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Upon entering the systemic circulation, drugs can distribute into the interstitial and intracellular fluid of various tissue cells. This distribution is facilitated by the binding of drugs to different cellular components within tissues, which may lead to drug accumulation in specific areas. Drugs bound to tissue components serve as reservoirs that release free drugs back into the system, prolonging the drug's overall action. However, this accumulation can also result in local toxicity.
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Hepatic clearance refers to the volume of blood cleared of a drug by the liver per unit of time. It plays a crucial role in drug metabolism and elimination. While hepatic clearance is commonly estimated by subtracting renal clearance from total body clearance, other pathways, such as pulmonary or biliary clearance, may also contribute. However, these pathways are generally less significant than hepatic and renal clearance.
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Drug Distribution: Volume of Distribution01:25

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The volume of distribution refers to the theoretical volume necessary to contain the entire amount of an administered drug at the same concentration observed in the blood plasma. The body's intracellular fluid compartment, which makes up two-thirds of the total body water, is contrasted with the extracellular fluid compartment—comprising plasma and interstitial fluid—that accounts for one-third. The volume of distribution can vary depending on the characteristics of the drug.
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Drug Distribution: Plasma Protein Binding01:29

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Drugs predominantly attach to plasma proteins, with only a small percentage remaining unbound. The unbound portion can be calculated as one minus the bound fraction. Acidic drugs form large, inactive complexes by reversibly binding to plasma albumin, which prevents them from diffusing across biological barriers. These drug-protein complexes act as reservoirs for the drugs. As the concentration of unbound drugs decreases, these complexes quickly dissociate to release the free drug, maintaining...
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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
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Targeted Broader Sharing for Liver Continuous Distribution.

Michal A Mankowski1, Nicholas L Wood2, Allan B Massie1,3

  • 1Department of Surgery, NYU Grossman School of Medicine, NYU Langone Health, New York, NY.

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Summary
This summary is machine-generated.

A new liver allocation score (CAS-TBS) balances geographic disparities by adjusting sharing policies. This method reduces transplant waitlist deaths and improves equity in liver distribution across regions.

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Area of Science:

  • Transplantation research
  • Organ allocation policy
  • Health equity

Background:

  • US organ allocation reforms aim to enhance equity and accessibility.
  • The Organ Procurement and Transplantation Network (OPTN) is adopting continuous liver distribution.
  • A composite allocation score (CAS) prioritizes candidates using factors like proximity and medical urgency.

Purpose of the Study:

  • To develop a geographically heterogeneous CAS (CAS-TBS) addressing regional variations in liver availability.
  • To balance liver transplant listings and donations across diverse geographic areas.
  • To refine the CAS for the OPTN's continuous distribution framework.

Main Methods:

  • Designed a geographically heterogeneous CAS with targeted broader sharing (CAS-TBS).
  • Assigned donor hospitals to broader or nearby sharing categories.
  • Adjusted donor-candidate distance allocation points based on sharing strategy.

Main Results:

  • Distributing >75% of livers with broader sharing in regions 2 and 10, and 95% with nearby sharing in regions 5 and 1, reduces geographic disparity.
  • CAS-TBS decreased median Model for End-stage Liver Disease at transplant (MMaT) by 2.1 points in high-MMaT areas and increased it by 0.65 points in low-MMaT areas.
  • Reduced median transport distance and waitlist deaths in a 3-year simulation.

Conclusions:

  • CAS-TBS methodology can create geographically heterogeneous allocation scores aligned with transplant priorities.
  • This approach supports the OPTN's continuous distribution project.
  • The simulated benefits of CAS-TBS over the standard CAS were modest but significant.