ADMET 7
ADMET Overview
1. Introduction to ADMET
ADMET: Acronym for Absorption, Distribution, Metabolism, and Excretion, key pharmacokinetic properties of drugs.
2. Components of ADMET
Absorption: How the drug enters systemic circulation, involves routes and mechanisms.
Routes/Sites of Administration: Different methods used to deliver the drug (e.g., oral, transdermal).
Mechanisms of Absorption: Dynamic processes that govern the entry of the drug into circulation (e.g., passive diffusion, active transport).
Prodrugs: Inactive compounds that metabolize into active drugs.
Absorption-based DDIs (Drug-Drug Interactions): Interactions that alter the absorption of drugs.
Distribution: Refers to how the drug disperses throughout the body.
Models of Distribution: Various theoretical frameworks explaining how drugs distribute in the body compartments.
Volume of Distribution: A pharmacological parameter that quantifies the distribution of a drug throughout body fluids and tissues.
Equation: , where is the dose and is the concentration in the plasma.
Sequestration: Process where drugs are stored in specific body compartments (e.g., fat, muscle).
Blood-Brain Barrier (BBB) / Central Nervous System (CNS) Penetration: Examines how and if drugs can cross the BBB to affect the CNS.
Distribution-based DDIs: Interactions that modify the distribution of concurrent medications.
Metabolism: The biochemical process that converts the active drug into inactive or active metabolites.
Sites of Metabolism: Specific organs or tissues (e.g., liver) where drug metabolism primarily occurs.
Influencing Factors: Various factors that affect metabolism (e.g., age, genetic factors, liver function).
Types of Chemical Reactions: Different metabolic reactions such as oxidation, reduction, hydrolysis, etc.
Metabolic Pathways & Enzymes: Pathways through which drugs are biotransformed and the enzymes (e.g., CYP450) involved.
Metabolism-based DDIs: Interactions that affect the metabolic rate or pathways of drugs.
Elimination: The process of removing the drug or its metabolites from the body.
Routes of Clearance: Various pathways through which drugs are eliminated (e.g., renal clearance).
Influencing Factors: Factors that affect elimination such as renal function.
Toxicity: Further details to be discussed in subsequent terms.
ADMET Metabolism: Active Metabolites
1. Overview of Active Metabolites
Active Metabolite: A metabolite that possesses pharmacological activity itself and contributes to the therapeutic effect of the parent drug.
2. Learning Objectives for Active Metabolites
Identify marketed drugs that function as active metabolites of other drugs.
Define and differentiate relevant terms regarding active metabolites.
3. Terms & Definitions
Pharmacophore: The specific three-dimensional arrangement of atoms or groups necessary for a drug's biological activity, responsible for targeting specific receptors.
Example: A diagram representing the pharmacophore for binding at the benzodiazepine site on the GABAA receptor showing diazepam and its derivatives.
4. Importance of Active Metabolites
They can prolong the action of the parent drug, increasing therapeutic effectiveness and affecting dosage regimens.
5. Mechanism of Action
Active metabolites must retain specific characteristics in size, shape, and electronic distribution to effectively bind to the same drug target as the parent drug.
6. Examples of Active Metabolites
Paliperidone (Invega®): Active metabolite of risperidone; hydroxylation process influenced by enzyme CYP2D6, forms the palmitate ester.
Desvenlafaxine succinate (Pristiq®): Active metabolite of venlafaxine; characterized by O-dealkylation through CYP2D6, making up 55% of the dose.
Nortriptyline HCl (Pamelor®): Active metabolite of amitriptyline; formed by N-dealkylation via CYP2C19.
Desloratadine (Clarinex®): Result of the hydrolysis of loratadine, involving CYP3A4 and CYP2D6.
Oxazepam (Serax®): Derived from diazepam through oxidation processes influenced by CYP2C19 and CYP3A4.