General Rules

1. Get a mental picture of what's going on "inside". (Think about anatomy and histology in terms of "how things work.")
2. Drugs MUST have some ability to dissolve in WATER to move around (be absorbed, reach sites of action). In almost all cases,
drugs must also have a certain degree of lipid solubility to move around (leave and enter capillaries, enter and leave cells).
Solubility is a preference not an absolute. "Water Soluble", "Lipid Soluble"
3. Perspective limits what you can appreciate and leads to what may seem like strange statements:
o We can only sample from the blood stream. (just a fact)
o What we describe is about the entire MASS of drug administered. We generally talk about a "fraction" of the drug
dose that does X (e.g., 60% is eliminated in urine) Individual molecules are "on their own."
o Drug is not "in the body" until it is in the blood stream. A molecule of drug that has just reached portal circulation from
the gi tract may or may not have been absorbed yet. A molecule of drug that reaches the portal circulation via the
systemic circulation HAS been absorbed.
4. Pharmacokinetics needs to be understood as a WHOLE. You should expect that SOME parts don't make sense until you've
seen ALL the parts.
5. Understand Equillibrium:
o Drug effects are USUALLY proportional (though not always linear) to drug concentration at the site of action.
o Drug concentrations in the blood stream (measured in either serum or plasma) are USUALLY proportional (and
usually linear) to drug concentrations at the site of action.
o Drug concentration in the blood stream is ALMOST ALWAYS an excellent predictor of drug action (either efficacy or
toxicity) even though they may not be identical to the concentration in the target tissue.
6. Pharmacokinetics are the consequence of physiologic processes (that may or may not be altered by disease).
7. "Species differences in pharmacokinetics are the PRIMARY difference between Veterinary pharmacology and Human
pharmacology". Disease-induced differences are the PRIMARY difference between basic and clinical pharmacology.
Do you understand proportional? linear? equillibrium?
Administration Routes
General Principles
Drugs dissolve in body fluid (water).
Drugs enter the circulatory system by moving from one fluid "place" to another (often with the fluid, sometimes not).
Drugs must enter the circulatory system before they can be distributed to sites of action.
(Drugs for enteric effects and topical effects are an obvious exception.)
Therefore, drugs are not IN the body until they are IN the bloodstream.
Oral Administration
Advantages
Convenient, cheap, no need for sterilization, variety of dose forms
(fast release tablets, capsules, enteric coated, layered tablets, slow release, suspensions, mixtures)
You can get the dose back if you move fast enough.
Disadvantages
Variability due to physiology, feeding, disease, etc.
Intractable patients
First-pass effect
Efficiently metabolized drugs eliminated by the liver before they reach the systemic circulation.
Table 1. Location of processes involved in the absorption of oral drugs.
Process
Primary Location
Secondary Location(s)
Tablets disintegrate (a suspension forms)
Stomach
Duodenum for enteric coated forms
Drug dissolves from suspension
Stomach
Duodenum
Drug in lipid suspension may be picked up by lacteals (absorption) Duodenum, jejunum, ileum
Drug in solution crosses mucosa (absorption)
Duodenum, jejunum
Stomach, Ileum, colon
Patient and Pharmaceutical Factors
Pill compression, coatings, suspending agents, etc.
GI transit time (too slow or too fast), inflammation, malabsorption syndromes
Regional differences
Stomach - most species (Abomasum - ruminants, C3 - camelids)
mechanical preparation
"flat" absorptive surface
pH extreme
Rumenoreticulum (C1 & C2 - camelids)

stratified squamous epithelium

pH varies with diet
metabolism by bacterial flora
significant volume of fluid compared to body water
Small Intestine (all species)
large absorptive surface
specialized absorptive functions
relatively neutral pH
Colon/Rectum (all species)
accessible
large absorptive surface
Intramuscular Administration
Advantages
MORE CONSISTENT absorption vs oral or sub-cutaneous
Certainty of administration
Depot or sustained effect possible (procaine penicillin G, methylprednisolone acetate, desoxycorticosterone pivalate)
IM is a viable route for unconscious, vomiting or fractious patients; last resort for dehydrated patients.
MOST of the time, IM = IV for efficacy / potency
Disadvantages
More difficult for owners (small patients)
Pain
Muscle Damage
Dose cannot be recovered.
Injectable dose forms
Drug

Vehicle

Dose Form

Water Sol

Water Sol Aqueous Solution

Water Sol

Lipid Sol

Lipid Sol

Water Sol Suspension

Lipid Sol

Lipid Sol

Suspension

Lipid Solution

Process
1. Drug in suspension or lipid solution dissolves in tissue fluid (takes time, may slow absorption)
2. Drug in aqueous solution only has to MIX with the tissue fluid (immediately available for absorption).
3. Drug in tissue fluid solution diffuses into capillaries
4. Drug (in solution) in capillaries is carried to circulatory system.
ANY of these processes can be "rate limiting" for absorption. (Rate limiting - if multiple steps must occur, the SLOWEST process
controls the overall rate).
Bolus injection roughly spherical
aqueous solution mixes with tissue fluid for rapid absorption. The drug is already dissolved in "water", so dissolution in tissue fluid is not
rate-limiting. Entry of drug into circulatory system limited (only) by rate of blood flow to the tissue.
blood flow varies by body region/muscle group, so exercise may affect absorption rate
lipid soluble vehicle The bolus remains relatively spherical. Lipid vehicle must "degrade" or dissolve very slowly. Mixing and dissolution
in tissue fluid occurs from surface of bolus, so entry of drug into circulatory system limited by rate of drug "dissolution". (Movement from
the "bolus" to the tissue fluid).
Occasionally, vehicle may be absorbed more rapidly than drug. Then the drug "falls" out of solution in the tissue and dissolves very
slowly.
Produces tissue residues
Reduces effect
Patient and Pharmaceutical Factors
Drug and vehicle solubility

pH extremes
Regional blood flow variability
Subcutaneous Administration
Advantages
Can be given by the owner (small patients)
Vasoconstrictor can be added to prolong effect at site of interest
Disadvantages
Variability
Process
Much like intramuscular (though the architecture of the tissue is much different)
Patient and Pharmaceutical Factors
More autonomic control over blood flow (than muscle)
dehydration, cold, stress, DECREASE blood flow heat INCREASES blood flow< /p>
Topical
Advantages
IF FOR systemic therapy - easy painless application (e.g., mass medication of cattle)
IF FOR skin therapy - reduced systemic effects / enhanced skin effects
Disadvantages
Patients groom themselves (topically applied, orally absorbed)
Toxic skin reactions
Variable blood flow to skin
COMPLEX relationship between drug, vehicle, skin physiology. IF FOR systemic effect DO NOT assume absorption will happen.
Studies indicate everything from "pretty good" to "zero" with the same preparation.
Process
Diffusion through stratified epithelium
"Passage" through adnexal structures
Patient and Pharmaceutical Factors
Lipid solubility and molecule size
Skin hydration and abrasion
Area of application
Ambient and patient temperature
Be suspicious of topical formulations from compounding pharmacies. Some work, some don't. SEE:Hoffman SB, Yoder AR,
Trepanier LA. Bioavailability of transdermal methimazole in a pluronic lecithin organogel (PLO) in healthy cats. J Vet Pharmacol Ther.
2002 Jun;25(3):189-93.
Vehicle effects
"like" vehicles retain drug on skin surface
(e.g., aqueous drug in aqueous vehicle, lipid drug in lipid vehicle)
drugs in "unlike" vehicles leave the vehicle to move to skin
(e.g, aqueous drug in lipid suspension, lipid drug in aqueous suspension)
Intraperitoneal
Advantages
Larger absorptive surface area than IM / Subcutaneous
Disadvantages
Drugs or vehicles may cause peritonitis
Damage to organs by needles
Injection into organs
Process
Similar to subcutaneous
Greater blood flow
Less flow regulation
Patient and Pharmaceutical Factors
Generally restricted to laboratory animals
Intrathecal
Advantages

Direct delivery to site of action

Disadvantages
Difficult dose calculation
CSF volume is not proportional to body weight
Toxicity likely, and toxicity may be unusual
Introduce infection into a VERY bad location.
Process
Absorption is usually by diffusion and very slow
Intra-articular
Advantages
Direct delivery to site of action. High concentrations can be produced in the joint.
Disadvantages
It may be difficult to hit the joint space depending on the species (size of joint space).
Difficult dose calculation
Joint space volume depends on disease
Recommended doses tend to be larger than necessary.
Irritation of joint surfaces/capsule (chemical effects, biochemical/physiologic effects.)
Introduce infection. (PSGAG - Adequan - injections now generally get "antimicrobial chaser".)
Joint "flushes" don't count.
Process
Absorption from the site to systemic circulation is variable but often quite fast. Systemic concentrations of the drug may be produced.
Effects in joint may not persist. (Drug and dose form dependent)
"Regional" (Intra-arterial, Interosseous, Intravenous with tournequet)
Advantages
High concentrations of drug delivered to tissues increases desired effect (e.g., antibacterial action) for similar systemic exposure
(compared to traditional administration modalities). These techniques appear to produce extremely high concentrations "pointed at"
(this is not really targeting) the tissue of interest. Used primarily for anti-tumor therapy and infectious disease therapy when blood
supply is questionable. Evidence documenting clinical outcomes is scarce.
Disadvantages
Dose calculation is best guess. Dosing is still really systemic. Approach to tourniquet use varies.
Arteries are logical injection sites, difficult to canulate. Intra-arterial lines difficult to insert/maintain. Veins are flowing the wrong way,
tournequets required. Injection into bone medullary cavities?
Limited number of efficacy studies (especially in animals)
Process
Produce AND SUSTAIN high blood-to-tissue gradient to increase tissue concentrations of drug. Requires sustained infusion or
application of tourniquet following bolus dosing.
Varies FROM: systemic dose given by regional vein after tournequet application. Retain tournequet for extended time period (1/2 hour?
more?) TO: intraarterial injection of supplemental dose calculated on the size of the region served by the artery TO: supplemental dose
or full systemic dose in bone marrow cavity
Patient and Pharmaceutical Factors
Rather expensive procedure; GO GET TRAINING from somebody who uses this routinely.
Per rectum
Advantages
Access to GI abosption in unconscious or vomiting patients
Drug can be recovered before absorption is complete
Disadvantages
Animals may not willingly retain the drug
Process
As for oral without mechanical preparation by stomach
Physical and Physiologic "spaces" (Figure)
Vascular space = plasma / plasma water + RBCs (lots) +WBCs (a few)

Don't forget the intracellular space inside the vascular space...

Size
~ 7% of body weight
Equilibria
between water and various plasma / serum proteins
between ionized and unionized drug
between plasma and cells
Distribution in 10 to 30 minutes (mixing)
Tissue space (intracellular fluid / cells)
Size
The rest (excepting structural protein, bone matrix)
Equilibria
between water and various tissue proteins
between ionized and unionized drug
between water and cells
Distribution in minutes to hours/days
Extracellular Space - exists in both vascular and tissue spaces
Size
~ 15 - 20% of body weight
includes extracellular fluid in bloodstream (plasma)
Equilibria
between water and proteins
between ionized and unionized drug
Distribution in 30 minutes to 1.5 hours
Intracellular space - exists in both vascular and tissue spaces
Size
~ 35 - 45% of body weight
Equilibria
between ionized and unionized drug
intracellular pH different (lower) than extracellular
Distribution in 30 minutes to 12+ hours
Reserved spaces
Special barriers between plasma and tissue fluid
CSF
aqueous humor
prostatic fluid
Distribution in minutes to never
Most dosing situations -> irrelevant
Important if the disease is in the reserved space.
Movement between spaces
Vascular space (extracellular) to tissue (extracellular) space
Transcytotic
Endothelial junctions with inflammation
Diffusion through endothelial cell membranes
Carried in cells or on proteins in very special circumstances
Extracellular space (of tissue) to intracellular space (of tissue)
Diffusion through lipid bilayer of cells
Active uptake by cells (few drugs, few cell types)
Vascular extracellular space to vascular intracellular space (drugs can move into RBCs and WBCs)
Diffusion through lipid bilayer of cells
WBCs may actively acquire certain drugs
Diffusion limited distribution
Diffusion is usually slow (relative to mixing and distribution within vascular system)
Tissue distribution of the drug controlled by the ability of the drug to diffuse into the tissue
Blood flow limited distribution
Diffusion can be VERY rapid
Tissue distribution of the drug controlled by the rate of drug delivery to the tissue (total mg/minute) which is controlled by blood flow /
gram of tissue
Brain and liver concentration rise faster than muscle or fat

Enterohepatic circulation
How does it work?
Drug or it's Phase II conjugate excreted in bile
Drug reabsorbed or Conjugate cleaved by bacteria and drug reabsorbed
What does it mean?
Volume of distribution of the drug is higher
Elimination rate for drug is lower in spite of efficient hepatic metabolism / secretion
Why do you care?
Interrupt to improve drug elimination
Insecticide poisonings, phenobarbital overdoses, etc.
Figure 1. Enterohepatic circulation

Mammary excretion
How does it work?
Non-ionic Diffusion (lipid solubility and size dependence)
Inflammation reduces barriers to penetration (masititis)
Ion trapping
normal milk pH = 6.6 (slightly acidic versus blood).
Mastitic milk pH is slightly higher
Why do you care?
May affect treatment of some bacterial infections of the mammary gland
Nursing animals may be exposed to toxic concentrations of drug in the milk.
Salivary excretion
How does it work?
Non-ionic diffusion into salivary secretions
Drug in saliva passes into GI tract
What does it mean?
Ruminants
Recycle certain drugs like enteroheptic circulation (prolonged elimination)
Trap certain drugs in the rumen pH dependent (enhanced elimination)
Non-ruminants
Little effect on elimination possible
Drug Elimination
Biotransformation
Conversion of a drug entity to a metabolite
Usually inactivates the drug
generally reduces drug activity
MAY activate the drug
Major route of elimination for lipid soluble and protein bound drugs (because other routes are not efficient).

Chemical mechanisms
Oxidation, hydroxylation, hydrolysis, reduction, conjugation (acetylation, glucuronidation, sulfation, etc.)
Rates, clearance controlled by...
Metabolic activity for a specific drug
Blood flow to the organ
Health of the organ and health of the circulatory system
Organs involved
Liver (most important for most drugs)
Lungs (especially for autocoids)
Kidneys
Figure 2. Hepatic metablism, note that the ratio of drug entering the liver to
that leaving the liver remains constant, despite the change in
concentration. NOTE: This principle applies to all routes of elimination.

Biliary excretion
Active secretion
Drugs with molecular weights > 300
mostly conjugates of original drug
Passive secretion
Drugs with molecular weights < 300
biliary concentrations similar to plasma water
Renal excretion
Overall renal elimination can be a combination of three processes:
(Glomerular filtration + tubular secretion) - passive reabsorption = renal elimination
Figure 3. Efferent blood supply of the
nephron enters/leaves the glomerular
tuft, then bathes the tubule/collecting
duct before leaving the kidney. A
PORTION of the plasma water is
diverted into the nephron as it passes.

Nephron image courtesy of Blausen

Medical
Nephron Animation
Glomerular filtration (all unbound drug - in plasma water - ends up in in GF)
passive elimination of drug dissolved in plasma water
ionized and unionized
NOT protein bound drug
Tubular secretion (only a few drugs, even protein bound)
energy dependent excretion by proximal kidney tubule
organic acid and organic base pumps
includes protein bound drugs
competition between acids or between bases
Passive reabsorption (only a few drugs, small lipid soluble)
drug movement from renal tubule back to blood stream
lipid soluble drugs
unionized drug molecules
normal concentrating ability
Passive reabsorption can be reduced by disease (accidental) or by therapy (intentional)
increases elimination rate of the drug
DOES NOT WORK if reabsorption is not an important part of normal elimination

How?
high urine production
reduced tubular concentations of EVERYTHING
reduced contact time with epithelium
alter urine pH
ionized drug cannot be reabosrbed
acids trapped in alkaline urine
bases trapped in acid urine
renal elimination of aspirin can go from 2% to 30% of total elimination
Pharmacokinetic Modeling
Volume of Distribution
The volume of fluid that "appears" to contain the amount of drug in the body (based on the plasma concentration).
Partially determines the relationship between dose and plasma concentration
Defines the volume of fluid that must be processed by organs of elimination
Roughly describes "tissue penetration"
May not equal an actual physiologic space.
Equation(s)

One compartment plot (Figure)

Cp0 is the plasma concentration at time = 0 (IV adminsitration ONLY)
Units
Liters or milliliters describing whole animal
Liters/kg or milliliters/kg
Table 2. Representative (theoretical) volumes of distribution.
Scenario
Physiologic Space
Drug distributed only to plasma
Blood volume = 7% of body weight
water
Plasma water = 55% of blood
volume
Drug distributed evenly in
Extracellular fluid volume = 25% of
extracellular fluid only
body weight
Drug distributed evenly extracellular Intracellular fluid volume = 40% of
+ intracellular fluid only
body weight

Volume of distribution
0.0385 liters/kg

0.25 liters/kg
0.65 liters/kg

Drug distributed evenly in

Extracellular fluid volume + 3x
extracellular fluid and concentrated intracellular fluid volume
3x in intracellular fluid

1.45 liters/kg

Figure 4. 100 mg of a drug is added to a 10 liter fish tank

filled with water. A sample is taken after equillibrium is
reached. The chemical properties of the drug control its
"attraction" to the glass.

Figure 5. 100 mg of a drug (different drug than figure 4

above) is added to a 10 liter fish tank filled with water. A
sample is taken after equillibrium is reached. The
chemical properties of the drug control its "attraction" to
the glass.

Clearance
(e.g., Hepatic Clearance)
The volume of plasma water cleared of the drug during a specified time period.
Equation(s):
Organ clearance is calculated by determining the flow (Q) and the efficiency of extraction
Total body clearance (Clt) is the sum of all organ clearances

Experimentally we determine clearance by determining the Volume of distribution and the elimination rate constant (Figures 5-7)
Units:
Volume / unit time (l/hr, l/min, ml/hr etc) describing whole animal
Volume / kilogram / unit time (l/kg/hr, ml/kg/min etc.)
Rate constant of elimination
The fraction of the volume of distribution cleared per unit time (or)
The slope of the natural log plot of the drug concentration versus time profile (Figure)
Equation(s)
"Produced" by the relationship between the volume of distribution and the total clearance:

Determined from the slope of the "elimination portion" of the drug concentration vs time profile (curve).

Units
-1
-1
/hr, /min, hr , min
Figure 5. Determining the "pharmacokinetics" of the fish tank.

Figure 6. Arithmetic plot of dye concentrations versus time.

(lz = 0.0693 hrs-1, Vz =1 l/kg, Dose = 100 mg, T1/2 = 10 hrs, Clt =
0.0693 l/kg/hr).

Multiply the concentration by the Vz (Cp X Vz) to determine the amount in the body at each time point. Subtract the amount in the body
at one time point from the amount in the body at the PREVIOUS time point to determine the amount eliminated during the time
"interval."
Figure 7. Semi-Logarithmic plot of dye concentrations versus
time.
(lz = 0.0693 hrs-1, Vz =1 l/kg, Dose = 100 mg, T1/2 = 10 hrs,
Clt = 0.0693 l/kg/hr).

Although the amount eliminated from the body is less and less for each time interval, the FRACTION of the amount eliminated during
each interval is constant. This is demonstrated by the semi-log plot.
Elimination half-life
The time for elimination of one half of the total amount in the body.
Units
Hours or minutes
Application(s)
Tissue Residues
At 5 x T1/2 97% has been eliminated
Make sure you use the longest half-life (gentamicin example)
Metabolites may be more important than the drug
Extremely slow absorption from injection site may be the primary cause of residues.
Approach to steady state
Steady state exists when defined plasma concentrations (peak, average, trough) are identical following each administered dose during
chronic therapy.
At 5 x T1/2 concentrations are 97% of steady state values no matter what the dose and interval.
Digoxin, maximum effects of digoxin may appear as late as 8 days after therapy is initiated
The relationship between dose interval and half-life determines the need for a loading dose.
A loading dose is an initial dose of drug given to shorten the time to reach the steady-state concentrations.

Figure 8. Approach to steady state. The figure represents a hypothetical situation in that the dose interval equals the drug
half-life.

Absorption rate constant

The absorption rate constant describes the rate of drug movement (oral, IM, SC, etc.) from the dose to the circulatory system.
Units
-1
-1
/hr, /min, hr , min
Application
In combination with other factors, ka determines the time required to reach the peak concentration (Cmax) following a dose of drug and
the peak drug concentration.
Fraction of dose absorbed (F)
When a drug is administered by any route OTHER than IV, it is rare that the entire dose is absorbed
Oral
Destroyed in GI tract, passes out in feces before it is absorbed, binds to ingesta, etc.
IM
Hydrolysis of drug in tissue, drug binding to injection site, abcess formation, etc.
Units
Either percentage of dose or fraction of the dose (59% = 0.59)
Application
The fraction of the dose absorbed determines a drug's bioavailability (how much gets into the blood stream). Bioavailability is a
common measure used to compare two different drug formulations (tablets vs. elixir) or to compare products sold by two different
manufacturers (trade name drugs vs. generics).
Bioequivalence
Two drug products are bioequivalent if the nature and extent of therapeutic and toxic effects are equal following administration
Although similar and related, equal bioavailability (F) does not guarantee bioequivalence.
Figure 9. Two dose forms of the same drug are depicted.
These two dose forms have equal bioavailability and they are
bioequivalent.

Figure 10. Two dose forms of the same drug are depicted.
These two dose forms have equal bioavailability but they
are NOT bioequivalent.

Pharmacokinetic Models
Physiologic models
Attempt to describe the actual events which control drug absorption, distribution, and elimination
Derived from measurements of drug concentrations in specific fluids (bile, portal and hepatic veins, tissue fluids, urine, etc.).
Deal with an organ, a tissue or an organ system
Combined to describe functions and processes
Mathematic models
Attempt to accurately predict the time course of drug concentrations in one (usually blood or plasma) or two (urine as well) body
fluids. Predictions are generally made for tissues which can be sampled from intact patients.
"Pharmacokinetics" on package inserts represent these kinds of model.
Modeling begins with a single dose experiment:
A dose of drug is administered, samples are taken at timed intervals after dosing, samples are analyzed for drug concentrations.
Drug concentrations are then plotted and analyzed mathematically to determine the drug's clearance, the rate constant of elimination,
half-life, and the volume of distribution of the drug.
Body compartments
DO NOT ASSUME THAT ANY REAL PHYSIOLOGIC BODY SPACE IS BEING DESCRIBED BY MATHEMATICAL MODELS.
Central Compartment
Blood volume
Organs of elimination

Peripheral compartment
Muscle
Subcutis
Lung tissue
Deep compartments
Fat (poor blood supply, lipid soluble drugs)
Kidneys (aminoglycosides)

THE NUMBER OF COMPARTMENTS IS NOT A PHARMACOLOGICAL PROPERTY OF THE DRUG.

N compartments represents the amount of detail available considering the "experimental conditions".
Number of samples
Sample timing
Obesity, starvation, dehydration, etc.
Difference in rates of distribution into various tissues (2 volumes cannot be separated if individual rate constants are similar).
N compartments may be arbitrarily reduced if the level of detail available is unnecessary.
Most clinical monitoring reduces "truth" to a one compartment open model
Figure 7. Linear and semi-logarithmic plots of Pharmacokinetic models. The two compartment models were generated by INCLUDING
samples at 5, 15, 25 and 30 minutes.

Dose Dependent Behavior

For most drugs (99%), it is logical to assume that the relationship between the dose we give and the concentration(s) that the dose
produces in the body are linear. (We double the dose, the concentrations double, the effects double). The PHARMACOKINETICS of
these drugs are said to be dose-independent.
Occassionally, drug dosing behave differently:

If the pharmacokinetics of ABSORPTION change when we increase the dose (the absorption rate decreases as the dose
increases -- as would be the case for the "ball" of drug described earlier in these notes under "routes of administration"), the
drug is said to exhibit dose-dependent absorption. Doubling the dose produces less than a doubling of tissue
concentrations and effects.
If the pharmacokinetics of ELIMINATION change when we increase the dose (clearance and the elimination rate constant
decrease as the dose increases), the drug is said to exhibit dose-dependent elimination . Doubling the dose
produces MORE than a doubling of tissue concentrations and effects.

Although we have described pharmacokinetics as being "first-order" throughout these notes, the real absorption and elimination
behavior of drugs obeys Michaelis-Menton kinetics. That is, first-order at "low" doses (most drugs at therapeutic doses), zero-order at
"high" doses and mixed-order in between.
Michaelis-Menton Kinetics
Order
Example
First Order (The pharmacokinetics of MOST drugs is first order at therapeutic doses.)
A fraction the dose of drug is absorbed per unit time
A fraction of the amount of drug in the body is eliminated per unit time.
Plots
Arithmetic plots of concentration vs. time will be a curve with a positive deflection (slope becomes less negative with time).
A semi-log plot will be a straight line or series of straight lines (multiple compartments).
As long as elimination remains first order:
There will be a half-life of elimination
Increasing or decreasing the dose will produce a proportional increase or decrease in the plasma concentration and in drug effect.
A steady state will be achieved for ANY rate of drug administration.
Zero order (special dose forms, high concentrations of some drugs)
A constant amount of drug is absorbed per unit time (or)
A constant amount of drug is eliminated per unit time
Plots
Arithmetic plots of concentration vs. time will fall on a straight line
Semi-log plots have a negative deflection (slope becomes more negative with time)
If elimination is zero order:
Drug may accumulate infinitely
There is no "half-life"
Abbreviation Term
Units
Definition
Clt

Clearance, Total

l/hr/kg

The sum of all individual organ clearances. Usually

determined by plasma sampling.

Clr

Clearance, Renal

l/hr/kg

The clearance "performed" by the kidney.

Clh

Clearance, Hepatic

l/hr/kg

The clearance "performed" by the liver.

Cmax

Peak plasma
concentration

mg/ml (or)
mg/liter

Highest plasma concentration achieved following a

single non-intravenous dose of a drug.

Cp

Plasma concentration

mg/ml (or)
mg/liter

Plasma concentration, may be folled by a subscript for

time (Cpt see Cp0 below)

Cp0

Plasma concentration at mg/ml (or)

time zero
mg/liter

The plasma concentration at zero time. Determined

by extrapolating the plasma concentration versus time
"curve" back to the Y (concentration) axis.

Fraction of dose
absorbed

None or %

Portion of a non-intravenous dose of drug that

reaches the systemic circulation.

T1/2

Half life of elimination

hrs (or)
minutes

Time required to eliminate 50% of any amount of drug

from the body.

Tmax

Time of the peak plasma hrs (or)

concentration
minutes

The time that the Cmax (above) is achieved following

a single non-intravenous dose of a drug.

Vz

Volume of distribution

The volume calculated using the intercept of the "z"

portion of a curve and the Y axis.

L/kg

Equation

Units

Application

hr , /hr, min , /min

Calculates slope of a line for a natural log plot of plasma concentration versus
time data.

liters, milliliters if dose is in mg;

liters/kg or milliliters/kg if dose
is in mg/kg

Extrapolate plasma concentration versus time "curve" back to the Y

(concentration) axis. The intercept is Cp0. The dose is the intravenous bolus
dose.

mg or mg/kg

You can calculate the amount of drug in the body at any time =t if you know
the volume of distribution and the plasma concentration at that time Cpt.

L/hr/kg or l/hr

Clearance is calculated following a pharmacokinetic experiment as the

product of volume of distribution and elimination rate constant.

-1

-1

-1

-1

hr , /hr, min , /min

In the animal the elimination rate constant is the RESULT of the total body
clearance of the drug and the volume of distribution into which the drug is
distributed. (lz is not usually calculated this way).
Five times the elimination half-life determines:

5 x T1/2

hrs, min.

97% of the time to reach steady state

The time to eliminate 97% of the drug