4-Pharmacokinetics I

General Principles of Drug Therapy
Integrated Scientific and

Clinical Pharmacology
Pharmacokinetics I:
ADME
Marc Imhotep Cray, M.D.
BMS / CK-CS Teacher
http://www.imhotepvirtualmedsch.com/
Topics Outline
ABSORPTION METABOLISM
Ionization Rates of Metabolism
Molecular Weight Microsomal P450 Isoenzymes
Dosage Form Enzyme Induction and Inhibition
Routes of Administration ELIMINATION
DISTRIBUTION Pharmacokinetic Changes with Aging
Plasma Protein Binding
Selective Distribution
2
Pharmacokinetics (PK) study of ADME
Absorption drug in
Distribution
Metabolism
Excretion drug out = Elimination
Movement of drug molecules through various
physiologic compartments drug deposition
Processes that determine drug delivery to (in)

and removal from (out) molecular targets
Drug concentration-Time relationship
3
Pharmacokinetics Overview
PK what the body
Understanding PK
does to a drug
parameters, enable
design of optimal drug
regimens, including :
route of
administration
(RoA),
dosage,
dosing interval, and
duration of Tx
Modified from: Lippincott Illustrated
Reviews: Pharmacology. 6e. (2014)
Pharmacokinetics Overview (2)
Goodman and Gilman's The Pharmacological Basis of Therapeutics 12e, (2011)
Interrelationship of absorption, distribution,

binding, metabolism, and excretion of a drug and
its concentration at its sites of action 5
Important Properties Affecting

Drug Absorption
Chemical properties Physiologic variables:

acid or base gastric motility
degree of ionization pH at the absorption site
polarity area of absorbing surface
molecular weight blood flow
lipid solubility presystemic elimination
or...partition coefficient ingestion w/wo food
6
Routes of Drug Administration (RofA)

 Absorption is how the patient’s body
takes in (absorbs) the drug in question
RofA:
 Enteral, meaning absorbed
through intestines: oral and rectal
 Parenteral, meaning absorbed

without intestines: intravenous
(IV), intramuscular (IM),
subcutaneous (SQ ), inhaled,
topical, or transdermal
Lippincott Illustrated Reviews,

Pharmacology. 6e. (2015)
Enteral Routes
of Administration
Bioavailability (F)
 F is how much of what is ingested makes it into the systemic
circulation
 Drugs administered intravenously bypass absorption, thus

have a bioavailability of 1 (100%)
 Oral drugs have < 100% bioavailability (< 1) because:

1) not everything is absorbed (incomplete
tablet breakdown, barriers to absorption across gut mucosa,
gastric acid or enzymatic destruction)
2) after absorption through intestines into portal vein, drug
first passes through liver, where some of drug is
metabolized before reaching systemic circulation-termed
first pass metabolism
9
First-pass metabolism
Any substance absorbed through
the intestinal mucosa
(except at end of the rectum)
will drain into the portal system
and be processed by the
liver before reaching the
systemic circulation
From Brenner GM, Stevens CW. Pharmacology.

10
3rd ed. Philadelphia: Elsevier; 2009.
Oral Ingestion
• Governed by:
surface area for absorption, blood flow, physical
state of drug, concentration
occurs via passive process
In theory: weak acids optimally absorbed in
stomach, weak bases in intestine
In reality: overall rate of absorption of drugs is
always greater in intestine (surface area, organ
function)
11
Forms of Oral Drugs
Fastest  liquids: syrups, elixirs
 Suspensions
 Powders
Slowest  pills: capsules, tablets
12
Rate of Appearance in Blood

 Dependent on rate of dissolution
 Rate of absorption from GI tract
For example:
Timed release capsules
dissolve at different rates
Enteric coating pills

dissolve in alkaline fluid
13
Effect of Changing
Rate of Gastric Emptying
Ingestion of a solid dosage form with a glass of cold
water will accelerate gastric emptying
accelerated presentation of drug to upper intestine
significantly increases absorption
Ingestion with a fatty meal, acidic drink, or with
another drug with anticholinergic properties, will
retard gastric emptying
Sympathetic output (as in stress) also slows
emptying
14
Sublingual (SL) Administration

Absorption from oral mucosa has special significance
for certain drugs despite small surface area
Nitroglycerin (SL-NTG) - nonionic, very lipid soluble
Due to venous drainage into superior vena cava, this
route “protects” from first-pass liver metabolism
15
Rectal Administration
Advantages:
Useful when oral administration is precluded by
vomiting or when patient is unconscious
Approx. 50% of drug absorbed from rectum will
bypass liver, thus reducing influence of first-pass
hepatic metabolism
Disadvantages:
Irregular and incomplete absorption
Irritation
Patient aversion
16
Parenteral Routes
of Administration
Subcutaneous
 Slow and constant absorption
 Slow-release pellet may be implanted
 Drug must not be irritating
18
Intramuscular
 Rapid rate of absorption from aqueous solution,
depending on the muscle
 Perfusion of particular muscle influences rate of
absorption: gluteus vs. deltoid
 Slow & constant absorption of drug when injected in
an oil solution or suspension
19
Intra-arterial administration
 Occasionally a drug is injected directly into an
artery to localize its effect to a particular
organ, e.g., for liver tumors, head/neck
cancers
 Requires great care and should be reserved
for those with experience
20
Intrathecal administration
 Necessary RofA if the blood-brain barrier
and blood-CSF barrier impede entrance into
CNS
 Injection into spinal subarachnoid space:

used for local or rapid effects of drugs on
the meninges or cerebrospinal axis, as in
spinal anesthesia or acute CNS infections
21
Intraperitoneal administration
 Peritoneal cavity offers a large absorbing

surface area from which drug may enter
the circulation rapidly
 Seldom used clinically
 Infection is always a concern
22
Pulmonary Absorption
 Inhaled gaseous and volatile drugs are
absorbed by the pulmonary
epithelium and mucous membranes
of respiratory tract
 almost instantaneous absorption

 avoids first-pass metabolism
 local application
23
Topical Application
 Mucous membranes
 Drugs are applied to mucous membranes of
conjunctiva, nasopharynx, vagina, colon,
urethra, and bladder for local effects
 Systemic absorption may occur (e.g.

antidiuretic hormone via nasal mucosa)
24
Topical Application (2)

 Skin
 Few drugs readily penetrate skin
 Absorption is proportional to surface area
 More rapid through abraded, burned or denuded skin
 Inflammation increases cutaneous blood flow and,
therefore, absorption
 Enhanced by suspension in oily vehicle and rubbing into
skin
25
Topical Application (3)

 Eye
 topically applied ophthalmic drugs are used
mainly for their local effects
 systemic absorption that results from drainage
through nasolacrimal canal is usually undesirable
 not subject to first-pass hepatic metabolism
26
Routes of Administration Summary Table (1)

RofA ABSORPTION PATTERN ADVANTAGES DISADVANTAGES
Oral • Variable; affected by many • Safest and most common, • Limited absorption of some drugs
factors convenient, and economical RofA • Food may affect absorption
• Patient compliance is necessary
• Drugs may be metabolized before
systemic absorption
Intravenous • Absorption not required • Can have immediate effects • Unsuitable for oily substances
• Ideal if dosed in large volumes • Bolus injection may result in adverse
• Suitable for irritating substances effects
and complex mixtures • Most substances must be slowly
• Valuable in emergency situations injected
• Dosage titration permissible • Strict aseptic techniques needed
• Ideal for high molecular weight
proteins and peptide drugs
Subcutaneous • Depends on drug diluents: • Suitable for slow-release drugs • Pain or necrosis if drug is irritating
Aqueous solution: prompt • Ideal for some poorly soluble • Unsuitable for drugs administered in large
Depot preparations: slow and suspensions volumes
sustained
Intramuscular • Depends on drug diluents: • Suitable if drug volume is moderate • Affects certain lab tests (creatine
Aqueous solution: prompt • Suitable for oily vehicles and certain kinase)
Depot preparations: slow and irritating substances • Can be painful
sustained • Preferable to intravenous if patient • Can cause intramuscular
must self-administer hemorrhage (precluded during
anticoagulation therapy)
27
Routes of Administration Summary Table (2)
RofA ABSORPTION PATTERN ADVANTAGES DISADVANTAGES
Transdermal • Slow and sustained • Bypasses the first-pass effect • Some patients are allergic to
(patch) • Convenient and painless patches, which can cause irritation
• Ideal for drugs that are lipophilic and • Drug must be highly lipophilic
have poor oral bioavailability • May cause delayed delivery of drug
• Ideal for drugs that are quickly to pharmacological site of action
eliminated from the body • Limited to drugs that can be
taken in small daily doses
Rectal • Erratic and variable • Partially bypasses first-pass effect • Drugs may irritate the rectal
• Bypasses destruction by stomach acid mucosa
• Ideal if drug causes vomiting • Not a well-accepted route
• Ideal in patients who are vomiting, or
comatose
Inhalation • Systemic absorption may • Absorption is rapid; can have • Most addictive route (drug can
occur; this is not always immediate effects, Ideal for gases enter the brain quickly)
desirable • Effective for patients with respiratory • Patient may have difficulty
Problems, Dose can be titrated regulating dose
• Localized effect to target lungs: lower • Some patients may have
doses used compared to that with difficulty using inhalers
oral or parenteral administration
• Fewer systemic side effects
Sublingual • Depends on the drug: Few • Bypasses first-pass effect • Limited to certain types of drugs
drugs (for example, • Bypasses destruction by stomach acid • Limited to drugs that can be
nitroglycerin) have rapid • Drug stability maintained because taken in small doses
direct systemic absorption the pH of saliva relatively neutral • May lose part of the drug dose if
Most drugs erratically or • May cause immediate pharmacological swallowed 28
incompletely absorbed effects
Physicochemical Factors In Transfer of

Drugs Across Membranes
 Cell Membranes
 Passive Properties
 Carrier-Mediated Transport
29
Facts...
 “ADME of a drug all involve its passage across cell
membranes”
 Drugs generally pass through cells rather than

between them
 Thus, the plasma membrane is the common
barrier
 Passive diffusion depends on movement down a
concentration gradient
30
1. Molecular Size
 In general, smaller molecules diffuse more readily across
membranes than larger ones because the diffusion
coefficient is inversely related to the sq. root of the MW
 This applies to passive diffusion but NOT to specialized

transport mechanisms (active transport, pinocytosis)
 tight junction: MW <200

 diffusion through large fenestrations in capillaries: MW 20K-
30K
31
2. Lipid-Solubility
Oil:Water Partition Coefficient
The greater the partition coefficient, the higher the
lipid-solubility of the drug, and the greater its diffusion
across membranes
A non-ionizable compound (or the non-ionized form of

an acid or a base) will reach an equilibrium across the
membrane that is proportional to its concentration
gradient
32
Absorbed from stomach in 1 hour (% of dose)

50
580
40
52
30
20
10
1
Other things (MW, pKa) being equal,
absorption of these drugs is 0
barbital secobarbital thiopental
proportional to lipid solubility (pKa 7.8) (pKa 7.9) (pKa 7.6)
33
3. Ionization
• Most drugs are small (MW < 1000) weak electrolytes
(acids/bases)
• This influences passive diffusion since cell membranes are
hydrophobic lipid bilayers that are much more permeable to
the non-ionized forms of drugs
The fraction of drug that is non-ionized depends on its

chemical nature, its pKa, and the local biophase pH...
34
Ionization (2)
 You can think of properties this way:
 ionized = polar = water-soluble
 non-ionized = less polar = more lipid-soluble
 Think of an acid as having a carboxyl: COOH / COO_

 Think of a base as having an amino: NH3+ / NH2
*For both acids and bases, pKa = acid dissociation constant, the pH at
which 50% of the molecules are ionized.
 Example:
weak acid = aspirin (pKa 3.5)
weak base = morphine (pKa 8.0)
35
Weak acid Weak base

H+ extracellular H+
pH BH+
A- B
HA
HA A- B BH+
intracellular
H+ pH H+
* The pH on each side of the membrane determines the equilibrium on each side
36
A Useful Concept...
Drugs tend to exist in the ionized form
when exposed to their “pH-opposite”
chemical environment.
 Acids are increasingly ionized with
increasing pH (basic environment),
whereas…
 Bases are increasingly ionized with
decreasing pH (acidic environment).
37
+
HA acid pH base HB
cromolyn sodium (2.0) diazepam (3.3)

2
furosemide (3.9) 4 chlordiazepaxide (4.8)
sulfamethoxazole (6.0) 6 triamterene (6.1)

phenobarbital (7.4) cimetidine (6.8)
7.4
phenytoin (8.3) 8 morphine (8.0)
- chlorthalidone (9.4) 10 amantadine (10.1) B

A
38
Henderson-Hasselbalch Eqn.
[protonated]
log = pKa - pH
[unprotonated]
39
40
Problem: What percentage of phenobarbital (weak acid, pKa = 7.4)

exists in the ionized form in urine at pH 6.4?
pKa - pH = 7.4 - 6.4 = 1 take antilog of 1 to get the ratio

between non-ionized (HA) and
antilog of 1 = 10 ionized (A-) forms of the drug:
if pH = pKa then HA = A-
if pH < pKa, acid form (HA) will always predominate
if pH > pKa, the basic form (A-) will always predominate
Ratio of HA/A- = 10/1
% ionized = A- / A- + HA X 100 = 1 / (1 + 10) X 100 = 9% ionized

41
Problem: What percentage of cocaine (weak base, pKa =8 .5)

exists in the non-ionized form in the stomach at pH 2.5?
take antilog of 6 to get the ratio
pKa - pH = 8.5 - 2.5 = 6
between ionized (BH+) and non-ionized
antilog of 6 = 1,000,000 (B) Forms of the drug:
if pH = pKa then BH+ = B

if pH < pKa, acid form (BH+) will always predominate
if pH > pKa, the basic form (B) will always predominate
Ratio of BH+/B = 1,000,000/1
% non-ionized = B / (B + BH+) X 100 = 1 X 10-4 % non-ionized or 0.0001%
42
In a Suspected Overdose...
 The most appropriate site for sampling to identify the
drug depends on the drug’s chemical nature
 Acidic drugs concentrate in plasma, whereas the

stomach is a reasonable site for sampling basic drugs
 Diffusion of basic drugs into the stomach results in

almost complete ionization in that low-pH environment
43
naproxen (weak acid, pKa 5.0)

gastric juice plasma
pH 2.0 pH 7.4
HA = 1.0 HA = 1.0
+ +
A- = 0.001 A- = 251
total total
HA + A- = 1.001 HA + A- = 252
morphine (weak base, pKa 8.0)

small intestine plasma
pH 5.3 pH 7.4
HB+ = 501 HB+ = 4
+ +
B = 1.0 B = 1.0
total total
+ +
HB + B = 502 HB + B = 5
44
Other aspects….
 amphetamine (weak base, pKa 10)

 its actions can be prolonged by ingesting bicarbonate to
alkalinize the urine...
 this will increase the fraction of amphetamine in non-ionized
form, which is readily reabsorbed across the luminal surface of
the kidney nephron...
 in overdose, you may acidify the urine to increase kidney
clearance of amphetamine
45
Other aspects….
 Certain compounds may exist as strong electrolytes
 This means they are ionized at all body pH values
 They are poorly lipid soluble
Examples:
strong acid = glucuronic acid derivatives of drugs.
strong base = quaternary ammonium compounds such as
acetylcholine
46
Membrane Transfer
passive carrier-mediated endocytosis

diffusion active passive
ATP
ADP-Pi
47
Facilitated Diffusion
 This is a carrier-mediated process that does NOT
require energy
 Movement of substance can NOT be against its
concentration gradient
 Necessary for transport of endogenous
compounds whose rate of movement across
membranes by simple diffusion would be too slow
Example: Insulin
48
Special carriers
 Substances that are important for cell function
and too large or too insoluble in lipid to diffuse
passively through membranes
 eg, peptides, amino acids, glucose.
 These kind of transport, unlike passive diffusion,

is saturable and inhabitable
Active transport - requirement of energy

Facilitated diffusion - needs no energy
49
Special carriers (2)

Carrier-mediated transport is important
for some drugs that are chemically related
to endogenous substances
The transporter proteins also mediate
drug efflux
 P-glycoprotein /MDR1
 MRP transporters
Function as a barrier system to protect
cells
50
MDR1/P-glycoprotein
P-glycoprotein: P-glycoprotein 1
(permeability glycoprotein, abbreviated
as P-gp or Pgp) also known as
multidrug resistance protein 1 (MDR1)
or ATP-binding cassette subfamily B
member 1 (ABCB1) is an important
protein of the cell membrane that
pumps many foreign substances out of
cells.
Produced by the mdr-1 gene

(Characterization of the human MDR1 gene. 2005).
51
Active Transport
 Occurrence:
 neuronal membranes, choroid plexus, renal tubule cells,
hepatocytes
 Characteristics:
 carrier-mediated
 Selectivity
 competitive inhibition by congeners
 energy requirement *
 Saturable
 movement against concentration gradient *
*differences from facilitated diffusion

52
Endocytosis, Exocytosis, Internalization

Endocytosis (or pinocytosis): a portion of the plasma
membrane invaginates and then pinches off from the
surface to form an intracellular vesicle
Example:
This is the mechanism by which thyroid follicular cells, in
response to TSH, take up thyroglobulin (MW > 500,000).
53
Drug Absorption and Bioavailability (F)

 Absorption describes the rate and extent at which a drug
leaves its site of administration
 Bioavailability (F) is the extent to which a drug reaches its

site of action, or to a biological fluid (such as plasma) from
which the drug has access to its site of action
54
Pharmacokinetics
Locus of Tissue
action reservoirs
“receptors”
Bound Free Bound Free
Systemic
circulation
Absorption Free drug Excretion
Bound drug Metabolites
Biotransformation
55
AUC = area under the curve

AUC oral
plasma concentration of drug

Bioavailability = AUC injected i.v. X 100
AUC
injected i.v.
AUC
oral
time
56
Factors Modifying Absorption

 drug solubility (aqueous vs. lipid)
 local conditions (pH)
 local circulation (perfusion)
 surface area
57
Bioequivalence
 Drugs are pharmaceutical equivalents if they contain the same
active ingredients and are identical in dose (quantity of drug),
dosage form (e.g., pill formulation), and route of
administration
 Bioequivalence exists between two such products when the
rates and extent of bioavailability of their active ingredient are
not significantly different
58
Distribution
 Once a drug is absorbed into the bloodstream, it may be
distributed into interstitial and cellular fluids
 The actual pattern of drug distribution reflects various

physiological factors and physicochemical properties of the
drug
59
Phases of Distribution
 first phase
 reflects cardiac output and regional blood flow
 Thus, heart, liver, kidney & brain receive most of the drug during
the first few minutes after absorption
 next phase
 delivery to muscle, most viscera, skin and adipose is slower,
and involves a far larger fraction of the body mass
60
Drug Reservoirs
 Body compartments where a drug can accumulate are reservoirs
 Have dynamic effects on drug availability.
 plasma proteins as reservoirs (bind drug)

 cellular reservoirs
 Adipose (lipophilic drugs)
 Bone (crystal lattice)
 Transcellular (ion trapping)
61
Pharmacokinetics
Locus of Tissue
action reservoirs
“receptors”
Bound Free Bound Free
Systemic
circulation
Absorption Free drug Excretion
Bound drug Metabolites
Biotransformation
62
Protein Binding
 Passive movement of drugs across biological membranes
is influenced by protein binding
 Binding may occur with plasma proteins or with non-
specific tissue proteins in addition to the drug’s receptors
***Only drug that is not bound to proteins (i.e., free or

unbound drug) can diffuse across membranes
63
Plasma Proteins
 albumin
- binds many acidic drugs
 α1-acid glycoprotein
- binds basic drugs
 The fraction of total drug in plasma that is bound is
determined by
1. its concentration
2. its binding affinity
3. the number of binding sites
 At low concentration, binding is a function of Kd (dissociation
constant); at high concentration it’s the # of binding sites
64
Plasma Proteins (2) Example

Thyroxine (thyroid hormone T4)
 > 99% bound to plasma proteins (PPB)
 The main carrier is the acidic glycoprotein thyroxine-binding
globulin [Thyroxine Binding Globulin (TBG)]
 very slowly eliminated from the body, and has a very long half-
life
65
Drugs Binding Primarily to Albumin

barbiturate probenecid
benzodiazepines streptomycin
bilirubin sulfonamides
digotoxin tetracycline
fatty acids tolbutamide
penicillins valproic acid
phenytoin warfarin
phenylbutazone
66
Drugs Binding Primarily to

α1-Acid Glycoprotein
alprenolol lidocaine
bupivicaine methadone
desmethylperazine prazosin
dipyridamole propranolol
disopyramide quinidine
etidocaine verapamil
imipramine
67
Drugs Binding Primarily to

Lipoproteins
amitriptyline
nortriptyline
68
Bone Reservoir
 Tetracycline antibiotics (and other divalent metal ion-chelating
agents) and heavy metals may accumulate in bone
 They are adsorbed onto the bone-crystal surface and eventually
become incorporated into the crystal lattice
 Bone then can become a reservoir for slow release of toxic

agents (e.g., lead, radium) into the blood
69
Adipose Reservoir
• Many lipid-soluble drugs are stored in fat
• In obesity, fat content may be as high as 50%, and in

starvation it may still be only as low as 10% of body weight
• 70% of a thiopental dose may be found in fat 3 hr. after

administration (see next slide)
70
Thiopental
A highly lipid-soluble i.v. anesthetic
 Blood flow to brain is high, so maximal brain concentrations
brain are achieved in minutes and quickly decline
 Plasma levels drop as diffusion into other tissues (muscle)
occurs
 Onset and termination of anesthesia is rapid
 The third phase represents accumulation in fat (70% after 3 h)
 Can store large amounts and maintain anesthesia
71
Thiopental (2) Graphic Illustration

100
blood
(as percent of initial dose)
Thiopental concentration
brain
muscle adipose
50
0
1 10 100 1000
minutes
72
GI Tract as Reservoir
 Weak bases are passively concentrated in stomach from blood
because of large pH differential
 Some drugs are excreted in bile in active form or as a conjugate

that can be hydrolyzed in intestine and reabsorbed
In the above two cases, and when orally administered drugs

are slowly absorbed, GI tract serves as a reservoir
73
Redistribution
 Termination of drug action is normally by biotransformation /
excretion, but may also occur as a result of redistribution
between various compartments
 Particularly true for lipid-soluble drugs that affect brain and heart
74
Placental Transfer
 Drugs cross the placental barrier primarily by simple passive
diffusion
 Lipid-soluble, nonionized drugs readily enter fetal bloodstream
from maternal circulation
 Rates of drug movement across placenta tend to increase
towards term as tissue layers between maternal blood and
fetal capillaries thin
75
Clinical Pharmacokinetics
Fundamental hypothesis:
 A relationship exists between the pharmacological or toxic
response to a drug and the accessible concentration of the
drug (e.g., in blood)
Important parameters:
 volume of distribution (Vd)
 clearance (CL)
 bioavailability (F)
76
Volume of Distribution
 Volume of distribution (Vd) relates the amount of drug in
the body to the plasma concentration of drug (Cp)
**The apparent volume of distribution is a calculated space

and does not always conform to any actual anatomic
space**
Note: Vd is the fluid volume the drug would have to be

distributed in if Cp were representative of the drug
concentration throughout the body
77
Total body water

plasma volume
extracellular
plasma
3 liters
interstitial
volume interstitial volume
15 liters
intracellular
volume
intracellular 12 liters
42 liters
27 liters
78
At steady-state plasma concentration (Css):
total drug in body (mg)

Vd = ------------------------------
plasma conc. (mg/ml)
79
Example of Vd
• The plasma volume of a 70-kg man ~ 3L, blood volume ~
5.5L, extracellular fluid volume ~ 12L, and total body
water ~ 42L.
• Givens: If 500 mg of digoxin were in his body, Cp would be
~ 0.7 ng/ml
• Dividing 500 mg by 0.7 ng/ml yields a Vd of 700L, a value
10 times total body volume! Huh?
• Digoxin is hydrophobic and distributes preferentially to

muscle and fat, leaving very little drug in plasma
• The digoxin dose required therapeutically depends on
body composition
80
Clearance (CL)
• Clearance is the most important property to consider when a
rational regimen for long-term drug administration is designed
– The clinician usually wants to maintain steady-state drug
concentrations known to be within the therapeutic range
– CL = dosing rate / Css
– CL = rate of elimination / Css
– (volume/time) = (mass of drug/time) / (mass of drug/volume)
81
Clearance (2)
• Clearance does not indicate how much drug is removed but,
rather, the volume of blood (or plasma) that would have to be
completely freed of drug to account for the elimination rate.
– CL is expressed as volume per unit time
82
Clearance (3)
Sum of all process
contributing to
disappearance of drug
from plasma
Drug in plasma at Drug concentration in plasma is less
concentration of 2 mg/ml after each pass through elimination /
metabolism process
Remember:
CL = dosing rate / Css
CL = rate of elimination / Css
Drug molecules disappearing from
plasma at rate of 400 mg/min
CL = 400 mg/min
= 200 ml/min
2 mg/ml
83
Clearance (4)
Example: cephalexin, CLp = 4.3 ml/min/kg
• For a 70-kg man, CLp = 300 ml/min, with renal clearance

accounting for 91% of this elimination
• So, the kidney is able to excrete cephalexin at a rate such that

~ 273 ml of plasma is cleared of drug per minute
• Since clearance is usually assumed to remain constant in a
stable patient, the total rate of elimination of cephalexin
depends on the concentration of drug in plasma
84
Clearance (5)
Example: propranolol, CLp = 12 ml/min/kg or 840
ml/min in a 70-kg man
The drug is cleared almost exclusively by the liver
Every minute, the liver is able to remove the amount of drug
contained in 840 ml of plasma
NB:
Clearance of most drugs is constant over a range of
concentrations
This means that elimination is not saturated and its rate is
directly proportional to the drug concentration:
this is a description of 1st-order elimination
85
CL in a given organ
CL in a given organ may be defined in terms of blood flow and
[drug]
Q = blood flow to organ (volume/min)
CA = arterial drug conc. (mass/volume)
CV = venous drug conc.
rate of elimination = (Q x CA) - (Q x CV) = Q (CA-CV)
86
87
Further study:
 eNotes: GP- General Principles of Drug Action
 Drug-Receptor Interactions, Morris ZS, Golan DE and (or)
 Brody’s Human Pharmacology: Ch.1 Pharmacodynamics- Receptors and

Concentration-Response Relationships
 Enzyme kinetics Notes
 MedPharm Wiki| PK and PD, Pgs. 73-88
 Pharmacology Course Website
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4-Pharmacokinetics I

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4-Pharmacokinetics I

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General Principles of Drug Therapy

Integrated Scientific and

Pharmacokinetics (PK) study of ADME

Processes that determine drug delivery to (in)

Pharmacokinetics Overview (2)

Goodman and Gilman's The Pharmacological Basis of Therapeutics 12e, (2011)

Interrelationship of absorption, distribution,

Important Properties Affecting

Chemical properties Physiologic variables:

Routes of Drug Administration (RofA)

 Parenteral, meaning absorbed

Lippincott Illustrated Reviews,

 Drugs administered intravenously bypass absorption, thus

 Oral drugs have < 100% bioavailability (< 1) because:

From Brenner GM, Stevens CW. Pharmacology.

Forms of Oral Drugs

Fastest  liquids: syrups, elixirs

Slowest  pills: capsules, tablets

Rate of Appearance in Blood

Enteric coating pills

Sublingual (SL) Administration

 Slow and constant absorption

 Slow-release pellet may be implanted

 Drug must not be irritating

 Injection into spinal subarachnoid space:

 Peritoneal cavity offers a large absorbing

 Seldom used clinically

 Infection is always a concern

 almost instantaneous absorption

 Systemic absorption may occur (e.g.

Topical Application (2)

Topical Application (3)

Routes of Administration Summary Table (1)

Physicochemical Factors In Transfer of

 Drugs generally pass through cells rather than

 This applies to passive diffusion but NOT to specialized

 tight junction: MW <200

A non-ionizable compound (or the non-ionized form of

Absorbed from stomach in 1 hour (% of dose)

The fraction of drug that is non-ionized depends on its

 Think of an acid as having a carboxyl: COOH / COO_

Weak acid Weak base

cromolyn sodium (2.0) diazepam (3.3)

furosemide (3.9) 4 chlordiazepaxide (4.8)

sulfamethoxazole (6.0) 6 triamterene (6.1)

phenytoin (8.3) 8 morphine (8.0)

- chlorthalidone (9.4) 10 amantadine (10.1) B

Problem: What percentage of phenobarbital (weak acid, pKa = 7.4)

pKa - pH = 7.4 - 6.4 = 1 take antilog of 1 to get the ratio

Ratio of HA/A- = 10/1

% ionized = A- / A- + HA X 100 = 1 / (1 + 10) X 100 = 9% ionized

Problem: What percentage of cocaine (weak base, pKa =8 .5)

if pH = pKa then BH+ = B

% non-ionized = B / (B + BH+) X 100 = 1 X 10-4 % non-ionized or 0.0001%

 Acidic drugs concentrate in plasma, whereas the

 Diffusion of basic drugs into the stomach results in

naproxen (weak acid, pKa 5.0)

morphine (weak base, pKa 8.0)

 amphetamine (weak base, pKa 10)

passive carrier-mediated endocytosis

 These kind of transport, unlike passive diffusion,

Active transport - requirement of energy

Special carriers (2)

Produced by the mdr-1 gene

*differences from facilitated diffusion

Endocytosis, Exocytosis, Internalization

Drug Absorption and Bioavailability (F)