Biopharmaceutics &
Pharmacokinetics
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1980 by Appleton-Century-Crofts.
ISBN 978-0-07-160393-5
MHID 0-07-160393-X
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Dr. Leon Shargel has over 30 years experience in Austin and her PhD from the University of California
both academia and the pharmaceutical industry. He at San Francisco (USCF), and postdoctoral training
has been a member or chair of numerous national in metabolism and dermatology also at UCSF. She is
committees involved in state formulary issues, bio- the recipient of the AAPS Young Investigator Award
pharmaceutics and bioequivalence issues, institutional and the AACP Grant for New Investigators. She has
review boards, and a member of the USP Biophar- been an NIH and NSF Study Section Reviewer, and
maceutics Expert Committee. Dr. Shargel received a reviewer for numerous scientific journals. She has
a BS in pharmacy from the University of Maryland published over 60 scientific papers, books, chapters, and
and a PhD in pharmacology from the George Wash- abstracts, including Biopharmaceutial Drug Design
ington University Medical Center. He is a registered and Development, Vol. 2. In addition, Dr. Wu-Pong
pharmacist and has over 150 publications includ- is a 2005 graduate of the Grace E. Harris Leadership
ing several leading textbooks in pharmacy. He is a Institute and a fellow of the 2010–11 AACP Academic
member of various professional societies including Fellow Leadership Program.
the American Association Pharmaceutical Scien-
tists (AAPS), American Pharmacists Association Dr. Andrew Yu has over 30 years of experience
(APhA), and the American Society for Pharmacol- in academia, government, and the pharmaceutical
ogy and Experimental Therapeutics (ASPET). industry. Dr. Yu received a BS in pharmacy
from Albany College of Pharmacy and a PhD in
Dr. Susanna Wu-Pong is Associate Professor and pharmacokinetics from the University of Connecticut.
Director of the Pharmaceutical Sciences Graduate He is a registered pharmacist and has over 30
Program at Virginia Commonwealth University publications and a patent in novel drug delivery. He
(VCU). She has been a faculty member at VCU had lectured internationally on pharmaceutics and
School of Pharmacy for 18 years. She received her drug delivery.
BS in pharmacy from the University of Texas at
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The publication of this sixth edition of Applied Biop- • The growing importance of drug transporters,
harmaceutics and Pharmacokinetics represents over CYP enzymes, and influence of pharmacogenet-
30 years in print. We are grateful to our readers for ics on long-term drug response and other rel-
their loyalty and helpful suggestions throughout the evant topics have been updated to reflect current
years. As with the previous editions, we want to con- knowledge and application of pharmacokinetic/
tinue to maintain our original scope and objectives. pharmacodynamics to drug therapy.
This text integrates basic scientific principles • Chapter 15 is expanded and re-titled, Drug
with drug product development and clinical phar- Product Performance, In Vivo: Bioavailability
macy practice. and Bioequivalence, to reflect the consideration
The major objective is to provide the reader with of bioequivalence as an in vivo measure of drug
a basic and practical understanding of the principles product performance and that bioequivalence is
of biopharmaceutics and pharmacokinetics that can important in both brand and generic drug product
be applied to drug product development and to drug development.
therapy. This revised and updated edition of the text • Chapter 16 is now titled, Impact of Drug Product
remains unique in teaching basic concepts that may Quality and Biopharmaceutics on Clinical
be applied to understanding complex issues associ- Efficacy. This chapter describes the types of
ated with in vivo drug delivery that are essential for safety and efficacy risks and various means for
safe and efficacious drug therapy. preventing them including the roles of drug prod-
The primary audience is pharmacy students uct quality and drug product performance.
enrolled in pharmaceutical science courses in phar- • In addition, the concept of quality-bydesign (QbD)
macokinetics and biopharmaceutics. This text fulfills may be applied to improve critical quality attributes
course work offered in separate or combined courses essential for drug product safety and efficacy
in these subjects. Secondary audiences for this text- • Practical examples and questions are included
book are research and development scientists in phar- to encourage students to apply the principles in
maceutics, biopharmaceutics, and pharmacokinetics. patient care and drug consultation situations.
• Active learning and outcome-based objectives are
There are many improvements in this edition. highlighted.
• Chapter Objectives are added at the beginning of
each chapter Leon Shargel
• Chapter Summary at the end of each chapter. Susanna Wu-Pong
• Frequently Asked Questions are seeded within each Andrew B.C. Yu
chapter to help the student focus on key concepts.
• Most chapters are revised to reflect our current
understanding of drug disposition, pharmacody-
namics, and drug therapy.
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xv
∞
Cmax Maximum steady-state drug DB Amount of drug in body
concentration; see also Cssmax DE Drug eliminated
Cmin Minimum concentration of drug DGI Amount of drug in gastrointesti-
∞
Cmin Minimum steady-state drug nal tract
concentration; see also Cssmin DL Loading (initial) dose
Cp Concentration of drug in plasma Dm Maintenance dose
Cp0 Concentration of drug in plasma DNA Deoxyribonucleic acid
at zero time (t = 0) (equivalent DN Normal dose
to C0) DP Drug in central compartment
Cp∞ Steady-state plasma drug Dt Amount of drug in tissue
concentration (equivalent to CSS) Du Amount of drug in urine
Cp Last measured plasma drug D0 Dose of drug
n
concentration D0 Amount of drug at zero time
CSS Concentration of drug at steady (t = 0)
state E Pharmacologic effect
Cssav Average concentration at steady e Intercept on y axis of graph
state relating pharmacologic response
Cssmax Maximum concentration at to log drug concentration
steady state eGFR Estimate of GFR based on an
Cssmin Minimum concentration at MDRD equation
steady state Emax Maximum pharmacologic effect
Ct Concentration of drug in tissue E0 Pharmacologic effect at zero
cGMP Current good manufacturing drug concentration
practices EC50 Drug concentration that pro-
CKD Chronic kidney disease duces 50% maximum pharma-
ClCr Creatinine clearance cologic effect
ClD Dialysis clearance ELS Extended least square
Clh Hepatic clearance ER Extraction constant (equivalent
Clint Intrinsic clearance to Eh); extraction ratio
Cl′int Intrinsic clearance (unbound or F Fraction of dose absorbed
free drug) (bioavailability factor)
Clnr Nonrenal clearance f Fraction of dose remaining in
ClR Renal clearance the body
ClRu Renal clearance of uremic fe Fraction of unchanged drug
patient excreted unchanged in urine
ClT Total body clearance fu Unbound fraction of drug
COX-1 Cyclo-oxygenase-1 FDA US Food and Drug
CRF Case report form Administration
CRFA Cumulative relative fraction f(t) Function representing drug
absorbed elimination over time (time is
Cv Drug concentration in venous the independent variable)
plasma f ′(t) Derivative of f(t)
%CV Percent coefficient of variation GFR Glomerular filtration rate
CYP Cytochrome P-450 GI Gastrointestinal tract
D Amount of drug (mass, eg, mg) GMP Good Manufacturing Practice
DA Amount of drug absorbed [I] [I] is the inhibitor concentration
in an enzymatic reaction