Pharmacokinetics

Ken-Ichi Takemaru
Assistant Professor
BST 7-182, 4-7976
takemaru@pharm.stonybrook.edu
 Pharmacokinetics vs. Pharmacodynamics

Fig. 3-1. The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration)
and pharmacodynamic (concentration-effect) component (Basics & Clinical Pharmacology, Katzung, 2007)
 Lithium vs. Activase (Alteplase)

Li+
MW = 7
Mood-stabilizing drug (bipolar disorder)
Oral administration

Activase (Recombinant tissue plasminogen activator)

MW = 59,050 (527 amino acids)
Blood clot-dissolving enzyme
Administered into the vascular compartment by IV injection
 Pharmacokinetic Processes

Figure 4-1. The four basic pharmacokinetic processes (Pharmacology for Nursing Care, Lehne, 2004).

• Pharmacokinetics is the study of drug movement throughout the body, which determines the
concentration of a drug at its sites of action (‘what the body does to the drug’).
 Routes of Drug Administration

Table 3-1. Routes of drug administration (Principles of Pharmacology, Golan et al., 2005)

First-pass metabolism
Routes of Parenteral Drug Administration

Table 3-2. Routes of parenteral drug administration (Principles of Pharmacology, Golan et al., 2005)
 Passage of Drugs across Membranes
1, Channels and pores: very few drugs with low molecular weights
cross membrane via channels or pores.

2, Transport systems: important for certain drugs and also utilized for
renal excretion.

3, Membrane diffusion: most drugs diffuse through the membrane.

A drug must be lipid soluble, and polar molecules can not penetrate
membranes. Figure 4-2. Structure of the cell membrane
(Pharmacology for Nursing Care, Lehne, 2004)

In the absence of any other factors, a drug will enter a cell until the intracellular and extracellular
concentrations of the drug are equivalent. Fick’s law of diffusion states the net drug flux across
the membrane:

Rate of diffusion = Partition coefficient x Surface Area x (C2-C1)

Thicknessmembrane
C1: intracellular concentration of drug
C2: extracellular concentration of drug

This equation applies to an ideal situation where there is an absence of complicating factors such as
pH and charge gradients across the membrane.
 Effect of pH on Drug Absorption

Weak acid Weak base

Dissociation Curve: Aspirin
HA H+ + A- BH+ B + H+
100

Percent HA
75

50 pK 3.5

25

0
1 2 3 4 5 6
pH

Stomach Plasma

Henderson-Hasselbach equation
[A-]
________
[B]
pH = pKa + log pH = pKb + log ________ +
[HA] [BH ]
 pH Trapping across Lipid Bilayers

Henderson-Hasselbach equation
[HA]
pKa = pH + log ________ -
[A ]

In case of a weakly acidic drug with a pKa of 4

(stomach pH=1):

Fig. 3-2. pH trapping across lipid bilayers

(Principles of Pharmacology, Golan et al., 2005)

[HA] [HA] [HA]

4 = 1 + log ________- 3 = log ________ - 1,000 = ________ -
[A ] [A ] [A ]

In stomach, the uncharged form of the drug exists 1,000 times the concentration of charged from;
99.9% of the drug is in the uncharged form. In contrast, in plasma, 99.9% of the drug is charged.

pH trapping is also applied to other situations such as breast milk (pH = 6 to 7) vs. plasma and
urine (pH = 4.6 to 8) vs. plasma.
Morphine is a weak base with pK = 8.0. If the pH of breast milk is 6.8 and that of plasma is
7.4, calculate the distribution of morphine in plasma vs. breast milk.
From rearranging the Henderson-Hasselbach equation: [B]/[BH+] = 10 (pH-8.0)
Plasma Breast milk
pH = 7.4 pH = 6.8

[Bp]/[BH+p] = 10 -0.6 = 0.251 [Bbm ]/[BH+bm ] = 10 -1.2 = 0.0631

Neutral form equilibrates across the plasma membrane
[Bp] = [Bbm ] Let’s simplify this as [B]

[B]/[BH+p] = 0.251 [B]/[BH+bm ] = 0.0631

[BH+p]/[B] = 1/0.251 = 3.98 [BH+bm ]/[B] = 1/0.0631 = 15.8

[BH+p]/[B] + 1 = 3.98 + 1 [BH+bm ]/[B] + 1 = 15.8 + 1

[BH+p] + [B]/[B] = 4.98 [BH+bm ] + [B]/[B] = 16.8

[Btotalp ]/[B] = 4.98 [Btotalbm ]/[B] = 16.8

[Btotalp ] = 4.98  [B] [Btotalbm ] = 16.8  [B]

The ratio [Btotalbm ]/[Btotalp ] = 16.8/4.98 = 3.37

Morphine is 3.37 times more concentrated in breast milk than in plasma.

Renal Elimination of Drugs and Metabolites

Glomerular filtration

Passive tubular reabsorption

Active tubular secretion

Nephron
Fig. 4-2. Renal excretion of drugs
(Modern Pharmacology, Craig & Stitzel, 2004)

• Each kidney contains about one million functional filtering units called nephrons.
• The kidneys filter about 45 gal (180 L) of blood each day.
 Time Course of Drug Responses

Peak conc.
✖ ✖ ✖ ✖ ✖ ✖ ✖ ✖ ✖ ✖ ✖ ✖
✖
✖ ✖ ✖ ✖ ✖ ✖ ✖ ✖ ✖ ✖ ✖ ✖
✖ ✖
✖ Trough conc.
✖ ✖
✖
✖
✖

(MEC)

Figure 4-15. Drug accumulation with repeated administration

(Pharmacology for Nursing Care, Lehne, 2004)
Figure 4-14. Single-dose time course (oral) A drug with a half-life of 1 day.
(Pharmacology for Nursing Care, Lehne, 2004) 2 gm given once a day on days 1 through 9.
What happens if you take 1 gm of the drug every 12 hours instead?
Acetaminophen’s toxic conc. is 30 times greater than the MEC.
Lithium’s toxic conc. is only 3 times greater than the MEC.

How do you predict time course of drug action?

 Single Compartment Model

A highly simplified model of a human being, which consists of a

single well-stirred compartment (Vd) into which a quantity of
drug Q introduced, and from which it can escape either by being
metabolized or being excreted.

Fig. 8-6. Single-compartment pharmacokinetic model

(Pharmacology, Rang et al., 2003)

First-order kinetics

Fig. 3-7, B. Schematic model of drug distribution and elimination

(Principles of Pharmacology, Golan et al., 2005)
 First-Order Kinetics
• First-Order Kinetics: a constant fraction of drug is handled per unit of time.
Examples: 1. hepatic metabolism when enzymes are not saturated
2. glomerular filtration
3. radioactive decay
• The majority of drugs are eliminated by first-order kinetics.

• The rate of elimination is directly proportional to drug concentration.

Fig. 8-7. Predicted behavior of single-compartment model following intravenous drug administration at time 0.
(Pharmacology, Rang et al., 2003)
 First-Order Drug Elimination
The decrease in the plasma concentration of drug X
over time can be written as:

-d[X]/dt = k[X] (k is the elimination rate constant)

Slope = -k/2.3 Rearrange: d[X]/[X] = -kdt
Integrate: ln[X] = -kt + C
Log10 [X] Evaluate the value of C (the constant of integration):
when t = 0, [X] = [X]0, thus C = ln[X]0
Substitute: ln[X] = -kt + ln[X]0

ln[X] = ln [X]0 - kt or log [X] = log [X]0 - kt/2.3

time
ln([X]/[X]0) = -kt

[X] = [X]0 e-kt

[X] is the plasma drug concentration at any time t after administration

([X]0 , initial plasma drug concentration; k, elimination constant).
 Two-Compartment Model

Fig. 8-6. Two-compartment pharmacokinetic model. The peripheral Fig. 3-7, C. Schematic model of drug distribution and elimination
compartment represents the tissues while the central compartment (Principles of Pharmacology, Golan et al., 2005)
represents the plasma. (Pharmacology, Rang et al., 2003)

Fig. 8-6. Kinetics of diazepam elimination in humans following

a single oral dose. (Pharmacology, Rang et al., 2003)

The kinetics are biexponential, representing the process of transfer

between plasma and tissues (fast phase) and elimination from the
plasma (slow phase). Therefore, it still follows the first-order kinetics.
 Zero-Order Kinetics (Saturation Kinetics)
• In a few cases, the time course of disappearance of drug from the plasma does not follow
the exponential patterns but initially linear (i.e. drug is removed at a constant rate that is
independent of plasma concentration).

Fig. 8-12. Saturating kinetics of alcohol elimination in

humans. The rate of disappearance of ethanol from the
plasma is constant at about 4 mmol/l per hour
irrespective of its plasma concentration because the rate
of oxidation by the alcohol dehydrogenase reaches a
maximum at low ethanol concentrations.
(Pharmacology, Rang et al., 2003)

• Zero-Order Kinetics: a constant amount of drug is handled per unit time.

Examples: 1. absorption from a sustained release preparation
2. drug given by an infusion pump
3. hepatic metabolism of drug when enzymes are saturated
 Bioavailability (F)
Bioavailability (F)= fraction of a drug reaching the systemic circulation
(quantity of drug reaching systemic circulation/quantity of drug administered)

For a drug administered orally, bioavailability is less than 100% for two main reasons;
incomplete extent of absorption and first-pass elimination.
Hepatic extraction ratio (ER, first-pass elimination) = CLliver (L/h/70kg)
Q (hepatic blood flow; 90L/h/70kg)

F = extent of absorption (f) x (1-ER)

Morphine is almost completely absorbed (f=1), so that loss in

the gut is negligible. However, the hepatic extraction ratio for
morphine is 0.67, so (1-ER) is 0.33. The bioavailability
of morphine is therefore expected to be about 33%.

Fig. 3-3. Bioavailability following administration of

a single dose of drug
(Principles of Pharmacology, Golan et al., 2005)
 Volume of Distribution (Vd)
Represents the fluid volume required to contain the total amount of absorbed drug in
the body at a uniform concentration equivalent to that in the plasma at a steady state.

Vd = Amount of drug in the body (Dose)

Concentration of drug in blood or plasma
(Cp)
If 500 ug of digoxin were in the body of a 70-kg subject, a plasma concentration of approximately
0.7 ng/ml would be observed. Vd = 500,000/0.7 = 714 L. Hence, digoxin distributes widely
throughout the body.

Ibuprofen typically exhibits a Vd of 10.8 L. Thus, this drug does not distribute widely to into
tissues.

• Drugs (digoxin) that are highly distributed to extravascular compartments (fat and muscle) have
a high Vd.

• Drugs (ibuprofen) that are primarily retained within the vascular compartment have a relatively
low Vd.

• Vd can be altered by liver or kidney disease.

 Plasma Protein Binding

• Albumin is the most abundant plasma protein and is responsible

for drug binding.

• Because a highly protein-bound drug tends to remain within the

vasculature, such a drug often has a relatively low Vd.

• Co-administration of two or more drugs, each of which is highly

bound to plasma protein, could results in higher-than-expected
plasma concentration of the free form of either or both drugs.

• Phenytoin is approximately 90% bound to plasma proteins, leaving

10% of the concentration in the blood as free drug and available for
pharmacological action and metabolism.

Fig. 3-5. Protein Binding and Drug Trapping

(Principles of Pharmacology, Golan et al., 2005)
 Clearance (CL)
CL is the efficiency of irreversible elimination of drug from the body, and
involves both metabolism and elimination of drug.
CL is defined as the volume of plasma that was completely cleared of the drug
per unit of time (e.g., 100 mL/min).

CL = Rate of elimination / Concentration of drug in plasma (Cp)

CLSystemic = CLKidney + CLLiver + CLOther
 Half-Life (t1/2 ) (1)
t1/2 = the time required to change the amount of drug in the body by one-half during elimination.

Need logarithmic increase in dose

to get linear increase in duration [X] = [X]0 e-kt
of action. Doubling the dose increases
duration of action by one half-life.
[X]0/2 = [X]0 e-kt 1/2
1/2 = e-kt 1/2
2 = ekt 1/2
log scale

ln 2 = kt1/2
0.69 = kt1/2
t1/2 = 4 h
t1/2 = 0.69/k

MEC
(minimum effective concentration)
Half-Life (t1/2 ) (2)

Table 3-5. Factors affecting drug half-life

(Principles of Pharmacology, Golan et al., 2005)
 Relationship between Clearance, Vd, and t1/2
Renal clearance describes the efficiency with which a drug or metabolite is excreted by the kidney.
c = drug concentration in plasma = gm/ml
u = drug concentration in urine = gm/ml
v = volume of urine = ml
then uv/t = gm/time = the rate of drug excretion into urine
Divide this by c
uv/tc = ml/time = clearance = the volume of plasma that
was completely cleared of the drug in the time interval.

Relating CL to t1/2 and Vd

From the first order elimination, the rate of drug excretion is -dX/dt = kX,
and if elimination is occurring only by the kidney then
kX = uv/t, and since X = total amount of drug in body, X = c Vd,
Consequently,
k c Vd = uv/t or k Vd = uv/tc = clearance or t1/2 = 0.69 Vd/clearance

CL = Vdk or t1/2 = 0.69 Vd/CL

 Dosage Regimen
• A rational dosage regimen is based on a target concentration that will produce the desired
therapeutic effect.
• Absorption, distribution, metabolism, and excretion, each influences the design of an
optimal dosing regimen for a drug.
• Therapeutic window is the safe opening between the minimum therapeutic concentration and
the minimum toxic concentration of a drug

Fig. 3-11. Therapeutic subtherapeutic, and toxic drug dosing

(Principles of Pharmacology, Golan et al., 2005)
 Maintenance Dosage
At steady state, the dosing rate (rate in) must equal the rate of elimination (rate out).
Dosing rate = Rate of elimination = CL x Target Concentration (TC)

If the drug is given by a route that has a bioavailability less than 100%,
Dosing rate = CL x Target Concentration (TC)
Bioavailability (F)

If intermittent doses are given,

Maintenance dose = Dosing rate x Dosing interval
 Maintenance Dosage: Example
A target plasma theophylline concentration of 10 mg/L is desired to relive acute bronchial asthma
in a patient. If the patient is a nonsmoker and otherwise normal except for asthma, clearance is
2.8 L/h/70 kg. Since the drug will be given via IV, F = 1.
Dosing rate = CL x TC = 2.8 L/h/70 kg x 10 mg/L = 28 mg/h/70 kg

If the asthma attack is relieved, the clinician might want to maintain this plasma level using oral
theophylline, which is given every 12 hours. Foral = 0.96.
Maintenance dose = Dosing rate x Dosing interval = 28 mg/h x 12 hours = 350 mg
F 0.96
If an 8-hour dosing interval was used, the ideal dose would be 233 mg; and if the drug was given
once a day, the dose would be 700 mg.

Fig. 3-6. Relationship between frequency of dosing and maximum plasma concentrations when a steady state theophylline plasma level of 10 mg/L is desired.
(Basics & Clinical Pharmacology, Katzung, 2004)
 Loading Dose
Initial (loading) dose to rapidly achieve a therapeutic concentration when the Vd is
large
Loading dose = Vd x Target Concentration (TC)

For example, warfarin has a Vd of 9.8 L (70 kg), when a TC is 1.01 mg/L, loading
dose is calculated as
Loading dose = 9.8 L x 1.01 mg/L = 9.90 mg

• A loading dose may be desirable if the time required to attain steady state by the
administration of drug at a constant rate (four elimination half-lives) is long relative to
the temporal demands of the condition being treated such as arrhythmia.

• The use of a loading dose has significant disadvantages. Sensitive patients may be
exposed to a toxic concentration of a drug. In addition, if the drug has a long half-life,
it will take a long time for the concentration to fall.
Adjustment of Dosage with Compromised Clearance
Drugs cleared by the renal route require adjustment of clearance in proportion to renal
function (renal disease or reduced cardiac output).

Corrected dose = Average dose x Patient’s creatinine clearance

(measure for glomerular filtration rate)
 Table 3-1. Pharmacokinetic and pharmacodynamic parameters for selected drugs
(Basic & Clinical Pharmacology, Katzung, 2004)
The standard dose of a drug is based on trials in healthy volunteers with average ability to absorb,
distribute, and eliminate the drug.
 Problem 1

When 0.3 g of drug X is given by IV to a subject, the resulting drug

concentration is 15 mg/L. Calculate the volume of distribution.

Vd = Amount of drug in the body (Dose)

Concentration of drug in plasma (Cp)

= 300 mg/15 mg/L = 20 L

 Problem 2
An aminoglycoside has a normal elimination half-life of 90 minutes in young adults. However, in patients 70 to 90 years
old, its elimination half-life is increased to 270 minutes. The normal dose of the aminoglycoside is 12 mg/kg per day.
Assume that the volume of distribution per body weight is not changed by the patient’s age.
What should be the daily dose for an 80-year-old patient?

t1/2 = 0.693 x Vd / CL

CL for older patients must be 3 times lower than that for young patients.

Dose = Cp x CL x time interval

In older patients, Dose/3 = Cp x CL/3 x time interval

Dose for older patients = 12 mg/kg per day / 3 = 4 mg/kg per day
 Problem 3
Mr. Walsh is taking 5 mg of warfarin every 24 hours for his chronic atrial fibrillation.
The bioavailability of warfarin is 0.93, and its clearance is 0.192 L/h.
1. Calculate the steady-state plasma concentrations of warfarin.
2. Warfarin has a volume of distribution of 9.8 L. Calculate the loading dose.

1. The steady state is reached only when the amount of

drug entering the system is equivalent to the amount
being removed from it.

Bioavailability x Dose
Dosing interval = Css x Clearance

Bioavailability x Dose
Css = Dosing interval x Clearance

0.93 x 5 mg
= = 1.01 mg/L
24 h x 0.192 L/h

2. Loading dose = 9.8 L x 1.01 mg/L = 9.90 mg

 Problem 4
A known abuser of narcotic analgesics is brought to the emergency department in a
deep coma. His friends state that he took a large dose of IV morphine 6 hours
earlier. A blood sample shows a morphine level of 0.25 mg/L. Assuming that the
pharmacokinetics of morphine in this patient are similar to the population
pharmacokinetics (volume of distribution 200 L, clearance 46.2 L/hr, half-life 3
hrs), approximately how much morphine did the patient inject?
Plasma morphine conc. (log scale)

The plasma drug concentration at any time t after

1 mg/L
administration, [X], is given by the following equation:
[X] = [X]0 • e-kt ([X]0 , initial plasma drug concentration;
0.5 mg/L k, elimination constant).
k = CL/Vd

0.25 mg/L [X] = [X]0 • e-kt

[X] = D/Vd • e-CL/Vdt
0 3 6
Time (hr) D = 200 mg
 Problem 5
A compound is given as an intravenous bolus to a patient requiring a minimum plasma concentration of 40 mg/L for a
therapeutic effect. Given the relevant characteristics of this compound below and assuming a one-compartment model,
calculate how long the clinical effect will last following a one-gram dose. k = 0.1 hour -1 ; Vd = 8 L

Plasma drug conc. (log scale)

125 mg/L

Therapeutic window

40 mg/L

0 Time

The plasma drug concentration at any time t after administration, [X], is given by the following
equation:
[X] = [X]0 • e-kt ([X]0 , initial plasma drug concentration; k, elimination constant).
[X] = [X]0 • e-kt

40 mg/L = 1000 mg / 8 L x e-0.1t

t = 11.4 hours
 Problem 6
C.A., an 8-year-old, 25-kg boy, is taking ethosuximide for treatment of absence seizures. Considering the relevant
characteristics of the drug given below, calculate the maintenance dose required with a dosing interval of 12 hours.
Vd = 0.69 L/kg; t1/2 = 30 hours; Peak target plasma concentration at steady state = 80 ug/mL; Bioavailability = 93%

Plasma ethosuximide conc. (log scale)

Peak conc. 80 ug/mL

Trough conc.
12 h

Days

[X] = [X]0 • e-kt ; k = 0.693 / t1/2

Ctrough = [X]0 • e-kt = 80 ug/mL x e -(0.693/30h)x12h = 60.63 ug/mL

The amount of drug being eliminated during the dosing interval of 12 h =

(Cpeak - Ctrough ) x Vd x body weight (kg) = (80 ug/mL - 60.63 ug/mL) x 690 mL/kg x 25 kg =
334132.5 ug = 334.1325 mg

Maintenance dose = 334.1325 mg / Bioavailability = 334.1325 mg / 0.93 = 359.3 mg