does a paracetamol overdose occur

Glutathione pathway becomes saturated

Effect of habitual & binge drinking of alcohol on these P450 enzymes: CYP1A2, CYP2E1 and CYP3A4

Habitual Use: Induces Enzymes (up to 4x the level of non-drinkers)

Binge: Inhibits Enzymes

How does the habitual use of alcohol affect paracetamol metabolism

When CYP2E1 and CYP3A4 are induced by alcohol, a greater amount of paracetamol is converted to NAPQI.

CYP1A2, CYP2E1 and CYP3A4 are the p-450 isoforms which Oxidise paracetamol to NAPQI.

Hence in alcohol abusers, toxicity can occur with only slightly greater than recommended doses of paracetamol

Paracetamol OD Antidote

N-Acetylcysteine (NAC)

N-Acetylcysteine (NAC) is a precursor to what

Precursor to L-Glutathione

N-Acetylcysteine (NAC) works as a _______ donor

Behaves as Glutathione Donor

(increases Phase II of paracetamol metabolsim)

How does N-Acetylcysteine (NAC) work as a Paracetamol OD Antidote

Minimises Oxidative Stress

Reduces risk of Fulminant Hepatic Failure

Plasma paracetamol levels can only be interpreted if blood is taken within how many hours of ingestion

4

(check units & time of ingestion carefully when using a graph!)

For what kind of overdose would this graph not be used

A staggered overdose

Distribution is used to calculate what in what phase of trials

Calculation of a non-toxic dose for clinical trials

(Preclinical and Phase 1)

How would distribution info be used to optimise Vd

Introduction of e.g. basic group to drug to optimise Vd

True/False: an ideal drug would be exclusively metabolised by a CYP450 enzyme

False: Ideal drug would not exclusively metabolised by a CYP450 enzyme (as there are lots of polymorphisms)

The enzyme system responsible for the metabolism of most drugs is:

A. P-glycoprotein.

B. alkaline phosphatase.

C. creatine kinase.

D. cytochrome P-450.

E. HMG-CoA.

D. cytochrome P-450

Elimination section next……..

What are the major(4) & minor(2) routes of drug excretion

• Renal

• Biliary / GI

• Pulmonary

• Skin

Minor: Mammary (delivery to baby!) & Salivary (therapeutic drug monitoring)

3 processes involved in renal elimination

• Glomerular Filtation

• Active Tubular Secretion

• Passive Reabsorption across Tubular Epithelium

Molecules less than __kDa are filtered (enter filtrate) in glomerular filtration

20kDa

Why kind of molecules don’t get filtered in glomerular filtration

Protein bound drugs not filtered (plasma albumin = 68kDa)

How does tubular secretion work

Active carrier-mediated elimination

Can transport against electrochemical gradient and when drug protein bound

How does renal reabsorption work

Passive diffusion back across tubular epithelium

What happens to lipid soluble drugs in renal reabsorption?

Lipid-soluble drugs have high tubular permeability, meaning they easily cross cell membranes.

Because of this, after being filtered into the tubule, they tend to diffuse back into the blood rather than stay in the urine.

As a result, they are excreted slowly in urine because much of the drug is reabsorbed into the bloodstream.

What type of molecules (polar/non-polar)(water/lipid soluble) remain in urine during renal reabsorption

polar water soluble drugs remain in urine

How does a drug ever find its way into renal filtrate

Free drug in plasma (unbound) diffuses across capillary membrane into filtrate in Bowman’s capsule

Are drugs affected by pH or lipid solubility when diffusing into the filtrate in Bowman’s capsule

No

Speed of movement into Bowman’s capsule (GFR)

120 mL/minute

What affects GFR

• Renal Blood Flow

• Glomerular Filtration Rate

• Drug Binding to Plasma Protein

What % of plasma doesn’t get filtered in the glomerulus

80%

How many carrier systems are there to transport drugs to the lumen

2 carrier systems transport drugs to lumen

• 1 carries acid drugs

• Other carries bases

How are drugs moved into the filtrate in renal tubules

Active Tubular Secretion against the electrochemical gradient

Name a drug that relies on being actively secreted into the renal tubules

Penicillin

True/False the active secretion of penicillin into the renal tubules lumen relies on plasma protein binding

False

We know that the active secretion of penicillin into the renal tubules lumen doesn’t rely on plasma protein binding, but what does it rely on

carrier proteins in the renal tubules specifically transport the free (unbound) drug from the plasma into the tubular fluid. (shift the equilibrium between bound and unbound drug)

Give an example of how competition can occur between drugs that use the same carrier system - use penicillin as an example

probenecid inhibits the tubular secretion of penicillin, thereby prolonging penicillin’s plasma concentration and therapeutic effect.

We know that water is greatly reabsorbed, but what about the filtered drug

99% of filtered drug is reabsorbed passively

What type of drugs are reabsorbed and what types stay in the lumen → excreted

Lipophilic drugs cross easily → reabsorbed

Polar (metabolized) drugs stay in lumen → Excreted