http://www.speedlighter.

ca/2011/12/25/why-i-shoot-stills/courtney-craig-photo-by-michael-willems/

Pharmacokinetics WebQuest

Kimberly Koon, Pharm. D.

BW733
October 1, 2013 1
 Overview

Introduction Metabolism
Absorption sites,
IV, SubQ, IM CYP450, first-pass, pro-drugs
Oral, SL t1/2 vs duration of action
transdermal, rectal, vaginal, Excretion
inhalation, topical kidney
Distribution liver
models enterohepatic recycling
% cardiac output lungs
Vd Time vs. concentration graph

2
 Introduction
Pharmacokinetics: study of how body
processes drugs; think reverse-factory
Absorption
Distribution
Metabolism
Excretion
Pharmacodynamics: study of drug effects on
body
1. Dictionary. Merriam-Webster website. http://www.merriam-webster.com/dictionary/pharmacokinetics. Accessed September 27, 2013.
2. Pharmacokinetics1-introduction [video]. Handwritten Tutorials website. http://www.handwrittentutorials.com/videos.php?is=79.
Accessed September 27, 2013.
3
 Absorption
Absorption rate: time from entry to circulation
Bioavailability: percent that reaches circulation

IV drug infusion rate determined by

characteristics of drug compound
drugs with small volume and can be given as a bolus or push
(< 3 minutes) negate absorption time

Many IV drugs require slow infusion

Vancomycin red man syndrome
if drug given rapidly, more than
1 gram/hr Red man
syndrome

Red man syndrome. Daily EM website. http://www.dailyem.wordpress.com/2013/08/06/red-man-syndrome/. Accessed September 27,4 2013.
 Absorption
Subcutaneous Insulin pump
small volume bolus
slow absorption rate
infusions possible

Intramuscular rate varies according to drug

properties
absorption rate variable
no infusions

Services. St Vincents Hospital Sydney website. http://www.stvincents.com.au/index.php?option=com_content&task=view&id=751&Itemid=798.

Accessed September 29, 2013. 5
 Absorption
Oral absorption rate has wide variation
drug dissolution time
presence or absence of food
transport time across intestine
passive
active

Goole J, Lindley DJ, Roth W, et al. The effects of excipients on transporter mediated absorption. Int J Pharm 2010;393(1-2):17-31. 6
doi:10.1016/j.ijpharm.2010.04.0419. Accessed September 27, 2013.
 Absorption
Sublingual rapid
Transdermal/topical slow, systemic or local
Rectal unpredictable rate
Inhalation rapid absorption, local or systemic
Other: eye, ear, nose, vaginal most drugs stay
local
Delayed release delivery systems
extended-release capsules and tablets
Depot subcutaneous and IM injections
A first course in pharmacokinetics and biopharmaceutics. Biopharmaceutics and Pharmacokinetics website.
http://www.boomer.org/c/pl/index.html. Accessed September 27, 2013. 7
 Distribution
Time from circulation to target tissue: factors
are rate (cardiac output), volume, diffusion
model, drug properties.

one compartment model (linear kinetics): drug

absorbs and distributes quickly, ie bolus IV
molecules less than 10,000 grams/mole diffuse
freely through capillaries

8
 Distribution
two compartment model:
compartment 1
central circulatory system
rapidly perfused tissues and organs
cardiac muscle
brain
lungs
liver

compartment 2
peripheral circulatory sys.
deep organs and tissues
skeletal muscle
adipose tissue
skin

Two Compartment
Model

A first course in pharmacokinetics and biopjharmaceutics website 9

anesthesiologist book
 Distribution
three compartment model: drugs dependent on active
transport
V1 circulation and rapidly perfused tissues
V2 slowly perfused tissues
V3 third much slower equilibrium compartment

10
Woerlee GM. Gerrys Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org
 Distribution
Example of 3 compartment distribution model for transdermal drug delivery
system (patch) linked by 2 sets of rate constants.

Patch Compartment 2 Compartment 1 Compartment 3

x space coordinate
-L outer edge of matrix
t time
c(x,t) drug concentration
m(t) drug mass
p diffusivity
k12, k21, k23, k32 microconstants
Gopferich A, et al. Int J Pharm. 1991. ke elimination rate constant 11
c0 initial drug concentration in matrix
 Distribution
Rate of Distribution and Volume of Physiological Compartments
Compartment % Cardiac Output* (L/h) % Body Weight (body volume, L)**
Lung 100 (335) 0.8 (0.6)
Venous blood 100 (335) 5.57 (3.9)
Arterial blood 100 (335) 2.43 (1.7)
Other rapidly 38 (127) 83 (58.1)
perfused tissue
(brain)
Kidney 19 (64) 0.44 (0.3)
Slowly perfused tissue 18 (60) 5.16 (3.6)
(skin, muscle, fat, etc)
*Average cardiac output 335 L/h
**Average body weight = 70kg; average body density = 1 L/kg = body volume = 70L

http://2012.igem.org/Team:Slovenia/ModelingPK 12
 Distribution
Circulation Times
From where to where Time (seconds)
Arm vein to lung 5-8
Arm vein to left ventricle 6-8
Arm vein to tongue 12-15
Arm vein to brain 13-20
Foot vein to tongue 37-47
Right heart ventricle to ear (at level of 8
brain stem)
Arm to foot 21-35

Woerlee GM. Gerrys Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org 13
 Distribution
Volume of distribution (VD)
quantifies extent to which drug is present in
tissues (extravascular)
hypothetical volume required to contain all drug
in tissues at consistent concentration
does not reflect actual plasma or blood volume

Absorption of Fluorescent Chemotherapy Drug by

Murine Tumor Cells

Image from: Thurber GM, Yang KS, Reiner T, et al.

Single-cell and subcellular pharmacokinetic
imaging allows insight into drug action in vivo. Nat Commun. 2013;4:1504.
doi:10.1038/ncomms2506.
14
Buxton IL, Benet LZ. Chapter 2. Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman
& Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=16658120. Accessed October 2, 2013.
 Metabolism
Metabolism starts as soon as drug reaches
enzymes capable of metabolizing.
liver
kidney
no metabolism
proteolytic catabolism
large protein biotech
drugs
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf 15
https://elcaminogmi.dnadirect.com/grc/patient-site/psychiatric-drug-response/what-affects-psychiatric-drug-response.html
 Metabolism
CYP450 cytochrome
P450 enzyme system
liver and intestines
most common sites
P450 enzymes can be
inhibited (slowed),
induced (sped up)
drugs often compete
for same enzyme
subgroup

http://www.boomer.org/c/p4/c07/c0702.html
16
http://www.thebody.com/content/art875.html
 Metabolism
First-pass metabolism
occurs before drug reaches circulation
drugs with larger oral vs IV dose
propranolol
morphine
Prodrugs
enhanced bioavailability
avoids first-pass
metabolism

http://epharmacology.hubpages.com/hub/Pharmacological-Effects-Prodrugs-Definition-Examples-and-Sources-of-Drug-Information
17
 Metabolism
Half-life: t1/2
describes rate drug disappears from plasma
helpful with dosing parameters
exponential decline
Example: drug with 11 minute t1/2
1st 11 minutes concentration drops to 50%
2nd 11 minutes concentration drops to 25%
3rd 11 minutes concentration drops to 12.5%
4th 11 minutes concentration drops to 6.25%
Not to be confused with duration of action

Woerlee GM. Gerrys Real World Guide to Pharmacokinetics & Other Things. 1991 http://www.anesthesiaweb.org 18
 Metabolism
Drug effect does not necessarily relate to t1/2
drugs that bind irreversibly
omeprazole
t1/2 30-60 minutes
binds irreversibly and inactivates proton pumps on gastric parietal
cells
body must build new proton pumps before effects of omeprazole
completely gone
14 days average time to build a proton pump
drugs with atypical metabolism
bevacizumab binds endothelial cells
metabolism thought to be proteolysis at endothelial cell
t1/2 20 days

http://www.prilosecotc.com/LocaleData/enUS/Assets/Documents/Monograph.pdf
19
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000582/WC500029271.pdf
 Excretion
Most common routes
kidney
diffusion
active transport
liver
through bile duct into feces
Enterohepatic recycling
drug excreted into feces
metabolized in intestine and reabsorbed
oral contraceptives

20
http://www.boomer.org/c/p4/c16/c1604.html
 Excretion
Enterohepatic recycling

21
http://www.boomer.org/c/p4/c16/c1604.html
 Excretion
Kidney
some drugs pass through by diffusion (passive
transport)
some drugs pass by active transport into kidney
tubule
many renally excreted drugs require dose adjustments
based on renal function
creatinine clearance (CrCl) or glomerular filtration rate (GFR)
used to evaluate renal function
declines naturally with age
helpful online calculator: www.globalrph.com

22
http://www.boomer.org/c/p4/c16/c1604.html
 Excretion
Hemodialysis Hemodialysis Schematic

small molecules
water soluble drugs
drugs with low protein binding
Lungs
excretion of gases
anesthesia http://www.medbroadcast.com/test_and
_procedure_info_details.asp?TPid=8&Type
=1#.Ukxyuoasim4
alcohol

http://www.boomer.org/c/p4/c16/c1604.html 23
 Putting It All Together

Pharmacokinetic parameters
describing a typical plasma
concentration time profile after
an oral administration.

Cmax maximum concentration

tmax time to maximum concentration
Duration of action for this hypothetical drug: time above the minimum effective
concentration (MEC)
Therapeutic range: concentration above MEC but below maximum tolerated
concentration (MTC)
Area under curve (AUC) is a function of concentration and time that describes total
body exposure to drug

Figure 1. International Journal of Impotence Research website. www.nature.com/ijir/journal/v19/n3/fig_tab/3901522f1.html.

Accessed September 27, 2013. 24
 Phase 1 Clinical Trials
Phase 1 trials determine
pharmacokinetics in humans
using animal data extrapolate to
humans
LD50: dose required to kill 50% of the
non-human population
no-observed-adverse-effect level
(NOAEL) for animals
human equivalent dose (HED) of
NOAEL is calculated using body
surface area (BSA)
dose escalation studies
max tolerated dose (MTD)
time to max tolerated
other factors determined:
frequency
route
Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Clin
food/drug interactions Cancer Res. 2010
healthy volunteers if risk:benefit
acceptable Wood LF, Foote M eds. Targeted Regulatory Writing
Techniques. Basel, Switzerland:Birkhauser Verlag;252009.
 Phase 1 Clinical Trials
Traditional phase 1 trial design
dose escalated until 33% patients exhibit pre-
determined toxicity parameter
dose dropped down once to pre/toxic dose and this is
called maximum tolerated dose (MTD)
study continues with MTD to determine recommended
phase 2 dose (RP2D) and schedule
Molecularly targeted agents (MTAs) and non-cancer
agents ie biotech
often do not have DLTs
start safe dose according to animal data
escalate until toxicity or molecular-targeted effects seen
this dose is called max administered dose and sets RP2D
Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Clin Cancer Res. 2010
26
 Resources
For more information on pharmacokinetics:
Hand Written Tutorials:
http://www.handwrittentutorials.com/
Biopharmaceutics and Pharmacokinetics
David W.A. Bourne, B.Pharm., Ph.D. of the University of
Colorado
Free online textbook
http://www.boomer.org/c/p4/#topics
Woerlee GM. Gerrys Real World Guide to
Pharmacokinetics & Other Things. 1991
http://www.anesthesiaweb.org

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