ADMET 10

ADMET refers to the essential pharmacokinetic processes: Absorption, Distribution, Metabolism, Excretion, and Toxicity. Understanding ADMET is critical in medicinal chemistry.
- Absorption: the process of drug entry into the systemic circulation.
- Distribution: the dispersion of drugs throughout the fluids and tissues of the body.
- Metabolism: the biochemical modification of pharmaceutical substances by living organisms, often through enzymatic action.
- Excretion: the elimination of drugs from the body, typically via urine or feces.
- Toxicity: adverse effects that can occur following exposure to drugs.
Drug Targets:
- Active drug targets are those that produce the intended therapeutic effects.
- Inactive drug targets are those that do not contribute to the drug's desired pharmacological action.

Routes/Sites of Administration: Various pathways including oral, intravenous, transdermal, and inhalational.
- Mechanisms of Absorption: Processes by which drugs cross biological membranes, including passive diffusion, facilitated diffusion, active transport, and pinocytosis.
- Prodrugs: Medications that require metabolic conversion to an active pharmacological agent.
- Absorption-based DDIs: Drug-drug interactions that alter absorption, leading to changes in bioavailability.

Models of Distribution: Conceptual frameworks for understanding how drugs distribute throughout the body, e.g., one-compartment vs. multi-compartment models.
Volume of Distribution (Vd): Theoretical volume that relates the amount of drug in the body to the concentration of drug in the blood or plasma.
Sequestration: The process by which substances are confined to a particular area (e.g., binding to tissues, proteins).
Blood-Brain Barrier (BBB) / CNS Penetration: Limitations on drug delivery to the Central Nervous System based on permeability and lipid solubility.
- Distribution-based DDIs: Interactions that affect how drugs distribute within the body.

Sites of Metabolism: Regions in the body where metabolic processes predominantly occur (liver, intestines).
Influencing Factors: Factors affecting drug metabolism including age, genetics, diet, and environment.
Types of Chemical Reactions: Phase I (modification reactions such as oxidation, reduction) and Phase II (conjugation reactions).
Metabolic Pathways & Enzymes: Organ-specific pathways activated by enzymes that modulate drug effects and clearance.
- Metabolism-based DDIs: Interactions that alter the metabolic breakdown of drugs, leading to altered efficacy or toxicity.

Routes of Clearance: Pathways through which drugs are excreted, primarily via kidneys, liver, and lungs.
Influencing Factors: Variables that impact the rate of elimination such as age, organ function, and drug formulation.

Describe mechanisms underlying metabolism-based drug-drug and drug-food interactions.
- CYP450 Inhibitors and Inducers: Understanding how certain compounds alter the activity of cytochrome P450 enzymes.
- Dosage Adjustments: Recognizing potential dose modifications needed in response to CYP inhibition and induction.

Types of CYP450 Interactions:
1. Inhibition of CYP450: Reduction of enzyme activity, leading to increased levels of substrates and potential toxicity.
- Azoles: Drug class (e.g., itraconazole, ketoconazole) which inhibiting CYP3A4. These antifungals inhibit fungal P450 enzymes but also inhibit human CYP3A4.
- Common Drugs Affected: Antiarrhythmics (quinidine), antiepileptics (carbamazepine), benzodiazepines (alprazolam), cyclosporine, warfarin.
- Grapefruit Juice: Contains compounds that inhibit CYP3A4, affecting metabolism of statins and other medications.
1. Induction of CYP450: Increase in enzyme activity, potentially leading to decreased levels of substrates and reduced therapeutic effects.
- Barbiturates: Known inducers of CYP3A4, increasing metabolism of beta-blockers, oral contraceptives, and warfarin.
- Rifamycins: (e.g., rifampin, rifabutin) also known inducers of CYP3A4.
- St. John’s Wort: Herbal supplement that induces CYP3A4, affecting the metabolism of various drugs.

Inhibitors: Azoles (itraconazole, ketoconazole), grapefruit juice.
Inducers: Barbiturates (phenobarbital), rifamycins (rifampin), St. John’s Wort.

Understanding ADMET processes is crucial for predicting drug interactions and adjusting therapy to maintain efficacy while minimizing risks.
Clinical decisions must consider both the mechanisms of drug metabolism and the potential for significant pharmacokinetic alterations due to concurrent medications or food interactions.