Nonlinear pharmacokinetics occurs when the body's processing of a drug is saturated at higher doses, causing kinetics parameters like clearance and half-life to change with dose. Michaelis-Menten kinetics are commonly used to model nonlinear metabolism, where the metabolic rate approaches a maximum (Vmax) at high concentrations. Parameters like Vmax and KM can be estimated from steady-state dosing and concentration data by linearizing the Michaelis-Menten equation. Drugs like phenytoin exhibit nonlinear kinetics due to capacity-limited hepatic metabolism.
This document discusses linear and nonlinear pharmacokinetics. [1] Linear pharmacokinetics follow first-order kinetics where the rate of drug absorption, distribution, metabolism and excretion is proportional to dose. [2] Nonlinear pharmacokinetics occur when these processes become saturated at high doses due to limited enzyme or transporter capacity. [3] Michaelis-Menten kinetics are often used to model nonlinear processes and estimate parameters like Vmax and Km.
The document discusses compartment modeling and one compartment open models. It describes how the body can be represented as a single well-mixed compartment and outlines the assumptions of compartmental models. It then covers one compartment open models for intravenous bolus administration, intravenous infusion, and extravascular administration. For intravenous bolus administration, the elimination phase can be characterized by parameters like elimination rate constant, half-life, and clearance. Intravenous infusion allows for constant rate input into the compartment. Extravascular administration models absorption as either zero-order or first-order kinetics.
This document discusses phytosomes, which are herbal extracts bound to phospholipids. Phytosomes have several advantages over traditional herbal extracts, including enhanced absorption and bioavailability. The document outlines the structure and properties of phytosomes, comparing them to liposomes. It also describes the preparation process, evaluation methods, and applications of various phytosome formulations. Common phytosomes include silymarin (milk thistle) for liver health, grape seed for antioxidants, green tea for antioxidants and chronic diseases, and curcumin for anti-inflammatory effects. Phytosomes allow herbal constituents to be absorbed more effectively and produce better results than conventional herbal extracts.
This document discusses in vitro-in vivo correlations (IVIVCs). It defines IVIVC as a predictive mathematical model relating an in vitro property (e.g. dissolution rate) to an in vivo response (e.g. absorption rate). The document outlines the significance of IVIVCs in reducing bioequivalence studies and supporting biowaivers. It describes different levels of IVIVC (A, B, C) and parameters that can be correlated (dissolution rate to absorption rate; percent dissolved to percent absorbed). The document provides examples of IVIVC case studies and concludes that current regulatory guidelines only apply to oral dosage forms, while further research is needed to develop IVIVCs for other drug products.
This document discusses absolute and relative bioavailability. Absolute bioavailability is determined for the same drug in various formulations and measures the actual percentage of an administered non-intravenous dose that is absorbed into systemic circulation relative to an equivalent intravenous dose. Relative bioavailability compares drug exposures following extravascular administration to that of intravenous administration and is used to characterize a drug's inherent absorption properties from extravascular sites. Relative bioavailability compares the bioavailability of formulations of the same drug, usually to an established standard formulation.
The document discusses nonlinear pharmacokinetics and chronopharmacokinetics. Nonlinear pharmacokinetics occurs when the body's absorption, distribution, metabolism, or excretion of a drug becomes saturated at higher doses. This can cause the rate of drug elimination to decrease. Examples of processes that can become saturated include drug metabolism and renal excretion. Circadian rhythms can also impact drug pharmacokinetics by influencing absorption, distribution, metabolism, and excretion over 24-hour periods. Accounting for these temporal changes can improve drug therapy for circadian phase-dependent diseases.
Nonlinear pharmacokinetics occurs when the body's processing of a drug is saturated at higher doses, causing kinetics parameters like clearance and half-life to change with dose. Michaelis-Menten kinetics are commonly used to model nonlinear metabolism, where the metabolic rate approaches a maximum (Vmax) at high concentrations. Parameters like Vmax and KM can be estimated from steady-state dosing and concentration data by linearizing the Michaelis-Menten equation. Drugs like phenytoin exhibit nonlinear kinetics due to capacity-limited hepatic metabolism.
This document discusses linear and nonlinear pharmacokinetics. [1] Linear pharmacokinetics follow first-order kinetics where the rate of drug absorption, distribution, metabolism and excretion is proportional to dose. [2] Nonlinear pharmacokinetics occur when these processes become saturated at high doses due to limited enzyme or transporter capacity. [3] Michaelis-Menten kinetics are often used to model nonlinear processes and estimate parameters like Vmax and Km.
The document discusses compartment modeling and one compartment open models. It describes how the body can be represented as a single well-mixed compartment and outlines the assumptions of compartmental models. It then covers one compartment open models for intravenous bolus administration, intravenous infusion, and extravascular administration. For intravenous bolus administration, the elimination phase can be characterized by parameters like elimination rate constant, half-life, and clearance. Intravenous infusion allows for constant rate input into the compartment. Extravascular administration models absorption as either zero-order or first-order kinetics.
This document discusses phytosomes, which are herbal extracts bound to phospholipids. Phytosomes have several advantages over traditional herbal extracts, including enhanced absorption and bioavailability. The document outlines the structure and properties of phytosomes, comparing them to liposomes. It also describes the preparation process, evaluation methods, and applications of various phytosome formulations. Common phytosomes include silymarin (milk thistle) for liver health, grape seed for antioxidants, green tea for antioxidants and chronic diseases, and curcumin for anti-inflammatory effects. Phytosomes allow herbal constituents to be absorbed more effectively and produce better results than conventional herbal extracts.
This document discusses in vitro-in vivo correlations (IVIVCs). It defines IVIVC as a predictive mathematical model relating an in vitro property (e.g. dissolution rate) to an in vivo response (e.g. absorption rate). The document outlines the significance of IVIVCs in reducing bioequivalence studies and supporting biowaivers. It describes different levels of IVIVC (A, B, C) and parameters that can be correlated (dissolution rate to absorption rate; percent dissolved to percent absorbed). The document provides examples of IVIVC case studies and concludes that current regulatory guidelines only apply to oral dosage forms, while further research is needed to develop IVIVCs for other drug products.
This document discusses absolute and relative bioavailability. Absolute bioavailability is determined for the same drug in various formulations and measures the actual percentage of an administered non-intravenous dose that is absorbed into systemic circulation relative to an equivalent intravenous dose. Relative bioavailability compares drug exposures following extravascular administration to that of intravenous administration and is used to characterize a drug's inherent absorption properties from extravascular sites. Relative bioavailability compares the bioavailability of formulations of the same drug, usually to an established standard formulation.
The document discusses nonlinear pharmacokinetics and chronopharmacokinetics. Nonlinear pharmacokinetics occurs when the body's absorption, distribution, metabolism, or excretion of a drug becomes saturated at higher doses. This can cause the rate of drug elimination to decrease. Examples of processes that can become saturated include drug metabolism and renal excretion. Circadian rhythms can also impact drug pharmacokinetics by influencing absorption, distribution, metabolism, and excretion over 24-hour periods. Accounting for these temporal changes can improve drug therapy for circadian phase-dependent diseases.
This document discusses compartment modeling in pharmacokinetics. It defines a compartment as a group of tissues with similar blood flow and drug affinity. Compartment models represent the body as a series of compartments through which drugs move according to first-order kinetics. The two major types are mammillary models, with one central compartment connected to multiple peripheral compartments, and catenary models with compartments connected in series. Compartment models are simple and flexible, allowing prediction of drug concentration over time, though they lack full physiological relevance.
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
Tumour targeting and Brain specific drug deliverySHUBHAMGWAGH
The document discusses tumor targeting and brain specific drug delivery. It provides an introduction to targeted drug delivery and outlines strategies for tumor targeting including passive targeting via the enhanced permeability and retention effect, active targeting using ligands, and triggered drug delivery responsive to microenvironment changes. It also discusses challenges of drug delivery to the brain posed by the blood-brain barrier and factors that affect crossing it, as well as diseases related to the brain and strategies to enhance brain-specific drug delivery.
This document describes the one compartment open model for pharmacokinetics. It states that the body is treated as a single, homogeneous unit where drugs distribute rapidly throughout and move dynamically in and out. Elimination follows first-order kinetics. The model can describe intravenous bolus administration, continuous intravenous infusion, or extravascular administration where absorption is either zero-order or first-order. Distinction between these absorption processes can be seen when plotting amount of drug remaining to be absorbed versus time.
DISSOLUTION
Dissolution is defined as a process in which a solid substance solubilises in a given solvent.
(i.e. mass transfer from the solid surface to the liquid phase.)
Three Theories:
Diffusion layer model / Film theory
Danckwert’s model / Penetration or Surface renewal theory
Interfacial barrier model / Double barrier or Limited solvation theory
IN-VITRO-IN VIVO CORRELATION (IVIVC).pptxRAHUL PAL
An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.
This document discusses linear and nonlinear pharmacokinetics. Linear pharmacokinetics follow first-order kinetics and nonlinear pharmacokinetics follow Michaelis-Menten kinetics. Nonlinearity can occur due to saturation of drug absorption, distribution, metabolism or excretion processes. The Michaelis-Menten equation can describe nonlinear kinetics and data plots of drug concentration versus time can indicate nonlinear behavior.
This document discusses various compendial methods for drug dissolution testing. It begins by defining dissolution as the process where a solid substance solubilizes in a solvent, transferring mass from the solid surface to the liquid phase. It then describes the seven USP dissolution apparatus types and their applications for testing different drug products like tablets, capsules, modified release formulations and transdermal systems. The document provides details on factors that influence dissolution test design and the principles of operation for each apparatus type.
introduction
mechanisms of protein drug binding
binding of drugs
binding of drugs to blood components
determination of protein drug binding
factors affecting
significance
Drug absorption from the gastrointestinal tract can be influenced by many factors. The drug must first disintegrate, dissolve, and permeate the gastrointestinal membranes before being absorbed into systemic circulation. The rate of absorption is determined by the slowest of these steps. Factors that can affect absorption include the drug's physicochemical properties, dosage form characteristics, and patient factors like gastrointestinal pH, transit time, and presence of food or enzymes. Understanding these biopharmaceutical factors is important for optimizing drug product design and therapeutic efficacy.
This document discusses dissolution, which is defined as the process by which a solid substance solubilizes in a given solvent. Key points include:
- Drugs are classified into BCS classes based on their solubility and permeability. The four classes are high/high, high/low, low/high, and low/low.
- Noyes-Whitney and Hixson-Crowell equations describe dissolution kinetics under non-sink and sink conditions. Factors like surface area, diffusion coefficient, and concentration gradients impact dissolution rate.
- In vitro dissolution testing uses apparatus like baskets, paddles, and flow-through cells per BP and USP methods to simulate in vivo conditions and assess
This document discusses the two compartment model for intravenous bolus drug administration. It describes how drugs administered via this route can display biexponential decline from the body as the drug distributes into a central and peripheral compartment. Key parameters of the two compartment model are discussed, including apparent volume of distribution, drug clearance, biological half-life, elimination rate constants, and area under the curve. The two compartment model provides insight into drug absorption, distribution, and elimination kinetics.
This document describes the two compartment open model for drug distribution and elimination. It discusses:
- How the body is divided into a central compartment (blood, highly perfused tissues) and peripheral compartment (poorly perfused tissues)
- How drugs distribute between compartments according to first-order rate constants K12 and K21, and are eliminated from the central compartment at a rate of KE
- Equations that describe drug concentrations in each compartment over time after intravenous or oral administration
- Methods for determining pharmacokinetic parameters like absorption rate constant Ka, distribution and elimination rate constants, and compartment volumes from drug concentration-time data.
Plasma Drug Concentration Time Profile
Pharmacokinetic Parameter
Pharmacodynamic Parameter
Zero, First Order & Mixed Order Kinetic
Rates & Order Of Kinetics
Pharmacokinetic Models
Application Of Pharmacokinetic
1. Measurement of Bioavailability:
Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects.
For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
The design of the bioavailability study depends on the objectives of the study, the ability to analyze the drug (and metabolites) in biological fluids, the pharmacodynamics of the drug substance, the route of drug administration, and the nature of the drug product.
Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product.
1.1. Pharmacokinetic methods:
These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
1.2. Pharmacodynamic methods:
IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
They involve determination of bioavailability from:
Acute pharmacological response.
Therapeutic response.
1.3. In-vitro dissolution studies
Closed compartment apparatus
Open compartment apparatus
Dialysis systems.
1.4. Clinical observations
Well-controlled clinical trials
Properties of GI tract, pH partition hypothesis Naveen Reddy
Drug absorption from the gastrointestinal (GI) tract depends on several physiological factors:
1) Gastric emptying and intestinal transit time influence drug absorption by determining how long drugs remain in areas where absorption can occur. Faster emptying and transit generally increase absorption rate.
2) Water fluxes in the GI tract can impact drug dissolution and movement within the lumen, affecting absorption. Considerable water is secreted in the small intestine and mostly reabsorbed.
3) The permeability of drugs is affected by their solubility, ionization state, and lipophilicity, which determine how well drugs can pass through membranes according to the pH partition hypothesis. However, the microclimate pH at the membrane surface can differ
This document discusses pharmacokinetic models, including compartment models. It begins by defining pharmacokinetics and describing different types of pharmacokinetic models. It then focuses on compartment models, explaining that the body can be divided into compartments that exchange materials. It describes multi-compartment models and the two-compartment open model in particular. For the two-compartment model, it outlines the parameters such as apparent volume of distribution, elimination rate constant, and biological half-life. It also discusses nonlinear pharmacokinetics and the Michaelis-Menten equation for describing nonlinear processes.
Master Formula Record (MFR) is a master document for any
pharmaceutical product. MFR contains all information about the manufacturing process
for the product. MFR is prepared by the research and development team of the
company. MFR is used as reference standard for preparing batch manufacturing record (BMR) by manufacturing units.
The document discusses three main theories of drug dissolution:
1) Diffusion layer/film theory which describes dissolution as a two step process of drug dissolving from the solid to form a saturated film and then diffusing out of the film. The rate of dissolution is given by the Noyes-Whitney equation.
2) Danckwert's/surface renewal theory which accounts for eddies in the solution exposing new surface areas for dissolution. The rate is expressed as the product of the surface renewal rate and concentration gradient.
3) Interfacial barrier model which assumes the reaction at the solid surface is slower than diffusion, making interfacial transport the rate limiting step described by another equation.
This document discusses linear and non-linear pharmacokinetics. Linear pharmacokinetics follows first-order kinetics where the rate of change in drug concentration depends only on the current concentration. In non-linear pharmacokinetics, the rate depends on carrier enzymes that can become saturated at high drug concentrations, causing the kinetics to follow mixed or zero-order processes and parameters to change with dose. Non-linearity can be caused by saturation of absorption, distribution, metabolism or excretion processes. The Michaelis-Menten equation describes non-linear kinetics and parameters. Km and Vmax can be estimated from plasma concentration data using Lineweaver-Burk, Eadie-Hofstee or Han
The document discusses linear and nonlinear pharmacokinetics. It defines linear pharmacokinetics as processes where the rate is proportional to dose and pharmacokinetic parameters are unaffected by dose. Nonlinear pharmacokinetics occurs when rates become dose-dependent due to saturation of carriers, enzymes or receptors. It describes methods to detect nonlinearity including determining parameters at different doses. Causes include saturation of absorption, distribution, metabolism and excretion processes. The Michaelis-Menten equation is presented as a way to model saturable processes and methods to estimate Km and Vmax values are outlined, including at steady state concentrations.
This document discusses compartment modeling in pharmacokinetics. It defines a compartment as a group of tissues with similar blood flow and drug affinity. Compartment models represent the body as a series of compartments through which drugs move according to first-order kinetics. The two major types are mammillary models, with one central compartment connected to multiple peripheral compartments, and catenary models with compartments connected in series. Compartment models are simple and flexible, allowing prediction of drug concentration over time, though they lack full physiological relevance.
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
Tumour targeting and Brain specific drug deliverySHUBHAMGWAGH
The document discusses tumor targeting and brain specific drug delivery. It provides an introduction to targeted drug delivery and outlines strategies for tumor targeting including passive targeting via the enhanced permeability and retention effect, active targeting using ligands, and triggered drug delivery responsive to microenvironment changes. It also discusses challenges of drug delivery to the brain posed by the blood-brain barrier and factors that affect crossing it, as well as diseases related to the brain and strategies to enhance brain-specific drug delivery.
This document describes the one compartment open model for pharmacokinetics. It states that the body is treated as a single, homogeneous unit where drugs distribute rapidly throughout and move dynamically in and out. Elimination follows first-order kinetics. The model can describe intravenous bolus administration, continuous intravenous infusion, or extravascular administration where absorption is either zero-order or first-order. Distinction between these absorption processes can be seen when plotting amount of drug remaining to be absorbed versus time.
DISSOLUTION
Dissolution is defined as a process in which a solid substance solubilises in a given solvent.
(i.e. mass transfer from the solid surface to the liquid phase.)
Three Theories:
Diffusion layer model / Film theory
Danckwert’s model / Penetration or Surface renewal theory
Interfacial barrier model / Double barrier or Limited solvation theory
IN-VITRO-IN VIVO CORRELATION (IVIVC).pptxRAHUL PAL
An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.
This document discusses linear and nonlinear pharmacokinetics. Linear pharmacokinetics follow first-order kinetics and nonlinear pharmacokinetics follow Michaelis-Menten kinetics. Nonlinearity can occur due to saturation of drug absorption, distribution, metabolism or excretion processes. The Michaelis-Menten equation can describe nonlinear kinetics and data plots of drug concentration versus time can indicate nonlinear behavior.
This document discusses various compendial methods for drug dissolution testing. It begins by defining dissolution as the process where a solid substance solubilizes in a solvent, transferring mass from the solid surface to the liquid phase. It then describes the seven USP dissolution apparatus types and their applications for testing different drug products like tablets, capsules, modified release formulations and transdermal systems. The document provides details on factors that influence dissolution test design and the principles of operation for each apparatus type.
introduction
mechanisms of protein drug binding
binding of drugs
binding of drugs to blood components
determination of protein drug binding
factors affecting
significance
Drug absorption from the gastrointestinal tract can be influenced by many factors. The drug must first disintegrate, dissolve, and permeate the gastrointestinal membranes before being absorbed into systemic circulation. The rate of absorption is determined by the slowest of these steps. Factors that can affect absorption include the drug's physicochemical properties, dosage form characteristics, and patient factors like gastrointestinal pH, transit time, and presence of food or enzymes. Understanding these biopharmaceutical factors is important for optimizing drug product design and therapeutic efficacy.
This document discusses dissolution, which is defined as the process by which a solid substance solubilizes in a given solvent. Key points include:
- Drugs are classified into BCS classes based on their solubility and permeability. The four classes are high/high, high/low, low/high, and low/low.
- Noyes-Whitney and Hixson-Crowell equations describe dissolution kinetics under non-sink and sink conditions. Factors like surface area, diffusion coefficient, and concentration gradients impact dissolution rate.
- In vitro dissolution testing uses apparatus like baskets, paddles, and flow-through cells per BP and USP methods to simulate in vivo conditions and assess
This document discusses the two compartment model for intravenous bolus drug administration. It describes how drugs administered via this route can display biexponential decline from the body as the drug distributes into a central and peripheral compartment. Key parameters of the two compartment model are discussed, including apparent volume of distribution, drug clearance, biological half-life, elimination rate constants, and area under the curve. The two compartment model provides insight into drug absorption, distribution, and elimination kinetics.
This document describes the two compartment open model for drug distribution and elimination. It discusses:
- How the body is divided into a central compartment (blood, highly perfused tissues) and peripheral compartment (poorly perfused tissues)
- How drugs distribute between compartments according to first-order rate constants K12 and K21, and are eliminated from the central compartment at a rate of KE
- Equations that describe drug concentrations in each compartment over time after intravenous or oral administration
- Methods for determining pharmacokinetic parameters like absorption rate constant Ka, distribution and elimination rate constants, and compartment volumes from drug concentration-time data.
Plasma Drug Concentration Time Profile
Pharmacokinetic Parameter
Pharmacodynamic Parameter
Zero, First Order & Mixed Order Kinetic
Rates & Order Of Kinetics
Pharmacokinetic Models
Application Of Pharmacokinetic
1. Measurement of Bioavailability:
Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects.
For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
The design of the bioavailability study depends on the objectives of the study, the ability to analyze the drug (and metabolites) in biological fluids, the pharmacodynamics of the drug substance, the route of drug administration, and the nature of the drug product.
Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product.
1.1. Pharmacokinetic methods:
These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
1.2. Pharmacodynamic methods:
IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
They involve determination of bioavailability from:
Acute pharmacological response.
Therapeutic response.
1.3. In-vitro dissolution studies
Closed compartment apparatus
Open compartment apparatus
Dialysis systems.
1.4. Clinical observations
Well-controlled clinical trials
Properties of GI tract, pH partition hypothesis Naveen Reddy
Drug absorption from the gastrointestinal (GI) tract depends on several physiological factors:
1) Gastric emptying and intestinal transit time influence drug absorption by determining how long drugs remain in areas where absorption can occur. Faster emptying and transit generally increase absorption rate.
2) Water fluxes in the GI tract can impact drug dissolution and movement within the lumen, affecting absorption. Considerable water is secreted in the small intestine and mostly reabsorbed.
3) The permeability of drugs is affected by their solubility, ionization state, and lipophilicity, which determine how well drugs can pass through membranes according to the pH partition hypothesis. However, the microclimate pH at the membrane surface can differ
This document discusses pharmacokinetic models, including compartment models. It begins by defining pharmacokinetics and describing different types of pharmacokinetic models. It then focuses on compartment models, explaining that the body can be divided into compartments that exchange materials. It describes multi-compartment models and the two-compartment open model in particular. For the two-compartment model, it outlines the parameters such as apparent volume of distribution, elimination rate constant, and biological half-life. It also discusses nonlinear pharmacokinetics and the Michaelis-Menten equation for describing nonlinear processes.
Master Formula Record (MFR) is a master document for any
pharmaceutical product. MFR contains all information about the manufacturing process
for the product. MFR is prepared by the research and development team of the
company. MFR is used as reference standard for preparing batch manufacturing record (BMR) by manufacturing units.
The document discusses three main theories of drug dissolution:
1) Diffusion layer/film theory which describes dissolution as a two step process of drug dissolving from the solid to form a saturated film and then diffusing out of the film. The rate of dissolution is given by the Noyes-Whitney equation.
2) Danckwert's/surface renewal theory which accounts for eddies in the solution exposing new surface areas for dissolution. The rate is expressed as the product of the surface renewal rate and concentration gradient.
3) Interfacial barrier model which assumes the reaction at the solid surface is slower than diffusion, making interfacial transport the rate limiting step described by another equation.
This document discusses linear and non-linear pharmacokinetics. Linear pharmacokinetics follows first-order kinetics where the rate of change in drug concentration depends only on the current concentration. In non-linear pharmacokinetics, the rate depends on carrier enzymes that can become saturated at high drug concentrations, causing the kinetics to follow mixed or zero-order processes and parameters to change with dose. Non-linearity can be caused by saturation of absorption, distribution, metabolism or excretion processes. The Michaelis-Menten equation describes non-linear kinetics and parameters. Km and Vmax can be estimated from plasma concentration data using Lineweaver-Burk, Eadie-Hofstee or Han
The document discusses linear and nonlinear pharmacokinetics. It defines linear pharmacokinetics as processes where the rate is proportional to dose and pharmacokinetic parameters are unaffected by dose. Nonlinear pharmacokinetics occurs when rates become dose-dependent due to saturation of carriers, enzymes or receptors. It describes methods to detect nonlinearity including determining parameters at different doses. Causes include saturation of absorption, distribution, metabolism and excretion processes. The Michaelis-Menten equation is presented as a way to model saturable processes and methods to estimate Km and Vmax values are outlined, including at steady state concentrations.
Non-linear pharmacokinetics can occur when drug absorption, distribution, or elimination processes become saturated at high drug concentrations. This can cause the rate of drug clearance to change from first-order to zero-order kinetics with increasing doses. Non-linear kinetics results in plasma concentrations and pharmacokinetic parameters that are not proportional to the administered dose. Specific causes include saturation of drug metabolizing enzymes, plasma protein binding sites, or renal reabsorption/secretion mechanisms. Non-linear drugs have less predictable responses and greater potential for toxicity compared to linearly eliminated drugs.
- The document discusses nonlinear pharmacokinetics where parameters like clearance and volume of distribution change with dose. This occurs when transporters or enzymes involved in absorption, distribution, metabolism and excretion get saturated at high drug concentrations.
- The Michaelis-Menten equation is used to describe saturation kinetics and estimate parameters Km and Vmax. Various methods like Lineweaver-Burk, direct linear and graphical plots are presented to determine these values using in vivo or in vitro concentration and rate data.
- Estimation of Km and Vmax is also described at steady-state concentrations achieved after constant rate infusion or multiple dosing, through plots of steady-state concentration versus dosing rate.
This document summarizes one and two compartment open models for extravascular drug administration. It describes how compartment models are used to simplify drug distribution and elimination processes in the body. A one compartment open model is presented, showing drug absorption from extravascular administration followed by distribution and elimination from the body compartment. Equations are provided to describe drug behavior under zero-order and first-order absorption. Methods for estimating the absorption rate constant like residuals and Wagner-Nelson are also summarized. Finally, a two compartment open model is briefly introduced.
This document discusses pharmacokinetics and provides information about key concepts used in pharmacokinetics including:
- Logarithms and how they relate to calculating drug concentrations over time
- Differential and integral calculus which are used to develop equations to model rates of change in drug absorption and elimination over small time intervals
- How to write differential equations to model different rate processes like zero-order, first-order, and Michaelis-Menten kinetics
- The use of graphs including Cartesian and semi-log scales to plot drug concentration vs. time profiles
- Examples of using these concepts to solve pharmacokinetic problems
This document discusses pharmacokinetics and pharmacokinetic modeling. It begins with an introduction to first order kinetics and the equations used to describe first order reactions. It then discusses compartment modeling, describing one, two, and multi-compartment models. The document provides examples of pharmacokinetic parameters including elimination rate constant, volume of distribution, and fraction unbound. It concludes with an overview of linear vs non-linear pharmacokinetics and steady state concentrations.
Pharacokinetics power point for pharmacyemebetnigatu1
The document discusses various pharmacokinetic models used to describe drug movement in the body. It begins by defining pharmacokinetics and some key parameters. It then describes compartment models, including mammillary and caternary models, and provides an example of a one-compartment open model for intravenous bolus administration. This model assumes rapid distribution and first-order elimination. The document also discusses zero-order and first-order reaction kinetics and how they relate to pharmacokinetic processes. It provides examples of using compartment model equations to calculate drug concentrations over time and dosing requirements.
PHARMACOKINETIC MODELS
Drug movement within the body is a complex process. The major objective is therefore to develop a generalized and simple approach to describe, analyse and interpret the data obtained during in vivo drug disposition studies.
The two major approaches in the quantitative study of various kinetic processes of drug disposition in the body are
Model approach, and
Model-independent approach (also called as non-compartmental analysis).
1. The document outlines a lecture on pharmacokinetic models, which provide mathematical descriptions of how drugs move through the body over time.
2. Pharmacokinetic models are classified as compartmental models, non-compartment models, or physiological models. Compartmental models divide the body into compartments and use rate constants to describe drug movement between compartments.
3. Key pharmacokinetic parameters like volume of distribution, elimination rate constant, half-life, and clearance can be calculated from compartmental model equations to quantify a drug's absorption, distribution, metabolism, and excretion.
Here are the steps to solve this problem:
a. At a dose of 10 mg/kg, the plasma concentration would be 10 mg/kg / 20 L/kg = 0.5 mg/L = 500 μg/mL. Since this concentration is greater than the KM value of 50 μg/mL, the reaction order for metabolism would be zero order.
b. For zero order kinetics, the rate of elimination is equal to Vmax. So the time for 50% elimination is the dose (10 mg/kg) x 0.5 / Vmax. Vmax is given as 20 μg/mL/hr = 20 mg/kg/hr. Therefore, the time is 10 mg/kg x 0.5 / 20
This document discusses compartment modeling in pharmacokinetics. It begins by defining a mathematical model and compartment model. Compartmental models divide the body into compartments and use first-order kinetics to describe the movement of drugs between compartments. Common compartment models include one-compartment open models for intravenous bolus, intravenous infusion, and extravascular administration. Determination of pharmacokinetic parameters like absorption rate, elimination rate constant, and half-life are also covered.
Determination of absorption and elimination rates on base of compartment modelAbhinayJha3
This document provides information about determining absorption and elimination rates using compartment models. It discusses what compartment models are and describes one-compartment open models. It explains zero-order and first-order absorption models and how to calculate elimination rate constants. The document also discusses using urinary excretion data to estimate pharmacokinetic parameters when plasma concentration data is unavailable. Parameters like volume of distribution, clearance, excretion and elimination rate constants can be estimated from urinary excretion data using methods like the rate of excretion method.
Determination of absorption and elimination rates on base of compartment modelAbhinayJha3
This document provides information about determining absorption and elimination rates using compartment models. It discusses the concepts of absorption, elimination, and compartment models. It then describes the one-compartment open model and differences between zero-order and first-order absorption kinetics. The document outlines the absorption and elimination phases when following one-compartment kinetics. It also discusses using urinary excretion data to determine pharmacokinetic parameters when plasma level data is unavailable. The document was prepared by Abhinay Ashok Jha for his final year assessment on this topic.
The document discusses compartment modeling and the one-compartment open model for drug absorption and elimination. It describes the assumptions of the one-compartment model and the processes of input (absorption) and output (elimination). It then discusses the one-compartment open model for intravenous bolus administration, continuous intravenous infusion, and extravascular administration with zero-order or first-order absorption kinetics. Key pharmacokinetic parameters like elimination rate constant, half-life, volume of distribution, and clearance are also defined.
This document reviews open two compartment pharmacokinetic models. It discusses how a drug administered intravenously distributes between a central (plasma) compartment and peripheral (tissue) compartment. The fate of the drug in the compartments is estimated using Laplace transforms to derive mathematical formulas relating the drug concentrations over time. These formulas contain hybrid constants that can be used to calculate the pharmacokinetic parameters k, k12, and k21, which describe the drug distribution and elimination rates between compartments. The tissue concentration and biological half-life of the drug can then be predicted from these parameter values.
The study of absorption, distibution,metabolism,excretio of drug and their relationship to pharmacological response. In simple word ; what the body dose to the drug. Linear pharmacokinetics.In the pharmacokinetic parameter for drug would not change when difference dose or multiple dose of drug is given. Non linear pharmcokinetics-if any deviation cause linear pharmacokinetics called non linear, mixed, capacity – limited kinetics.
This document presents information on estimating the absorption rate constant using the method of residuals. It discusses absorption and compartment models, outlines the steps of the method of residuals for a one compartment model, and notes considerations like lag time, flip-flop phenomena, and applications and limitations of the method. The method involves plotting drug concentrations over time, obtaining slopes for the terminal and residual lines to determine the absorption and elimination rate constants. It is best suited for rapidly absorbed drugs following one-compartment kinetics.
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Michaelis Menten Equation and Estimation Of Vmax and Tmax.pptx
1. PRESENTED BY:
Deepak A. Thakre
M.Pharm I Year
Industrial Pharmacy
Department
Shri Sadashivrao Patil Shikshan Sanstha's
SMT. KISHORITAI BHOYAR COLLEGE OF PHARMACY,
KAMPTEE
GUIDED BY :
Dr. Jayshree B. Taksande
HOD Pharmaceutics
Department
TOPIC : 1. The Michaelis-Menten equation &
2. Estimating Km and Vmax
1
2. If metabolism is the only pathway of elimination, the rate of metabolism or elimination is defined by
the Michaelis-Menten equation.
The (Non- linear) kinetics of capacity-limited or saturable processes is best described by Michaelis-Menten
equation:
−
𝒅𝒄
𝒅𝒕
=
𝑽𝒎𝒂𝒙𝑪
𝐊𝐦+𝐂
------- (1)
Where,
–dc/dt = rate of decline of drug concentration with time,
Vmax = theoretical maximum rate of the process,
Km = Michaelis constant,
C= drug Concentration .
Three situations can now be considered depending upon the values of Km and C:
A] When Km = C
Under this situation, the equation (1) reduces to i.e. −
𝑑𝑐
𝑑𝑡
=
𝑉𝑚𝑎𝑥
2
-------(2)
i.e. the rate of process is equal to one-half its maximum rate.
2
3. 3
A plot of Michaelis-Menten equation (elimination rate dC/dt versus concentration C). Initially, the rate
increases linearly (first-order) with concentration, becomes mixed-order at higher concentration and then
reaches maximum (Vmax) beyond which it proceeds at a constant rate (zero-order).
4. Michaelis-Menten equation is generally used to explain the kinetics of in-vitro, few
enzyme catalyzed in-vivo and in-situ processes.
4
5. 5
B] Km>> C
When the concentrations are low, i.e. Km> C, then Km +C is approximately
equal to Km,
−
𝒅𝒄
𝒅𝒕
=
𝐕𝐦𝐚𝐱𝐂
𝐊𝐦
------------ equation .(3)
The above equation is identical to the one that describes first-order elimination
of a drug where Vmax/Km = KE. This means that the drug concentration in the
body that results from usual dosage regimens of most drugs is well below the
Km of the elimination process with certain exceptions such as phenytoin and
alcohol.
Because both Vmax and Km are constants, the metabolism rate is proportional
to the drug concentration and is constant (i.e., first-order process).
6. C] C>> Km
When the concentrations are high, i.e. C > Km, then
𝒅𝒄
𝒅𝒕
=
𝑽𝒎𝒂𝒙𝑪
𝑪
= 𝑽𝒎𝒂𝒙 ------- equation (4)
Equation 4 gives the zero order kinetics.
Therefore, it was concluded that at high plasma concentrations, first order kinetics were not seen.
The above equation is identical to the one that describes a zero-order process i.e. the
rate process occurs at a constant rate Vmax and is independent of drug concentration.
When given in therapeutic doses, most drugs produce plasma drug concentrations well below
the Km for all carrier mediated enzyme systems affecting the pharmacokinetics of the drug.
Hence most of the drugs at normal therapeutic concentrations follow 1st order rate processes.
Some of the drugs like phenytoin and salicylate saturate the hepatic mixed function oxidases at
higher therapeutic doses.
With these drugs, elimination kinetics is 1st order at low doses and mixed at high doses and
shows zero-order at very high therapeutic doses.
6
7. If a single IV bolus injection of drug D0 is given at t=0, the drug concentration, Ct in the
plasma at any time may be calculated by integrated form of Eq 1 is given by
𝑪𝒐−𝑪𝒕
𝒕
= 𝑽𝒎𝒂𝒙 −
𝑲𝒎𝑪
𝒕
𝑰𝒏
𝑪𝒐
𝒕
----equation (5)
Where C0 is the concentration at time t=0.
Alternatively the amount of the drug in the body after an IV bolus injection may be
calculated by the following relationship.
𝑫𝒐−𝑫𝒕
𝒕
= 𝑽𝒎𝒂𝒙 −
𝑲𝒎𝑪
𝒕
𝑰𝒏
𝑫𝒐
𝒕
------equation (6)
Where Do is the amount of the drug in the body at t=0.
…Equation (5)
…Equation (6)
Equation 6 can be used to study the decline of the drug in the body after the administration
of different therapeutic doses. Here, the Km and Vmax of the drug are unknown.
7
8. By rearranging the above Equation 6, time to decline a certain amount of the dose of a drug
can
be calculated by the following equation
𝑡 =
1
𝑉𝑚𝑎𝑥
𝐷𝑜 − 𝐷𝑡 + 𝐾𝑚 𝐼𝑛
𝐷𝑜
𝐷𝑡
-----equation (7)
Equation 7 explains an inverse relationship between the time for the dose to decline to a
certain amount of the drug in the body and Vmax.
Actually, Km can be said as the hybrid constant in enzyme kinetics that may represents both
forward as well as backward reaction.
It is equivalent to the concentration of the drug in the body at ½ Vmax.
The one compartment open model having capacity limited elimination pharmacokinetics
effectively explains the plasma drug concentration time profiles for a number of drugs.
8
9. 9
The parameters of capacity-limited processes like metabolism, renal tubular secretion
and biliary excretion can be easily defined by assuming one-compartment kinetics for
the drug and that elimination involves only a single capacity-limited process. The
parameters Km and Vmax can be assessed from the plasma concentration-time data
collected after i.v. bolus administration of a drug with nonlinear elimination
characteristics.
Rewriting equation
−
𝒅𝒄
𝒅𝒕
=
𝑽𝒎𝒂𝒙𝑪
𝐊𝐦+𝐂
---------equation (1)
Integration of above equation followed by conversion to log base 10 yields:
𝒍𝒐𝒈𝑪 = 𝒍𝒐𝐠𝐂𝐨 +
𝐂𝐨−𝐂
𝟐.𝟑𝟎𝟑𝐊𝐦
−
𝐕𝐦𝐚𝐱
𝟐.𝟑𝟎𝟑𝐊𝐦
-------(2)
Estimating Km and Vmax
10. 10
A semilog plot of C versus t yields a curve with a terminal linear portion having
slope –Vmax/2.303Km and when back extrapolated to time zero gives Y-
intercept log Co .The equation that describes this line is:
Fig: Semi-log plot of a drug given as i.v.
bolus with nonlinear elimination and
that fits one-compartment kinetics.
----equation (3)
11. 11
From equation 2 and 3 ( at low Plasma Concentration)
𝐿𝑜𝑔𝐶𝑜 = 𝑙𝑜𝑔𝐶𝑜 +
𝐶𝑜−𝐶
2.303𝐾𝑚
𝑙𝑜𝑔𝐶𝑜 − 𝑙𝑜𝑔𝐶𝑜 =
𝐶𝑜−𝐶
2.203𝐾𝑚
OR
𝑙𝑜𝑔
𝐶𝑜
𝐶𝑜
=
𝐶𝑜−𝐶
2.303𝐾𝑚
For this equation Km can be obtained.
Vmax can be Computed by Substituting the value of Km in the Slope value.
12. Estimating Km and Vmax
Method : Equation 1 gives the relationship of the drug biotransformation to the
concentration of the drug in the body. When an experiment is performed by
using different concentrations of the drug C, a series of reaction rates (V) may
be calculated for each concentration. Km and Vmax can then be determined by
using the special plots.
Hence,
V=
𝑽𝒎𝒂𝒙𝑪
𝐊𝐦+𝐂
------ equation (8)
Rearranging the above equation 8, [As Per Equation of Slope- 𝒚 = 𝒎𝒙 + 𝒄]
1
𝑉
=
𝐾𝑚
𝑉𝑚𝑎𝑥
1
𝐶
+
1
𝑉𝑚𝑎𝑥
-----equation (9)
Above Equation 9 gives the linear equation, when 1/V is plotted against 1/C,
the resultant intercept for the line is 1/Vmax and the slope is Km/Vmax
Fig: Plot of 1/V against 1/C for the determination of Km and Vmax
12