Pharmacokinetics

Pharmacokinetics refers processes that affect the

time course and distribution of drugs from injection
site to elimination site (usually liver or kidney)

--”what the body does to the drug”.

Pharmacodynamics refers to the time course of

drug action

--”what the drug does to the body”.

 Pharmacology

 Pharmacokinetics  Pharmacodynamics

 Administration  Dose response

 Absorption  Receptor activation

 Distribution  Efficacy

 Metabolism  Toxicity

 Excretion
PK - What do I want to know?
 How do I give the drug?
 Is it absorbed?
 How much is absorbed?
 Where does it go?
 How long does it stay there?
 How often do I have to give it?
 How does it leave the body?
Overview of the Process
 Routes of Administration

 Enteral
- Oral, Rectal, Sublingual
 Parenteral
- IV, IM, SubQ
 Other
- Transdermal
- Topical
- Inhalation
- Intranasal
 Absorption
 Transfer of drug from the site of administration to the systemic
circulation

 For IV administration adsorption is complete

- 100% of the administered drug reaches the circulation
- 100% of the drug is available (bioavailability)

 For all other routes of administration adsorption is variable and thus

bioavailability is variable
- It is always 100%
 Distribution – What is it?
 Process by which a drug reversibly leaves the blood stream
and distributes into the interstitium and/or the cells or tissues

 Once the drug enters the body, it has the potential to

distribute into one of the 3 compartments of body water

 Drugs do not disseminate equally into all body compartments

and distribute in unique ways
 Distribution
3 Compartments
 Plasma (4L)

 ECF (14L)
- Plasma + IF

 Total Body Water (42L)

- Plasma + IF + ICF

 Tissues
- Bone, adipose tissue
- Pregnancy - fetus
 Factors Influencing Drug
Distribution
 Method and location of administration
 Blood perfusion rate
 Capillary permeability
 Drug binding to plasma & tissue proteins
 Drug metabolism
 Renal Excretion
Metabolism (Biotransformation)
 Majority of biotransformation occurs in the liver

 Primary purpose is to inactivate the drug

 Converting the drug into a more excretable form

 Most drugs require biotransformation in order to be

excreted
 Some drugs are administered as prodrugs that require
biotransformation to become active
 Some drugs are metabolized to active drugs
 Some drugs are excreted unchanged
Where and how does excretion of
drugs occur?

 Bile

 Urine

 Exhaled air

 Sweat

 Saliva
 Intravenous Bolus Injection

uptake at
mass of target site
drug injected
plasma
removal by
kidney - urine

dm A Ninlets Noutlets
removal by
   AiQi    AjQ j  rA  WA( m )
dt i 1 j 1
liver &
non-target sites
 Intravenous Constant
Infusion

uptake at
Constant
target site
infusion
of
drug plasma
removal by
kidney - urine

dm A Ninlets Noutlets
removal by
   AiQi    AjQ j  rA  WA( m )
dt i 1 j 1
liver &
non-target sites
Concentration of Drug in the
Body
Maximal Safe Concentration, MSC
Minimum Effective Concentration,
MEC
Therapeutic Range

Dosage Regimen
 Ampicillin Pharmacokinetics
Bolus of ampicillin

PS
Ampicillin Peripheral
Central Compartment
Compartment
VT = 4.9 L
At Equilibrium k VB = 12 L
CB =  CT PS = 4.56 L/hr
metabolism, k = 20.6 L/hr
 = partition coef urine  = .784
 Ampicillin Pharmacokinetics
Equations
Bolus of ampicillin

PS
Ampicillin
Peripheral
Central
Compartment
Compartment

dCB
VB   W (m )  k eCB  k mCB
At Equilibrium ke, urine dt
CB =  CT dC T
VT   W (m )
km, metabolism dt
 = partition coef W ( m )  PS(CB  CT )
Final Ampicillin Equations

dCB PS k
 ( CB   C T )  CB
dt VB VB
dC T PS
 (CB  CT )
dt VT
k  k e  km
 Methods of Solution

•Combine coupled first order ODEs

into a single second order ODE
•Use Laplace Transforms
•Use ODE solver (e.g., Matlab ode45)
Ampicillin

Bolus
Response
Permeability Effect
 Multicompartmental Model
Methotrexate - 35 coupled ODEs
flow

volumes
 HW: Set up and solve (Matlab)
equations for ampicillin distribution
in the following model
ampicillin
bolus:
500 mg V1 = 12 L
V2 = 3.2 L
V3 = 2.7 L
central PS12 = 4 L/hr
V1 PS23 = 2 L/hr
ke PS12 ke = 2 L/hr
ISF, V2 km = 18 L/hr
PS23
target, V3
Equilibrium:
km C2 = .7 C1