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Related Concept Videos

Hepatic Drug Excretion: Enterohepatic Cycling01:17

Hepatic Drug Excretion: Enterohepatic Cycling

Enterohepatic cycling involves the active secretion of drugs and their metabolites into the bile via transporters in the canalicular membrane of hepatocytes. This secretion is an integral part of the digestive process, releasing these substances into the gastrointestinal (GI) tract.
Post-release drugs and metabolites can be reabsorbed into the body from the intestine. For conjugated metabolites like glucuronides, reabsorption requires enzymatic hydrolysis by intestinal microflora. This...
Drug Elimination: Non-Renal Routes01:23

Drug Elimination: Non-Renal Routes

The liver plays a pivotal role in eliminating drugs and their metabolites, primarily through a process known as biliary excretion. This process involves the hepatocytes, the primary cells in the liver that generate bile. A range of transporters actively expels polar drugs or hydrophilic drug metabolites into the bile, which transports the drugs and metabolites into the small intestine. From here, they are eventually expelled from the body through feces. In some instances, the original drug or a...
Drug Metabolism: Phase II Reactions01:14

Drug Metabolism: Phase II Reactions

Phase II reactions are essential for the detoxification and elimination of drugs from the body. These reactions involve the conjugation of parent drugs or their phase I metabolites with endogenous molecules, resulting in more hydrophilic drug conjugates. The primary conjugation reactions in this phase are sulfation and glucuronidation. Both sulfation and glucuronidation typically produce biologically inactive metabolites. However, in some cases involving prodrugs, active metabolites may be...
Introduction to Metabolism01:30

Introduction to Metabolism

Metabolism encompasses all biochemical reactions in a living organism, facilitating both the breakdown and synthesis of biomolecules. These metabolic processes are categorized into catabolic and anabolic pathways, which operate in a coordinated manner to ensure energy balance and cellular function.Catabolic Pathways and Energy ReleaseCatabolic pathways involve the breakdown of complex macromolecules such as carbohydrates, lipids, and proteins into smaller structures like monosaccharides, fatty...
Hepatic Portal System01:21

Hepatic Portal System

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Pharmaceutical substances known as xenobiotics are predominantly lipophilic and nonionized. This enables them to permeate lipid bilayers, such as cell membranes, and interact with intracellular target receptors. Lipophilic drugs have an advantage in crossing biological barriers and reaching their intended sites of action. However, lipophilic drugs often have a restricted capacity for renal expulsion or elimination from the body. When these drugs enter the kidneys and undergo glomerular...

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Arteriovenous Metabolomics to Measure In Vivo Metabolite Exchange in Brown Adipose Tissue
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Which metabolites circulate?

Cho-Ming Loi1, Dennis A Smith, Deepak Dalvie

  • 1Pfizer, Inc., 10646 Science Center Drive, San Diego, CA 92121, USA. cho-ming.loi@pfizer.com

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|March 5, 2013
PubMed
Summary

Fractional formation (fm) is key to metabolite-to-parent (M/P) ratios for many drug metabolites. Understanding metabolite clearance is crucial for assessing circulating metabolite abundance and drug safety.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Medicinal Chemistry

Background:

  • Characterizing circulating drug metabolites is vital for safety assessment, understanding pharmacologic activity, and predicting drug-drug interactions.
  • The metabolite-to-parent (M/P) ratio reflects metabolite abundance relative to the parent drug.

Purpose of the Study:

  • To review the relationship between drug metabolite abundance (M/P ratio) and drug characteristics.
  • To identify key determinants of high M/P ratios and understand factors influencing metabolite circulation.

Main Methods:

  • Analysis of M/P ratios from 125 drugs.
  • Correlation of M/P ratios with structural features, lipophilicity, protein binding, and fractional formation (fm).

Main Results:

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  • Fractional formation (fm) significantly determines M/P ratios for amine, alcohol, N-/S-oxide, and carboxylic acid metabolites.
  • Hepatic efflux is generally not limiting due to metabolite lipophilicity; active transport can play a role.
  • Prodrugs and arenol metabolites exhibit complex M/P ratio relationships requiring further investigation.

Conclusions:

  • Fractional formation is a primary driver of M/P ratios for common metabolite classes.
  • Metabolite lipophilicity and clearance significantly influence circulating levels, impacting safety and efficacy.
  • Further research into specific metabolite classes, like arenols, is needed for comprehensive understanding.