Introduction

• ADME, which stands for absorption, distribution, metabolism, and excretion, describes the processes that determine how a drug moves through the body.
• Understanding ADME is crucial for pharmacists as it helps predict drug behaviour, interactions, and potential side effects.

Absorption

• Definition: Absorption is the process of a drug entering the bloodstream from its site of administration.
• Factors Affecting Absorption:
  • Route of Administration: Different routes (oral, intravenous, intramuscular, etc.) have varying absorption rates.
  • Drug Formulation: The physical form of the drug (tablet, capsule, solution) influences its absorption.
  • Physicochemical Properties: A drug’s solubility, lipophilicity, and ionisation affect its ability to cross membranes and be absorbed.
• Bioavailability: The fraction of an administered drug dose that reaches the systemic circulation unchanged. It is crucial for determining appropriate dosages.

Distribution

• Definition: Distribution refers to the reversible transfer of a drug from the bloodstream to various tissues and organs.
• Factors Affecting Distribution:
  • Blood Flow: Well-perfused organs (heart, liver, kidneys) receive the drug faster.
  • Plasma Protein Binding: Drugs can bind to proteins in the blood, affecting their distribution and availability to target sites.
  • Tissue Binding: Some drugs accumulate in specific tissues, leading to localised effects or toxicity.
• Volume of Distribution (Vd): A theoretical volume that represents the extent of drug distribution in the body.
  • A large Vd indicates extensive distribution into tissues.
  • A small Vd suggests the drug is primarily confined to the bloodstream.

Metabolism

• Definition: Metabolism is the process by which the body chemically modifies a drug, primarily in the liver.
• Purpose of Metabolism:
  • Drug Inactivation: Convert active drugs into inactive metabolites for easier excretion.
  • Prodrugs: Transform inactive prodrugs into their active forms.
• Metabolic Reactions:
  • Phase I Reactions: Involve oxidation, reduction, or hydrolysis, often introducing or unmasking polar functional groups.
  • Phase II Reactions: Conjugation reactions, attaching polar molecules (e.g., glucuronic acid) to the drug, enhancing water solubility for excretion.
• Cytochrome P450 Enzymes: A superfamily of enzymes in the liver that play a crucial role in drug metabolism, particularly Phase I reactions. Variations in CYP enzyme activity can lead to drug interactions and interindividual variability in drug response.

Excretion

• Definition: Excretion is the process of removing drugs and their metabolites from the body.
• Routes of Excretion:
  • Renal Excretion: Elimination through urine, primarily for smaller, polar drugs and metabolites.
  • Biliary/Faecal Excretion: Drugs and metabolites excreted in bile and eliminated in faeces, often for larger, less polar compounds.
  • Other Routes: Excretion can also occur through sweat, saliva, breast milk, and exhaled air.
• Clearance: The rate at which a drug is removed from the body.
  • Total clearance is the sum of clearance by all eliminating organs.
  • Clearance is a critical parameter for determining dosing regimens.

Interplay of ADME Processes

• ADME processes are interconnected and influence a drug’s overall disposition in the body.
• Understanding these interrelationships is essential for optimising drug therapy.
• For example, a drug with high first-pass metabolism may require a higher dose or alternative route of administration to achieve the desired therapeutic effect.

Importance of ADME Studies

• Drug Development: ADME studies are crucial in all phases of drug development, from preclinical testing to post-marketing surveillance.
• Regulatory Submissions: Regulatory agencies require comprehensive ADME data to assess a drug’s safety and efficacy before approval.
• Clinical Practice: Understanding a drug’s ADME profile is essential for:
  • Individualised dosing regimens.
  • Predicting and managing drug interactions.
  • Addressing variability in drug response.

Emerging Trends in ADME

• Microdosing: Using sub-pharmacological doses of radiolabelled drugs to obtain early human ADME data.
• Accelerator Mass Spectrometry (AMS): A highly sensitive technique for quantifying drugs and metabolites in biological samples, allowing for microdosing studies.
• Fluorine-NMR (F-NMR): Using fluorine-containing drugs as probes to study ADME processes without the need for radiolabelled.
• Physiologically Based Pharmacokinetic (PBPK) Modelling: Using mathematical models to predict drug disposition based on ADME properties, facilitating drug development and individualised therapy.

Conclusion

• ADME is a fundamental concept in pharmacology, providing a framework for understanding drug disposition in the body.
• Pharmacists play a crucial role in applying ADME knowledge to ensure safe and effective drug therapy.
• As new technologies and approaches emerge, the field of ADME continues to evolve, enhancing our understanding of drug action and improving patient care.

References

1. Zamek-Gliszczynski, M. J., Hoffmaster, K. A., Nezasa, K., Tallman, M. N., & Brouwer, K. L. (2012). Integration of hepatic drug transporters and phase II metabolizing enzymes: Mechanisms of hepatic drug clearance. Pharmaceutical Research, 29(8), 1996-2007. Retrieved from NCBI

2. Knutson, C. G., McDonald, T. S., Wishart, D. S., & Patel, P. J. (2023). Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion. Drug Metabolism and Disposition, 51(6), 647-656. Retrieved from Drug Metabolism and Disposition

3. ScienceDirect. (n.d.). Absorption, Distribution, Metabolism, Excretion (ADME). Retrieved from ScienceDirect

4. Wilkinson, G. R. (2022). Pharmacokinetics: Processes of Absorption, Distribution, Metabolism, and Excretion. In Comprehensive Pharmacology. Oxford University Press. Retrieved from Oxford Academic