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Related Concept Videos

Nonlinear Pharmacokinetics: Overview01:19

Nonlinear Pharmacokinetics: Overview

Nonlinear or dose-dependent pharmacokinetics is a phenomenon that occurs when the pharmacokinetic parameters of certain drugs deviate from linear pharmacokinetics at higher doses. These drugs do not follow the expected first-order kinetics, where the rate of drug elimination is directly proportional to the drug concentration. Instead, they exhibit a nonlinear relationship, which can be attributed to several factors.
Nonlinearity can arise due to the saturation of plasma protein-binding or...
Nonlinear Pharmacokinetics: Causes of Nonlinearity01:22

Nonlinear Pharmacokinetics: Causes of Nonlinearity

Nonlinearity in drug pharmacokinetics is caused by various factors influencing how a drug is absorbed, distributed, metabolized, and excreted. Understanding these nonlinear processes is crucial for predicting drug behavior in the body and optimizing drug dosing regimens.
Nonlinear drug absorption can occur when the process is rate-limited by solubility, carrier-mediated transport systems, or saturation of the presystemic gut wall or hepatic metabolism. For instance, high doses of riboflavin...
Nonlinear Pharmacokinetics: Bioavailability and Protein-Drug Binding01:22

Nonlinear Pharmacokinetics: Bioavailability and Protein-Drug Binding

When a drug follows nonlinear pharmacokinetics, its bioavailability, the amount of the drug that reaches the systemic circulation, can change with different doses. This is due to the presence of a saturable pathway. The pathway becomes saturated as the drug concentration increases, decreasing the absorption rate. Consequently, the drug's bioavailability may be lower than expected at higher doses.
To quantify the extent of bioavailability, pharmacologists often use a parameter called .
Nonlinear Pharmacokinetics: Role of Transporters01:27

Nonlinear Pharmacokinetics: Role of Transporters

A drug's nonlinear kinetics can be influenced by a diverse range of transporter proteins that serve as crucial players in drug distribution. These transporters, found within cells, can enhance or reduce local drug concentrations by facilitating the influx or efflux of drugs. For instance, the expression of xenobiotic transporters can be influenced by factors such as age and gender, potentially impacting the linearity of drug response.
Polymorphisms occurring in drug transporters can alter...
Effect of Hepatic Disease on Pharmacokinetics: Drug Dosing and Hepatic Blood Flow01:26

Effect of Hepatic Disease on Pharmacokinetics: Drug Dosing and Hepatic Blood Flow

Chronic liver disease significantly impacts drug metabolism due to alterations in hepatic blood flow and enzyme accessibility. This disruption affects the body's pharmacokinetics—the movement and processing of drugs within the system. Key enzymes crucial for metabolizing medications become less accessible, changing how drugs are processed and utilized. Furthermore, liver disease influences the synthesis of plasma proteins, such as albumin and globulins, which play critical roles in drug binding...
Pharmacokinetic–Pharmacodynamic Relationship: Dose to Pharmacological Effect01:28

Pharmacokinetic–Pharmacodynamic Relationship: Dose to Pharmacological Effect

A drug’s dosage and pharmacokinetic properties determine how quickly it acts, how intense its effects are, and how long it lasts. Higher doses increase drug concentration at receptor sites, producing a hyperbolic curve when pharmacologic response is plotted against drug dose. Converting this scale to a log-linear format results in a sigmoidal curve, better representing dose–response relationships.For drugs following a one-compartment model, the pharmacologic response is directly proportional to...

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Instrumentation of Near-term Fetal Sheep for Multivariate Chronic Non-anesthetized Recordings
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A comparison of nonlinear pharmacokinetics of erythropoietin in sheep and humans.

P Veng-Pedersen1, J A Widness, L M Pereira

  • 1College of Pharmacy, Division of Pharmaceutics, University of Iowa, Iowa City, IA 52242, USA. veng@uiowa-edu

Biopharmaceutics & Drug Disposition
|August 10, 1999
PubMed
Summary

The elimination mechanism of erythropoietin (EPO) is unknown. Disposition Decomposition Analysis (DDA) revealed nonlinear pharmacokinetic behavior in newborn sheep and preterm infants, suggesting saturable elimination pathways.

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Area of Science:

  • Pharmacokinetics
  • Biochemistry

Background:

  • The in vivo elimination mechanism and responsible tissues for erythropoietin (EPO) remain unidentified.
  • Prior research suggests nonlinear pharmacokinetic (PK) behavior of EPO, indicating a saturable elimination process.

Purpose of the Study:

  • To analyze and compare the pharmacokinetic behavior of EPO in newborn sheep and preterm infants using Disposition Decomposition Analysis (DDA).
  • To quantify Michaelis-Menten parameters (V(m) and k(m)) for EPO elimination.

Main Methods:

  • Utilized Disposition Decomposition Analysis (DDA), a versatile system for analyzing nonlinear pharmacokinetic behavior.
  • Analyzed EPO PK data from newborn sheep and preterm infants.
  • Quantified V(m) (elimination capacity) and k(m) (degree of nonlinearity) parameters.

Main Results:

  • Both lambs and infants exhibited nonlinear EPO PK behavior, accurately analyzed by DDA.
  • Lambs demonstrated significantly higher V(m) (elimination capacity) and extrapolated linear clearances compared to preterm infants.
  • Lambs showed a greater degree of nonlinearity, indicated by significantly lower mean k(m) values than infants.
  • In vivo DDA-derived k(m) values were comparable to in vitro binding affinity data for EPO receptors.

Conclusions:

  • The DDA methodology effectively analyzes nonlinear EPO PK behavior in both sheep and humans.
  • Newborn sheep exhibit greater EPO elimination capacity and nonlinearity than preterm infants.
  • The sheep model is suitable for invasive studies to further elucidate EPO elimination mechanisms, potentially involving enzymatic degradation or receptor-mediated internalization.