1. Pharmacokinetics WebQuest
Kimberly Koon
Pharmacokinetics WebQuest
Kimberly Koon, Pharm. D.
BW733
October 1, 2013

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

3. Introduction
Pharmacokinetics: study of how body processes drugs; think reverse-factory
Absorption
Distribution
Metabolism
Excretion
Pharmacodynamics: study of drug effects on body
Dictionary. Merriam-Webster website. Accessed September 27, 2013.
Pharmacokinetics1-introduction [video]. Handwritten Tutorials website. Accessed September 27, 2013.

4. Absorption Absorption rate: time from entry to circulation
Kimberly Koon
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
Various types of administration routes and what affects absorption rates
Red man
syndrome
Red man syndrome. Daily EM website. Accessed September 27, 2013.

5. Absorption Subcutaneous
small volume bolus
slow absorption rate
infusions possible
Intramuscular rate varies according to drug properties
absorption rate variable
no infusions
Insulin pump
Services. St Vincent’s Hospital Sydney website.
Accessed September 29, 2013.

6. Absorption Oral absorption rate has wide variation
Kimberly Koon
Absorption
Oral absorption rate has wide variation
drug dissolution time
presence or absence of food
transport time across intestine
passive
active
Calcium (>800mg and quinolones) iron zinc
grapefruit
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.
doi: /j.ijpharm Accessed September 27, 2013.

7. Absorption Sublingual – rapid
Kimberly Koon
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
SL – good blood supply
A first course in pharmacokinetics and biopharmaceutics. Biopharmaceutics and Pharmacokinetics website.
Accessed September 27, 2013.

8. 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

9. Distribution two compartment model: compartment 2 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
anesthesiologist book

10. 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
Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things

11. 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
ke elimination rate constant
c0 initial drug concentration in matrix
Gopferich A, et al. Int J Pharm

12. % Cardiac Output* (L/h) % Body Weight (body volume, L)**
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
5.57 (3.9)
Arterial blood
2.43 (1.7)
Other rapidly perfused tissue (brain)
38 (127)
83 (58.1)
Kidney
19 (64)
0.44 (0.3)
Slowly perfused tissue (skin, muscle, fat, etc)
18 (60)
5.16 (3.6)
*Average cardiac output 335 L/h
**Average body weight = 70kg; average body density = 1 L/kg = body volume = 70L

13. 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 brain stem) 8
Arm to foot
21-35
Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things

14. 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: /ncomms2506.
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; Accessed October 2, 2013.

15. Metabolism
Metabolism starts as soon as drug reaches enzymes capable of metabolizing.
liver
kidney
no metabolism
proteolytic catabolism
large protein biotech
drugs

16. 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

17. Metabolism First-pass metabolism Prodrugs
occurs before drug reaches circulation
drugs with larger oral vs IV dose
propranolol
morphine
Prodrugs
enhanced bioavailability
avoids first-pass
metabolism

18. Metabolism Half-life: t1/2 Not to be confused with duration of action
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. Gerry’s Real World Guide to Pharmacokinetics & Other Things

19. Metabolism Drug effect does not necessarily relate to t1/2
drugs that bind irreversibly
omeprazole
t1/ 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

20. Excretion Most common routes Enterohepatic recycling kidney liver
diffusion
active transport
liver
through bile duct into feces
Enterohepatic recycling
drug excreted into feces
metabolized in intestine and reabsorbed
oral contraceptives

21. Excretion Enterohepatic recycling

22. 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:

23. Excretion Hemodialysis Lungs small molecules water soluble drugs
drugs with low protein binding
Lungs
excretion of gases
anesthesia
alcohol
Hemodialysis Schematic
_procedure_info_details.asp?TPid=8&Type
=1#.Ukxyuoasim4

24. 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.
Accessed September 27, 2013.

25. 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
food/drug interactions
healthy volunteers if risk:benefit acceptable
Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Clin
Cancer Res. 2010
Wood LF, Foote M eds. Targeted Regulatory Writing
Techniques. Basel, Switzerland:Birkhauser Verlag; 2009.

26. 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

27. Resources For more information on pharmacokinetics:
Hand Written Tutorials:
Biopharmaceutics and Pharmacokinetics
David W.A. Bourne, B.Pharm., Ph.D. of the University of Colorado
Free online textbook
Woerlee GM. Gerry’s Real World Guide to Pharmacokinetics & Other Things