Drug Metabolism and Kinetics (PK) Flashcards
What are the Three Phases of Drug Action
1) Pharmaceutical Phase: Disintegration of the pill / capsule in gastrointestinal tract (GI), release of the drug, dissolution of drug
2) Pharmacokinetic Phase: Absorption from GI tract into bloodstream and what the body does to the drug
3) Pharmacodynamic Phase: Mechanism by which the drug interacts with the molecular target. What the drug does to the body.
What makes a Good Drug?
(Pharmockinetcis + Pharmodynamics)
Pharmacokinetics =
Absorbed well by the body
Reaches target easily
Not modified, inactivated, or removed from the body too quickly
Pharmacodynamics =
Effective at targeting the disease process
Not toxic
What makes a Good Drug?
(Pharmockinetcis + Pharmodynamics)
Pharmacokinetics =
Absorbed well by the body
Reaches target easily
Not modified, inactivated, or removed from the body too quickly
Pharmacodynamics =
Effective at targeting the disease process
Not toxic
Potency vs Efficacy
Potency:
Dose required to achieve the effect.
Measured as the 50% effective concentration (EC50).
Units of concentration
Efficacy:
The maximal effect.
Measured as “response.”
Usually a percentage.
graph
increase
ADME
a) Absorption
b) Distribution
c) Metabolism
d) Elimination
a) Absorption
Process of drug entering the body and therapeutic agent entering the blood
b) Distribution
Drug may reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids of various compartments in the body
c) Metabolism
Biotransformation / chemical conversion of drug molecules
d) Elimination
Clearance of drugs and metabolites from the body (urine, bile, faeces)
Absorption - Routes of drug administration
Intramuscular - Oily vehicles Irritating Neutral (muscle)
Inhaled - Volatile Neutral (lung)
Neural - Transderm/Topical/ Subcuteneous (skin)
Intravenous - Polar/ charged High MW (molecular weight) drugs (systemic circulation)
Oral, Buccal Sublingual, Rectal (systemic circulation)
Stomach (pH 1-3):
Acidic/ neutral drugs
Intestine (pH 6-8):
Basic/ neutral drugs
Absorption - Factors affecting drug absorption
Solubility: Drugs need to be water-soluble to pass into the blood for distribution
Ionisation: Drugs need to be close to neutral to pass through membranes
Stability: Drugs need to be chemically stable until they reach their site of action
Factors affecting drug absorption:
Solubility: Drugs need to be water-soluble to pass into the blood for distribution
Ionisation: Drugs need to be close to neutral to pass through membranes
Stability: Drugs need to be chemically stable until they reach their site of action
Factors affecting drug distrobution:
Plasma solubility: Including binding to plasma proteins (bind and release)
Lipophilicity: Balance between water and fat solubility. Influences drug levels in blood, muscles, adipose tissue, and organs
Perfusion: Level of blood flow to a tissue. Major organs (heart, liver . . .) well perfused, but brain is a special case – blood-brain barrier.
Elimination
After metabolism, organisms want to get metabolites and exogenous molecules out of their system.
If the drug is removed without metabolism, the process is called excretion
Major routes: Urine (renal), faeces (biliary)
Minor routes: Exhalation (lungs), sweat / other bodily fluids
Metabolism
Metabolic enzymes attack drug molecules forming metabolites
Metabolites may be inactive, less active or even more active than parent drug molecules
They can also have a different activity – side effects and toxicity
Metabolism of drugs is necessary for:
Designing new drugs which do not form unacceptable metabolites
Designing pro-drugs / understanding pre-drug strategy
Understanding half-lives and tailoring drug action
Metabolism of drugs is necessary for:
Designing new drugs which do not form unacceptable metabolites
Designing pro-drugs / understanding pre-drug strategy
Understanding half-lives and tailoring drug action
How many metabolites will there be? . . . . Zero to many
For most drugs there will be fewer than 10 major metabolites, but there can be several “minor” metabolites
Minor metabolites are also important – accumulation of minor metabolites can be extremely toxic
No metabolites – sodium cromoglicate
1 major metabolite – oxazepam glucuronide
> 10 major metabolites - chlorpromazine
What are the Phases of Metabolism?
- Phase I Transformations
- Phase II Transformations
- Phase I Transformations
Mostly in liver
Chemical Modifications
Oxidation, Reduction, Hydrolysis
- Phase II Transformations
Mostly in Liver
Conjugation with an exretion-promoting group
E.g. glucuronic acid, sulfate, glycine (hydrophilic)
E.g. bile acids (hydrophobic)
What happens during metabolism - what is the goal?
Living organisms aim to eliminate all foreign materials as quickly as possible
Polar Drugs will be excreted quickly by the kidneys
Non-polar Drugs need to be chemically modified to make them more hydrophilic so they can be eliminated more easily
Phase I Metabolism
= Chemically diverse small molecules
transformed to more polar compounds
CYP- P450 Reactions
Hydroxylation
Epoxidation
Dealkylation
Deamination
Oxidation
Dehalogenation
Non-CYP Reactions
Oxidation
Hydrolysis
Reduction
Deamination
Phase I – CYP-P450 Enzymes
Haemoproteins (contain haem)
Located in the liver cells
Belong to the monooxygenases (class of enzymes)
33 different cytochrome P450 enzymes, split into four families (CYP1-CYP4)
Subfamilies within each family designated by a letter
Each enzyme within subfamily is designated by a number
Phase I - Mechanism of action
Split molecular oxygen so one of the oxygen atoms is introduced into the drug, the other ends up in water
Phase I – P450:
Explain step 1 of the Oxidation of Carbon:
- Oxidation of exposed alkyl groups / exposed regions of cycloalkyl rings
a) Oxidation of terminal methyl groups
b) Oxidation of penultimate
carbon on alkyl substituents
c) Oxidation at most exposed or most activated region of the cycloalkyl ring
Explain step 2 of the Oxidation of Carbon:
- Oxidation of activated carbon centres (next to sp and sp2 carbons) – they are more likely to be oxidised than exposed carbon atoms
Explain step 3 of the Oxidation of Carbon:
- Dealkylation of amines, ethers and thioethers via oxidation of activated carbon
Explain step 4 of the Oxidation of Carbon:
- Dehalogenation of alkyl halides
Oxidation to carboxylic acids by aldehyde dehydrogenases
Explain step 5 of the Oxidation of Carbon:
- Oxidation of alkenes and aromatic rings
Oxidation of unsaturated sp2 and sp carbon centres present in alkenes, alkynes and aromatic rings
Hydroxylation: introduction of hydroxyl group to a carbon
CHOOSE site that is opposite group because it is most activated
Hydroxylation
introduction of hydroxyl group to a carbon
Phase I – P450: Oxidation of Nitrogen
Phase I – P450: Oxidation of Sulfur and Phosphorous
C=S goes to Desulfurisation
Thiols can be oxidised to disulfides
Phosphorous is oxidated
Phase I – Catalysed by Flavin-containing Monooxygenases
Phase I – Catalysed by Other Enzymes
1. Oxidative Reactions
Primary alcohols»_space; (alcohol dehydrogenase / NAD+) secondary alcohols»_space;(NAD+) ketone
Aldehydes»_space; (dehydrogenase / NAD+)»_space; Primary amines»_space; (monoamine oxidases) aldehyde [oxidative deamination]
Phase I – Catalysed by Other Enzymes
2. Reductive Reactions
aldehyde (alcohol dehydrogenase)»_space; alcohol
Ketone (reductases / NADPH)»_space; alcohol
Alkyl halide»_space; R - H
Ar - NO2 (Nitro)»_space; Ar - NH2
RS– SR»_space; 2RSH
Phase I – Catalysed by Other Enzymes
3. Hydrolysis of esters and amides
Catalysed by non-specific esterases and amidases (peptidases) in plasma, liver, kidneys, intestine
ester (esterases)»_space; aldehyde + HO-R
Amino acid (peptidases)»_space; aldehyde + HNR2
Phase II Metabolism
Conjugation reactions generally result in more polar compounds. These are rapidly eliminated via urine and / or bile
A less polar molecule is attached to a suitable, more-polar “handle”
Glucuronidation
Sulfation
Amino acids (glutathione, glycine, glutamine)
Acetylation
Methylation
Phase II - Glucuronidation
Glucuronic acid conjugation is the most common reaction
Phenols, alcohols, hydroxylamines, carboxylic acids form O-glucuronides by reaction with UDP-glucuronate
The product is excreted in the urine (or bile if MW > 300 g/mol)
Sulphonamides, amides, amines and thiols form N- or S-glucuronides.
C-glucuronides are possible when there is an activated carbon next to carbonyl group
Glucuronic acid derives from amino asides;
sulphonamine
hydroxylamine
thiol
Phase II – Sulphate Conjugation
Less common and only involves phenols, alcohols, arylamines, N-hydroxy compounds
Catalysed by sulfotransferases, using the cofactor 3’-phosphoadenosine-5’-phosphosulfate
Phase II – Amino Acid Formation
Consider corboxylic acid group and its conjugate to amino acids
- Drugs bearing a carboxylic acid group can conjugate to amino acids by the formation of a peptide link
- The carboxylic acid is activated by formation of a coenzyme A thioester which is then linked to the amino acid
Explain the amino acid formation as an equation;
aldehyde (drug) [ATP / Acyl CoA synthetase]»_space; drug=O-AMP (which is alcyl group) [CoASH)»_space; Drug+O-SCoA (amino acid + N-acyltransferase)»_space; Drug=O-amio acid
Phase II – Glutathione Conjugate
Explain the main 2 steps that happen
(what reacts with what, what transforms to what)
The nucleophilic group of the tripeptide glutathione can react with electrophilic functional groups (epoxides, alkyl halides etc)
This forms glutathione conjugates which can be transformed to mercapturic acids (easily excreted in the bile)
Phase II – Methylation & Acetylation
What is the effect of Methylation and acetylation of the polarity of the drug?
Methylation?
Acetylation?
Methylation and acetylation decrease the polarity of the drug
Methylation (-CH3): Phenols, amines, thiols
Acetylation (-CH3C=O): Primary amines
Explain what the The First Pass Effect is;
Drugs that are taken orally pass directly to the liver once they enter the blood supply»_space; exposed to metabolism before they are distributed around the rest of the body
% of the drug will be transformed before it reaches its target
Drugs administered via a different route (e.g. injection, inhalation) avoid the first pass effect –distributed around the body before they reach the liver
Breakdown of phases of metabolism
PHASE I (Oxidation, Reduction, Hydrolysis)
PHASE II (conjugation)
DRUG > Primary metabolite > Secondary metabolite / Breakdown product > Conjugate > Breakdown of conjugates
Kinetics of Metabolism – 1st Order
The metabolic transformation of drugs is catalysed by enzymes
What kinetics do the reaction follow (who)?
Most of the reactions follow Michaelis-Menten Kinetics;
𝑽 (𝒓𝒂𝒕𝒆 𝒐𝒇 𝒓𝒆𝒂𝒄𝒕𝒊𝒐𝒏)= ( 𝑽𝒎𝒂𝒙 [𝑺])/(𝑲𝑴+[𝑺])
In most clinical situations, [S] «< KM, therefore:
𝑽 (𝒓𝒂𝒕𝒆 𝒐𝒇 𝒓𝒆𝒂𝒄𝒕𝒊𝒐𝒏)= ( 𝑽𝒎𝒂𝒙 [𝑺])/𝑲𝑴
Kinetics of Metabolism – Zero Order
(Consider size of [S] to Km)
With some drugs, the doses are very large, [S]»_space;> KM, therefore:
𝑽 (𝒓𝒂𝒕𝒆 𝒐𝒇 𝒓𝒆𝒂𝒄𝒕𝒊𝒐𝒏)= ( 𝑽𝒎𝒂𝒙 [𝑺])/([𝑺])= Vmax
ZERO order
The enzyme is saturated by a high free-drug concentration and the rate of metabolism remains constant over time (drugs such as aspirin, ethanol)
A constant amount of drug is metabolised per unit time and the rate of elimination is constant and does not depend on the drug concentration
1st order
The rate of drug metabolism and elimination is directly proportional to the concentration of free drug
A constant fraction of the drug is metabolised per unit time
