ADME Flashcards
Lipinski’s rule (rule of 5)
- H bond donor <5
- H-bond acceptor <10
- MW < 500
- cLogP <5
Explain Lipophilicity
Tendency of a compound to partition into a non-polar lipid matrix versus an aqueous
Traditionally, octanol and water are used
Explain logP
Log10 of the partition coefficient if the compound in organic/water layers, where all the molecules are neutral
Explain LogD
Log10 of the distribution coefficient if the compound in organic/water layers at a specified pH. Molecules might be ions or neutral
Explain pKa
Compound’s ionizability in an aqueous solution
Solubility is determined by:
- Compound structure
- State (solid/liquid)
- Solvent (type, pH, temperature)
- Measurement methods
Solubility is affected by:
Physicochemical properties:
- lipophilicity
- size
- pKa
- crystal lattice energy (crystal stacking, meeting point)
What are the modification strategies to improve solubility?
7
- Addition is ionizable groups
- Reduction of LogP
- Addition of H-bonds
- Addition of polar groups
- Reduction of MW
- Out-of-plane substitution
- Construction of a prodrug
What are the modification strategies for improving dissolution rate?
(4)
- Reduce the particle size
- Prepare am oral solution
- Formulation with surfactants
- Prepare a salt form
How much of potential drugs are excluded by the blood-brain barrier when going through the brain?
As much as 98%
What is the efflux?
It is the transport of a molecule out of a cell (for example with p-glycoprotein, Pgp)
Structure modifications strategies to improve brain penetration:
(6)
- Reduce Pgp efflux
- Reduce number of H-bond
- Increase lipophilicity
- Reduce MW
- Replace carboxylic groups
- Add intramolecular H-bonds
What are the two phases on metabolism and what is their mechanism?
Phase 1: modifications of the molecular structure
Phase 2: addition of polar groups to the molecular structure
Which ADME parameters does metabolism affect?
It increases clearance, reduces exposure, and is a major cause of low bioavailability
What is presystemic/first pass clearance?
It is when a drug is metabolised prior to reaching systemic circulation. It can occur in the gut and liver
What kind of interaction can occur when two molecules are co-injected?
One drug can inhibit the metabolism of the other. This could lead to toxic effects
What are the common phase 1 metabolic reactions?
Aliphatic oxidation, aromatic oxidation, alcohol oxidation, dehydrogenation, epoxidation, (N,S,O)-dealkylation
Réductions can also occur
What moiety can be added during phase 2 metabolism?
Glucuronic acid
The mechanism is called glucuronidation
Other than glucuronidation, what other polar moieties can be added during phase 2 metabolism?
Sulfations, acetylation, glycination and methylation can also occur
What is the main effect of metabolic stability?
It affects pharmacokinetics (PK)
The half-life determines the dose regimen on how…
How often the drug must be administered
The oral bioavailability determines the dose regimen on how….
How much of the drug should be administered
Inhibition of the P450 cytochrome family are part of phase … metabolism
Phase 1 metabolism
What are the structure modification strategies for phase 1 metabolism?
(8)
- Block the metabolite site by adding Fluorine
- Block the metabolite site by adding other blocking groups
- Remove labile functional groups
- Cyclization
- Change ring size
- Change chirality
- Reduce lipophilicity
- Replace unstable groups
What king of blocking groups can be added to block phase 1 metabolism?
Chlorine, but also more bulky aliphatic groups
What are the structure modification strategies for phase 2 metabolism?
(3)
- Introduce electron-withdrawing groups and steric hindrance
- Change phenolic hydroxyl to cyclic urea or thiourea
- Change phenolic hydroxyl to prodrug
What is a bioisostere?
It is a chemical substituent with similar physical/chemical properties. It produces similar biological properties
Plasma stability is important because…
Hydrolysis in plasma can be a major cause of compound clearance
Which functional groups are susceptible to plasma degradation?
(6)
Esters, amides, carbamates, lactams, lactones, sulfonamides
What kind of approach can take advantage of plasma reactions?
A prodrug approach; typically, esters are prepared, and activated through hydrolysis
What are antedrugs?
Antedrugs are active locally but rapidly degrade to inactive compounds once they reach the bloodstream.
What is the purpose of antedrugs?
It is to reduce side effects by minimising systemic toxicity of the drug
What are the structure modification strategies to improve plasma stability?
(3)
- Substitute an amide for an ester
- Increase steric hindrance
- Electron withdrawing groups decrease plasma stability (for antedrugs)
During the drug discovery process, drugs are exposed to many solutions:
- Organic solvents
- Aqueous buffers
- Bioassay buffers
- Dosing solutions
- GI tract
What is an excipient?
It is a secondary substance in a medication that can help stabilise/confer a therapeutic of the drug. It doesn’t react with the active drug
What are the structure modification strategies to improve solution stability?
(4)
- Eliminate/modify unstable groups
- Add an electron withdrawing group
- Isosteric replacement of labile functional group
- Increase steric hindrance
What are the applications of solution stability data?
7
- Provide an early alert to liabilities
- Selection of conditions for compound purification
- Develop structure-stability relationship
- Diagnose poor in vivo bioassay performance
- Diagnose poor in vivo performance
- Prioritize compound for in vivo animal studies
- Structure elucidation of solution stability products (using LC-MS) guides synthetic optimization
What can reduce in vivo exposure in the stomach/intestine?
Low pH and enzymatic hydrolysis
How does a software calculate the LogP of a new molecule?
By breaking up the structure in substructures where the value is known, and then adding all these values
