Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5480_Библиотеки_им_академика_М_И_Перельмана.pdf
X
- •PREFACE
- •CONTENTS
- •Pharmacokinetics
- •Clinical Pharmacokinetics
- •Pharmacodynamics
- •Bioavailability
- •Bioequivalence
- •1.1. Alternative Distinctness of Biopharmaceutics
- •1.1.1. Important Modalities Encountered by a Drug
- •1.2. Pharmacokinetics
- •1.3. Clinical Pharmacokinetics
- •Uncomplicated Drugs
- •1. Introduction
- •2. Biopharmaceutics Classification System (BCS)
- •3.1. Genesis of IVIVC
- •3.2. FDA Definition for IVIVC
- •3.3. Important Factors for Development of IVIVC
- •3.4. IVIVC Utilization in Novel Dosage Forms
- •3.5. Applications of IVIVC
- •4. Passage of Drugs across Biological Barrier
- •4.1. Simple Capillary Endothelial Barrier (CEB)
- •4.2. Cell Membrane Barrier (CMB)
- •4.3.1. Permeability of Cell and Capillary Membranes
- •4.3.2. Highlights of BBB as a Lipoidal Barrier
- •4.5. Placental Barrier (PB)
- •5. Factors Influencing Drug Absorption
- •5.1. Rate-Limited Stages in Oral Drug Absorption
- •5.2. Drug Absorption via Gastrointestinal Tract (GIT)
- •5.2.1. Cell Membrane Structure
- •Routes Adopted by Small Drug Molecules in Crossing Cell Membranes
- •5.2.2. Pathways of Drug Absorption
- •Important Points
- •5.2.3. Gastrointestinal (GI) Physiology
- •5.3. Fluid-Mosaic Model for Transcellular Diffusion of Polar Molecules
- •5.4. Gastrointestinal Physiology
- •5.4.1. Gastrointestinal Blood Flow
- •5.4.2. Gastrointestinal pH
- •5.5. Gastric Emptying
- •5.5.1. Mechanism of Gastric Emptying
- •Gastric Emptying Designates a Simple Mono-Exponential Process
- •5.6. Gastrointestinal Motility
- •6. Mechanisms of Drug Absorption
- •6.1. Passive Diffusion
- •6.1.2. Characteristic Features of Passive Diffusion
- •6.1.3. Fate of Lipophilic and Hydrophilic Substituted Drugs
- •6.1.4. Implication of Henderson and Hasselbalch Equation
- •6.2. Pore Transport (Convective Transport)
- •6.2.1. Highlights of Pore Transport
- •6.3. Carrier-Mediated Transport
- •6.3.1. Important Characteristic Features of Carrier-Mediated Transport
- •6.4. Active Transport
- •6.5. Facilitated Diffusion
- •6.6. Carrier-Mediated Intestinal Transport
- •6.7. Ionic Diffusion (or Electrochemical Diffusion)
- •6.7.1. Permeation Profile of Cationic Drug Molecules
- •6.8. Ion-Pair Transport
- •6.9. Endocytosis
- •7. Drug Absorption vs. Bioavailability
- •7.1. Preamble
- •7.2.1. Rate-Determining Step (RDS)
- •Disintegration
- •Dissolution
- •Various Absorption Steps Immediately after Oral Ingestion of Coated Tablets or Capsules
- •Preamble
- •7.3. Factor Influencing GI Absorption of a Drug from Its Respective Dosage Forms
- •7.3.1. Pharmaceutical Factors
- •Physicochemical Characteristic Features of Drug Substances
- •Dosage Form Characteristics Features and Pharmaceutic Ingredient
- •7.3.2. Patient-Related Factors
- •7.4.1. Drug Solubility and Dissolution Rate
- •7.4.2. Theories of Drug Dissolution
- •Diffusion Layer Model (or Film Theory)
- •Interfacial Barrier Model (or Double Barrier or Limited Solvation Theory)
- •Important Points
- •7.4.3. Particle Size and Drug Absorption
- •7.4.4. Polymorphic Crystals, Solvates and Drug Absorption
- •Important Points
- •Lipophilicity and Absorption of Drug
- •7.4.6. Limitations of pH-Partition Hypothesis
- •Critical Absorption of Ionized (Polar) Drugs
- •Crucial Presence of Aqueous Unstirred Diffusion Layer
- •7.4.7. Deviations from the pH-Partition Hypothesis
- •Microclimate pH
- •A Unifying Hypothesis
- •7.5.1. Product Form Characteristics
- •Formulati on Factors
- •Disintegration Time
- •Exempted Disintegration Tests for Certain Drug Products
- •Processing Variants
- •Granulation Variables
- •Wet Granulation Method
- •Disintegrants (or Disintegrating Agents)
- •Important Points
- •Coatings
- •Surfactants
- •Buffers
- •Colorants
- •Complexing Agents
- •Crystal Growth Inhibitors
- •Precompression Method
- •Applied Compression Force
- •Packing of Capsule Contents
- •7.5.2. Pharmaceutic Ingredients
- •Diluents (or Fillers)
- •Binders and Granulating Agents
- •Vehicles
- •Lubricants (or Anti-frictional Agents)
- •1. Introduction
- •2. Clinical Significance of Plasma Protein Drug Concentration Measurement
- •2.1. Significance of Drug–Protein Binding Complex
- •2.1.1. Serum Albumin
- •2.1.3. Lipoproteins
- •2.1.5. Erythrocytes [or Red Blood Cells (RBCs)]
- •3. Pharmacokinetic Models
- •3.1. Pharmacokinetic Models vis-à-vis Mathematical Models
- •Preferred Model for Analysis of Data
- •3.2. Classification of Pharmacokinetic Models
- •3.2.1. Compartment Models
- •Mammillary Model
- •3.2.2. Flow Models (or Physiologic–Pharmacokinetic Models)
- •Salient Features
- •Merits of Physiologic–Pharmacokinetic Models
- •3.2.3. Non-Compartmental Pharmacokinetics
- •Important Applications
- •Merits of Non-Compartmental Pharmacokinetics
- •3.2.4. Non-Linear Pharmacokinetics
- •Time-Dependent Pharmacokinetics
- •4. Pharmacokinetics of Drug Absorption
- •4.1. Zero-Order Absorption Rate Constant
- •4.1.1. Plasma Drug Level–Time Curve for a Drug Administered in Single Oral Dose
- •4.2. First-Order Absorption Rate Constant
- •4.3. The Loo–Riegelman and Wagner–Nelson Equations
- •4.3.1. Loo–Riegelman Equation
- •4.3.2. Wagner–Nelson Equation
- •5. Volume of Distribution and Distribution Coefficient
- •5.2. Presence of a Fraction of Drug Both Inside and Outside Plasma
- •5.3. Determination of Plasma Volume
- •5.4. Volume of Total Body Water (or Fluid)
- •6. Organ-Specific Clearance
- •6.1. Concept of Organ-Specific Clearance
- •6.2. Renal Clearance
- •6.2.1. Two Substances Used to Determine GFR
- •6.2.2. Active Tubular Secretion (ATS)
- •6.2.3. Kinetics of Urinary Excretion
- •6.3. Hepatic Clearance
- •6.3.1. Venous Equilibrium Model of Hepatic Clearance
- •6.4. Extra Hepatic/Non-Renal Elimination
- •6.4.1. Biliary Excretion
- •6.4.3. Foecal Excretion
- •6.4.4. Intestinal Excretion
- •6.4.5. Excretion via Saliva/Skin
- •6.4.6. Excretion via Milk
- •7. Non-Linear Pharmacokinetics
- •7.1. Preamble
- •7.2. Michaelis–Menten Equation
- •7.2.1. Accounting for Deviation of Michaelis–Menten Equation
- •7.2.2. Graphical Representation of Michaelis–Menten Equation
- •7.3. Drug Elimination by Capacity-Limited Process
- •7.4. Important Recognized Plot Variants in Non-Linear Pharmacokinetics
- •7.4.1. Lineweaver–Burk Plot (or Doubled-Reciprocal Plot)
- •7.4.2. Hanes–Woolf Plot
- •7.4.3. Woolf–Augustinsson–Hofstee Plot
- •7.4.4. Direct Linear Plot
- •8.1. Antihypertensives
- •8.2. Antiarrythmics
- •8.3. Antianginal Drugs
- •8.4. Pharmacokinetics of Nitroglycerin after Intravenous Infusion in Normal Subjects
- •8.4.1. Experimental Procedure
- •8.5. Antineoplastic Agents
- •8.6. Pharmacokinetics of Oral and Intravenous Fluorouracil in Humans
- •8.6.1. Experimental Procedure
- •8.7. Antibiotics
- •8.8.1. Experimental Procedure
- •Suggested Readings
- •Accumulation of Drug in Multiple Dosing
- •Reachable Time for Achieving Steady State in Multiple Dosing
- •Case Study 1
- •Suggested Readings
- •1. Introduction
- •1.1. Preamble
- •1.2. Definitions
- •2. Bioavailability
- •2.1. Preamble
- •Important Points
- •2.2 Absolute Bioavailability
- •2.3 Relative Bioavailability
- •2.4 Bioequivalance Assessment and Data Evaluation (or Importance of Bioequivalence)
- •2.4.1 Bioequivalence Assessment
- •2.4.3. Peak-Height Concentration
- •Example of a cardiac glycoside (e.g., Digoxin and Digitoxin):
- •2.5. Bioavailability Studies in Human: Pharmacokinetic Profiles
- •2.5.1 Comparison with a Reference Drug/Formulation
- •2.5.3 Drug Dissolution Rate and Bioavailability
- •Testing Models: For In Vitro Dissolution Technique
- •Important Factors Governing the In Vitro Dissolution Technique
- •The Drug Dissolution Estimation Apparatus
- •2.6. Statistical Methods for Bioavailability Studies
- •2.6.1 Methods of Data Analysis
- •2.6.2 Statistical Analysis
- •2.6.3. Statistical Interpretation of Bioequivalence Data
- •2.7. Factors that Decrease Bioavailability
- •2.7.1 Presystemic Metabolism
- •2.7.2 Instability
- •Hydrolysis of Weak Acidic Drugs (Penicillins) in Gastric Fluids
- •Delaying Absorption until Reaching Intestines
- •Important Points
- •Complexation
- •2.8. Factors that Increase Bioavailability
- •2.8.1. Overcoming Acute Bioavailability Issues
- •2.8.2. Physicochemical Characteristics of a Drug
- •Micronization
- •Surfactants (or Surface-Active Agents)
- •Salts of Drugs
- •Metastable Polymorphs
- •Change in pH of Drugs Microenvironment
- •Preferential Adsorption on Insoluble Carriers
- •Solvent Deposition
- •Solid Solutions
- •Eutectic Mixtures
- •Important Points
- •Solid Dispersions
- •Molecular Encapsulation (with Cyclodextrins)
- •3. Bioequivalence
- •3.1. Preamble
- •3.2. Design and Conduct of Bioequivalence Studies
- •Important Points
- •3.2.1. Criteria for the Design of Bioequivalence Study
- •Multiple-Dose Study vs. Single-Dose Study
- •Demerits of Multiple-Dose Bioequivalence Studies
- •3.2.2. Design
- •3.2.3. Subjects (or Volunteers)
- •3.2.4. Reference and Test Product
- •Important Points
- •3.2.5. Analytical Methods
- •Bioanalytical Methods
- •Assay of Biotransformation Product
- •Use of Radioactive Labelled Molecules
- •3.2.6. Investigation of Characteristic Features
- •3.2.7. Generalized Approach: Single-Dose Pharmacokinetic Bioequivalence Studies
- •Study Conduct
- •Collection of Sample and Sampling Times
- •4.1. Preamble
- •Important Points
- •4.1.1. Bioanalytical Instruments
- •4.2.1. Instrument to Be Used
- •4.3. Selection of GC/HPLC Column
- •4.3.1. pH of Mobile-Phase Buffer
- •Important Points
- •4.3.3. Column-Oven Temperature
- •4.3.4. Sample Injection Volume
- •4.3.5. Extra Column Volume
- •4.4. Method Validation
- •Index



Essentials of Biopharmaceutics
and Pharmacokinetics

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN

Essentials of
Biopharmaceutics
and Pharmacokinetics
Ashutosh Kar
Formerly
Professor, School of Pharmacy, Addis Ababa University,
Addis Ababa, Ethiopia
Dean, Chairman and Professor, Faculty of Pharmaceutical Sciences,
Guru Jambheshwar University, Hisar, India
Professor, School of Pharmacy, Al Arab Medical University,
Benghazi, Libya
Professor, College of Pharmacy, University of Delhi,
Delhi, India
Professor and Head, Department of Pharmaceutical Chemistry,
Faculty of Pharmaceutical Sciences, University of Nigeria,
Nsukka, Nigeria
ELSEVIER
A division of Reed Elsevier India Private Limited

Essentials of Biopharmaceutics and Pharmacokinetics
KAR
ELSEVIER
A division of Reed Elsevier India Private Limited.
Mosby, Saunders, Churchill Livingstone, Butterworth Heinemann and Hanley & Belfus are the Health Science
imprints of Elsevier
© 2011 Elsevier
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by
any means – electronic or mechanical, including photocopy, recording, or any information storage and
retrieval system – without permission in writing from the publisher.
ISBN: 978-81-312-2639-1
Notice
Knowledge and best practice in this fi eld are constantly changing. As new research and experience broaden our
knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are
advised to check the most current information provided (1) on procedures featured or (2) by the manufacturer
of each product to be administered, to verify the recommended dose or formula, the method and the duration
of administration, and the contraindications. It is the responsibility of the practitioner, relying on their own
experience and knowledge of the patient, and to take diagnoses, to determine dosages and the best treatment
for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither
the Publisher nor the Authors assume any liability for any injury and/or damage to persons or property arising
out or related to any use of the material contained in this book.
The Publisher
Registered Offi ce: 622, Indraprakash Building, 21 Barakhamba Road, New Delhi-110 001.
Corporate Offi ce: 14th Floor, Building No. 10B, DLF Cyber City, Phase II, Gurgaon-122002, Haryana, India.
Commissioning Editor: Nilabh Ranjan
Development Editor: Subodh K. Chauhan
Manager - Publishing Operations: Sunil Kumar
Manager - Production: N.C. Pant
Laser typeset by ACE PRO India P. Ltd.
Printed and bound at Rajkamal Electric Press, Kundli, Haryana, India.

Dedicated to
Leena
For the infi nite joy and for her amazing grandmothering
Aditi and Aryan
For the eternal sunshine they fi ll in our lives with

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN

PREFACE
Essentials of Biopharmaceutics and Pharmacokinetics correlates the intricacies involved in the interdisciplinary
interaction of two qualitative subjects. The text has been designed in a manner so as to help its readers
comprehend the subjects with the insight of a researcher. The primary objective of this textbook is to
provide the reader an in-depth knowledge of the principles of Biopharmaceutics and Pharmacokinetics,
which could be extended wisely to the product development as well as the drug therapies. The teachers
indeed would fi nd the subject matter quite user friendly and the students shall be able to grasp the basic
concepts of complex topics like critical drug-delivery modalities and effective safe drug therapy.
The pharmacy degree (B. Pharm.) students in all Indian universities shall be duly benefi tted from this
textbook because the course content in it has been carefully developed as per the latest prescribed syllabi
for B. Pharm. This book shall further enrich the knowledge of R&D scientists in the pharmaceutical
industry in general and those associated with Pharmaceutics, Biopharmaceutics and Pharmacokinetics
in particular.
The entire course content has been categorized into fi ve sections, namely
Section 1: Biopharmaceutics and Pharmacokinetics: What Do They Mean?
Section 2: Biopharmaceutics
Section 3: Pharmacokinetics
Section 4: Clinical Pharmacokinetics
Section 5: Bioavailability and Bioequivalence
Each section in the book deals with a brief introduction, defi nition, classifi cation, exemplifi cation,
laws, graphics, diagrammatic representations, illustrations and highlights, and concludes with Selected
Biography and Review Questions.
Besides maintaining a logical chain of continuity in all the fi ve sections in a lucid manner, an attempt
has been made to include very interesting examples that will create enough interest in the fi elds of
Biopharmaceutics and Pharmacokinetics.
The author solemnly believes that this book will provide a positive help and an urgent need to
all aspirant UG/PG pharmacy students across the various Indian universities. Any suggestions for
improvement of the book are invited.
The author would like to place on record the excellent help and cooperation by the entire publishing
team of Elsevier in bringing out this book in a record time frame.
Ashutosh Kar

7KLVSDJHLQWHQWLRQDOO\OHIWEODQN
Соседние файлы в папке Библиотека им академика М.И. Перельмана
