1. The pharmacokinetics of oral drug absorption depends on physicochemical properties of the drug, dosage form used, and gastrointestinal anatomy and physiology.
2. Drug absorption from the GI tract can be modeled using zero-order, first-order, or two-compartment models depending on the drug and dosage form.
3. The absorption rate constant (ka) can be estimated from plasma concentration-time data, urinary excretion data, or the fraction of drug absorbed over time to understand the overall rate and extent of drug absorption.
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
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
It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
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
It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.
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
Methods For Assesment Of Bioavailability Anindya Jana
Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. 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.
Bioavailability studies are important in the Primary stages of development of a suitable dosage form for a new drug entity, determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption, development of new formulations of the existing drugs, control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption
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).
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
Methods For Assesment Of Bioavailability Anindya Jana
Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. 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.
Bioavailability studies are important in the Primary stages of development of a suitable dosage form for a new drug entity, determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption, development of new formulations of the existing drugs, control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption
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).
Pharmacokinetics (PK) is the study of how the body interacts with administered substances for the entire duration of exposure (medications for the sake of this article). This is closely related to but distinctly different from pharmacodynamics, which examines the drug's effect on the body more closely.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
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.
Title: Sense of Taste
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 structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
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.
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.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
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.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
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The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
2. • Systemic drug absorption from GI tract/other
extravascular site depend on:
- Physicochemical properties of drug
-dosage form used
- Anatomy and physiology of absorption site
3. • Oral dosing, factors effect the rate and extent
of drug absorption:
- Surface area of GI tract
- Stomach emptying rate
- GI mobility
- Blood flow to absorption site
4. • Rate of change in the amount of drug in the
body, dDB/dt = dependent on relative rates of
drug absorption and elimination
• The net rate of drug accumulation in the body:
5. Plasma level-time curve of drug absorption and
elimination rate processes
Absorption phase- rate of drug
absorption greater than rate of drug
elimination
Elimination occurs whenever drug
present- even though absorption
predominates
At peak drug conc in plasma:
Immediately after time of peak
drug absorption, some drug may
still be at absorption site ( e.g. GI
tract.
Rate of drug elimination is
faster than rate of absorption-
postabsorption phase.
Drug at absorption site- depleted, rate
of absorption approaches 0, dDGI/dt=0
(now elimination phase)- represents
only the elimination of drug from the
body- 1st order process.
Elimination phase- rate of change in
the amount of drug in the body-
described as 1st order process
6. Zero-order absorption model
• Zero-order absorption- when drug is absorbed
by saturable process/ zero order controlled
release system
• DGI- absorbed systemically at a constant rate,
k0. drug- immediately/simultaneously
eliminated from body by 1st order process-
defined by 1st order rate constant, k.
7. • Rate of 1st order elimination, at any time:
• Rate of input = ko. ∴, net change per unit time
in the body:
• Integration of this equation, substitute DB=
VDCP:
• Rate of drug absorption, remain constant until
DGI depleted. Time for complete drug
absorption = DGI/ko. After this time, drug is not
available for absorption from gut, equation 1-
not valid. Drug conc in plasma- decline
according to 1st order process.
(1)
8. First-order absorption model
• Absorption- assume to be 1st order.
• Applies mostly to oral absorption of drugs in
solution/ rapidly dissolving dosage (tablets,
capsules)
• Oral drug- disintegrate of dosage form (if
solid)- drug dissolves into fluid of GI tract.
• Only drug in solution- absorbed in body
9. • Rate of disappearance of drug from GI:
- ka- 1st order absorption rate constant from GI
- F- fraction absorbed
- DGI- amount of drug in GI at any time, t.
• Integration of above equation,
10. • Rate of drug change in the body:
• =
• Drug in GI- 1st order decline (i.e. drug is
absorbed across GI wall), amount of drug in GI
at any time, t = D0e-kat.
• Value of F- vary from 0 (drug completely
unabsorbed) to 1 (fully absorbed).
11. • Integrate the equation- oral absorption
equation- to calculate drug conc (Cp) in plasma
at any time, t:
(2)
12. plasma level-time curve for drug given in
single dose
•Max plasma conc after oral dosing –
Cmax
•Time needed to reach max conc- tmax
•tmax- independent of dose, dependent
on rate constant for absorption, ka and
elimination, k
•At Cmax- peak conc
•Rate of drug absorbed= rate of drug
eliminated
•Net rate of conc change = 0
•At Cmax- rate of conc change:
Can be simplified:
(3)
(4)
13. • In order to calculate Cmax- the value of tmax is
determine by equation (4) and substitute to
equation (2).
• Equation (2)- Cmax is proportional to dose of
drug given (Do) and F.
• Elimination rate constant, k- may determined
from elimination phase of plasma level-time
curve.
14. • At later time intervals, when drug absorption
completed, e-kat ≈ 0, equation 2 reduce to
• ln this equation:
• Substitute to log:
(5)
15. • With equation (5), graph constructed by
plotting log Cp vs. t will yield straight line with
a slope of –k/2.3
16. • With similar approach, urinary drug excretion
data may be used for calculation of first-order
elimination rate constant, k
• Rate of drug excretion after single oral dose
drug:
• dDu/dt= rate of urinary drug excretion
- Ke = 1st order renal excretion constant
- F = fraction of dose absorbed
(6)
17. • Graph constructed by plotting dDu/dt vs. t,
yield curve identical to plasma level-time
curve
18. • After drug absorption virtually complete, -e-kat
approaches zero, equation (6) reduces to
• Taking ln of both sides, substitute for log
• When log (dDu/dt) vs. t, graph of straight line
is obtained with slope of –k/2.3.
• To obtain the cumulative drug excretion in
urine:
19. • Plot of Du vs t- give urinary drug excretion
curve.
Cumulative urinary drug excretion vs t, single oral
dose. Urine samples are collected at various time
period.
The amount of drug excreted in each sample is
added to amount of drug recovered in previous
urine sample. Total amount of drug recovered after
all drug excreted is Du∞
Du∞- max amount of active drug excreted
20. Determination of Absorption rate
constants from oral Absorption data
Method of residuals
• Assume ka>> k in equation (2), the value of 2nd
exponential will become significantly small (e-
kat ≈0)- can be omitted. When this happen=
drug absorption is virtually complete.
22. • Value of ka can be obtained by using the
method of residuals as described in chapter
before.
• If drug absorption begins
Immediately after oral admin
the residual lines obtained
will intercept on the y axis at
point A
23. Lag time
• sometimes, absorption of drug after single
dose does not start immediately, due to:
- Physiologic factors (stomach-emptying time
and intestinal motility)
- Time delay prior to commencement of 1st
order drug absorption- lag time
24. •Lag time- if 2 residual lines obtained by
feathering intersect at point greater than
t=0.
•Lag time t0- beginning of drug absorption.
•Equation to describe lag time:
Second expression that describes the
curve omits lag time:
25. Determination of ka by plotting % of
drug unabsorbed vs. time (Wagner-
Nelson)
• After single oral dose:
• Ab = DB + Du = amount of drug absorbed
• Ab∞= amount of drug absorbed at t= ∞
• Amount of drug excreted at any time t:
• DB, at any time = CpVD. At any time t, Ab is
26. • At t = ∞, Cp
∞= 0 (i.e. plasma conc is
neglectable), total amount of drug absorbed:
• Fraction of drug absorbed at any time
27. • Fraction unabsorbed at any time is
• Drug remaining in GI at any time, t:
• Therefore, fraction of drug remaining
28. • DGI/D0 = fraction of drug unabsorbed = 1-(Ab/Ab∞)
• Plot of 1-(Ab/Ab∞) vs. t gives slope = -ka/2.3
• The following steps use in determination of ka:
1. Plot log conc of drug vs. t
2. Find k from terminal part of slope, -k/2.3
3. Find [AUC]t0
4. Find k[AUC]t0 by multiplying each [AUC]t0 by k
5. Find [AUC]∞0 by adding up all the [AUC], from t=0 to t=∞
6. Determine 1-(Ab/Ab∞) value corresponding to each time
point t
7. Plot 1-(Ab/Ab∞) vs. t
29.
30. Fraction of drug uabsorbed vs time using Wagner-
Nelson method
•If fraction of drug unabsorbed,
gives linear line, then rate of drug
absorption, dDGI/dt- 1st order process
•Drug approaches 100% absorption,
Cp- becomes small- the terminal part
become scattered- not included for
estimation of slope.
1-(Ab/Ab∞)
31. Estimation of ka from urinary data
• Absorption rate constant, ka- can be estimated from
urinary excretion data- %of drug unabsorbed vs time.
• For one-compartment model:
- Ab= total amount of drug absorbed
- DB= amount of drug in body
- Du= amount of unchanged drug excreted from urine
- Cp= plasma drug conc
- DE= total amount of drug eliminated
- Ab= DB + DE
32. • Differential equation for Ab= DB + DE:
• Assuming 1st order elimination with renal
elimination constant ke:
• Assuming one-compartment model:
(7)
33. • Substitute VDCP into equation (7):
• Rearrange:
• Substitute dCp/dt into equation (8) and kDu/ke
for DE:
(8)
(9)
34. • Integrate equation (9) from 0 to t:
• At t=∞ all drug is absorbed, expressed as Ab∞
and dDu/dt=0. total amount of drug absorbed
is:
• Du∞= total amount of unchanged drug
excreted in urine
35. • Fraction of drug absorbed at any time t=
Abt/Ab∞.
• Plot of fraction of drug unabsorbed, 1-Ab/Ab∞
vs t gives slope = -ka/2.3, in which absorption
rate constant, ka obtained.
36. Determination of ka from two-
compartment oral absorption data
(Loo-Riegelman method)
• After oral administration of a dose of drug
exhibit two-compartment model, amount of
drug absorbed, Ab:
• Each can be expressed as:
37. • Substitute the above expression for Dp and
Du:
• Divide the above equation with Vp to express
the equation on drug conc:
• At t=∞, this equation become
(10)
(11)
38. • Equation (10) divided by equation (11)-
fraction of drug absorbed at any time:
• Plot of fraction of drug unabsorbed, 1-Ab/Ab∞
vs time gives –ka/2.3 as a slope from which
the value of ka is obtained.
39. • Cp and k[AUC]t0 calculated from Cp vs time.
• Values for (Dt/Vp) can be approximated by
Loo-Riegelman method:
• Ct = Dt/Vp, apparent tissue conc.
• (Cp)tn-1 = conc of drug at central compartment
for sample n-1.
40. Cumulative relative fraction absorbed
• Fraction of drug absorbed at any time- can be
summed or cumulated
• From equation , the term Ab/Ab∞
becomes cumulative relative fraction
absorbed (CRFA).
41. • In the Wegner-Nelson equation, Ab/Ab∞ or
CRFA- eventually equal unity- 100% (even
though drug may not be 100% bioavailable.
42. Significance of absorption rate
constant
• Overall rate of systemic absorption surrounded
by many rate processes:
- Dissolution of drug
- GI motility (ability to move spontaneously)
- Blood flow
- Transport of drug across capillary membrane to
systemic circulation
• Rate of drug absorption- net result of this
processes
43. • Calculation of ka- important in designing
multiple-dosage regimen
• Ka and k allows for prediction of peak and
plasma drug conc. following multiple dosing