The document summarizes Michaelis-Menten kinetics, which describes non-linear pharmacokinetics. It discusses how drug elimination via enzyme-mediated metabolic pathways can become saturated at high doses, following Michaelis-Menten kinetics. The document outlines methods to estimate the Michaelis-Menten constants Km and Vmax from drug concentration-time data. It also discusses factors that can cause non-linear pharmacokinetics and challenges in quantifying non-linear processes.
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
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).
This presentation will give the students a basic knowledge about the pharmacokinetics of durgs. It will help them clear the basics before digging deep into the topic.
Introduction
Mechanisms of protein drug binding
Kinetics of protein drug binding
Classes of protein drug binding.
1. Binding of drug to blood components.
(a) Plasma proteins
(b) Blood cells
2. Binding of drug to extravascular tissue protein
Determination of Protein-drug Binding
Factors affecting protein drug binding
Significance of protein/tissue binding of drug
Biopharmaceutics: Mechanisms of Drug AbsorptionSURYAKANTVERMA2
Biopharmaceutics is defined as the study of factors influencing the rate and amount of drug that reaches the systemic circulation and the use of this information to optimise the therapeutic efficacy of the drug products.
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
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).
This presentation will give the students a basic knowledge about the pharmacokinetics of durgs. It will help them clear the basics before digging deep into the topic.
Introduction
Mechanisms of protein drug binding
Kinetics of protein drug binding
Classes of protein drug binding.
1. Binding of drug to blood components.
(a) Plasma proteins
(b) Blood cells
2. Binding of drug to extravascular tissue protein
Determination of Protein-drug Binding
Factors affecting protein drug binding
Significance of protein/tissue binding of drug
Biopharmaceutics: Mechanisms of Drug AbsorptionSURYAKANTVERMA2
Biopharmaceutics is defined as the study of factors influencing the rate and amount of drug that reaches the systemic circulation and the use of this information to optimise the therapeutic efficacy of the drug products.
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.
pharmacokinetics is the important topic in both pharmacology and pharmaceutics in degree and masters level . the thorough knowledge in the fiels of pharmacokinetics will helps to choose the proper medicine to treat a particular disesse
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
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Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
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Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
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Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
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These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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1. Seminar on
MICHAELIS MENTEN
KINETICS
PRESENTED BY
MOHAMMED MUNAWAR ALI
(M.PHARM. 1 ST SEMESTER)
DEPT. OF PHARMACEUTICS
ST. PETER’S INSTITUTE OF
PHARMACEUTICAL SCIENCES,
VIDYANAGAR, HANAMKONDA. 506001.
AFFILIATED TO KAKATIYA UNIVERSITY
2. C ONTENTS
Introduction
Some pharmacokinetic aspects of Michaelis-Menten equation.
In vivo estimation of Km and Vm
Estimation of pharmacokinetic parameters concerned
Other Non-linear Processes
Problems in quantifying non-linear kinetics
Conclusion
References
2
3. I NTRODUCTION
Linear kinetics, wherein the change in plasma
concentration of drug due to absorption, distribution,
binding, metabolism or excretion is proportional to its
dose whether administered as single or multiple doses.
Drug biotransformation, renal tubular secretion, and
biliary secretion usually require enzyme or carrier
systems. These systems are relatively specific with
respect to substrate and have finite capacities, such
processes are called capacity limited process; commonly
called non-linear pharmacokinetics.
3
4. The pharmacokinetics of such drugs which follow non-
linear are said to be dose dependent, mixed order or
capacity limited process.
The kinetics of capacity limited process are best
explained by Michaelis-Menten equation, given as
This equation is derived from the following scheme.
E = conc. of enzyme
K-1 K C = conc. of drug
E+C K1
EC 2
E+M EC= conc. of enzyme-drug complex
M = conc. of metabolite
K2 and K-1 = first order rate constants
K1 = second order rate constant 4
5. Table-1
Causes of non linearity Examples
Absorption
Saturable transport in gut wall Riboflavin
Drug comparatively insoluble Griseofulvin
Saturablegut wall or hepatic metabolism on first pass Salicylamide, propranolol
Pharmacologic effect on GI motility Metoclopramide, chloroquine
Saturable gastric or GI decomposition Some penicillins
Distribution
Saturable plasma protein binding Phenylbutazone, salicylates
Saturable tissue binding Naproxen
Saturable transport into or out of tissues methotrexate
Renal elimination
Active secretion Penicillin G
Active reabsorption Ascorbic acid
Change in urine pH Salicylic acid
Saturable plasma protein binding Salicylic acid
Nephrotoxic effect at higher doses Amino glycosides
Diuretic effect Theophylline, alcohol
Extra renal elimination
Capacity limited metabolism Phenytoin, theophylline
Enzyme saturation or co-factor limitation Salicylic acid, alcohol
Saturable biliary secretion Tetracycline, indomethacin
Enzyme induction Carbamazepine
Hepatotoxic at higher doses Acetaminophen
Saturable plasmaproteinbinding Phenylbutazone
5
Altered hepatic blood flow Propranolol
Metabolite inhibition. Diazepam
6. SOME PHARMACOKINETIC
ASPECTS
Three conditions are considered here where the
michaelis-menten equation alter depending.
i) when Km=C
-dC/dt= Vm/2
ii) when Km>>> C
-dC/dt= (Vm/Km)C
iii) when Km<<< C
-dC/dt= Vm Fig 1
6
Source: Milo Gibaldi, Pharmacokinetics
7. In vivo ESTIMATION OF K m AND V m
When drug is administered via IV injection, eliminated by single capacity
limited process.
Solving the equation we get,
Modified form of which is,
Conversion to common logarithmic form
and solving for log C,
Fig 2.
Source: Milo Gibaldi, Pharamacokinetics
7
9. Considering the drug elimination involving one capacity limited process and
one or more first order processes, the rate of elimination is represented as,
Km<<<C
Km>>>C Plot -d ln C/dt Vs 1/C
where slope is Vm. To get
Km the eq. is considered at
lower concentration.
9
11. USAGE OF URINE DATA
K’
V’m kmu
K’m
V’m is maximum rate of metabolite,
K’ & kmu are first order rate constants,
K’m is michaelis-menten’s constant,
Cm is plasma drug conc. at midpoint of
collection interval.
Fig 5. 11
Source: Milo Gibaldi, Pharamacokinetics
13. For the case where linear pathways of elimination in parallel with a
non-linear process,
13
14. OTHER NON-LINEAR PROCESSES
I. CHRONOPHARMACOKINETICS
It refers to temporal changes in rate processes like absorption and
elimination which may be either cyclical or noncyclical.
aminoglycoside
II. ENZYME INDUCTION
Repeated doses of Carbamazepine induces the enzymes
responsible for its elimination.
14
15. III. PROTEIN BINDING
Plasma level- time profiles
of two drugs A and B where
A is 90% protein bound and
B does not bind with plasma
protein.
Ex: Valproic acid.
Fig 6.
Source: Leon Shargel, Applied biopharmaceutics
Pharamacokinetics
15
16. PROBLEMS IN QUANTIFYING NON-LINEAR
PHARMACOKINETICS
Estimation of Km and Vm assuming multi compartment would
be more approporiate rather than considering a one
compartment model.
One more problem encounters when a drug is eliminated via
more than one capacity limited processes.[Sedmen et al.] No
problem in Km, when it is in factor of 3.
Drugs which effect the hepatic blood flow in turn effecting the
rate of elimination. The mechanism by which these act are
altering the cardiac outflow.
16
17. CONCLUSION
Non linear pharmacokinetics is dose dependent and
does not occur significantly at lower doses of drug.
Probable reasons to occur may be attributed to change
in physiologic system or saturation or protein binding
or enzyme induction.
Though the level of complexity increases when it is
applied more realistic, assuming the process in a
single compartment several pharmacokinetic
parameters are estimated concerned.
17
18. REFERENCES
G. Levy. Pharmacokinetics of salicylate elimination in man. J.
Pharm. Sci. 54:959 (1965).
K. Arnold and N. Gerber. The rate of decline of
diphenylhydantoin in human plasma. Clin. Pharmacol. Ther.
11: 121 (1970).
N. Gerber and J. G. Wagner. Explanation of dose-dependent
decline of diphenylhydantoin plasma levels by fitting to the
integrated form of Michaelis-Menten equation. Res. Commun.
Chem. Pathol. Pharmacol. 3: 455 (1972).
L. Martis and R. H. Levy. Bioavailability calculations for
drugs showing simultaneous first -order and capacity-limited
elimination kinetics. J. Pharmacokinet. Biopharm. 1: 283
18
(1973) .
19. T. Tsuchiya and G. Levy. Relationship between dose and plateau
levels of drugs eliminated by parallel first-order and capacity-
limited kinetics. J. Pharm. Sci. 61:541(1972).
W. H. Pitlick and R. H. Levy. Time-dependent kinetics: I.
Exponential autoinduction of carbamazepine in monkeys. J. Pharm.
Sci. 66:647 (1977).
BIBILIOGRAPHY
Milo Gibaldi and Donald Perrier. Pharmacokinetics. Second
edition. Volume 15. Marcel Dekker INC. 272-289 (2006).
Leon Shargel, Susanna Wu-Pong and Andrew B.C Yu. Non-linear
Pharmacokinetics. Applied Biopharmaceutics and
Pharmacokinetics. Fifth edition. The McGraw-Hill Companies,
INC. 240-242 (2007)
19