Pharmacokinetics (Drug Disposition)
Drug Absorption, Distribution and Elimination

General Rules

Get a mental picture of what's going on "inside". (Think about anatomy and histology in terms of "how things work.")

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"

Understand Equillibrium:

Drug effects are USUALLY proportional (though not always linear) to drug concentration at the site of action.

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.

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.

Pharmacokinetics are the consequence of physiologic processes (that may or may not be altered by disease).

"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?

Routes of Administration (Drug Absorption)

General Principles

Drugs dissolve in body fluid (water).

Drugs enter the circulatory system as fluid enters the circulatory system.

Drugs must enter the circulatory system before they can be distributed to sights of action.

(Drugs for enteric 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.

Patient and Pharmaceutical Factors

Pill compression, coatings, suspending agents, etc.

GI transit time (too slow or too fast), inflammation, malabsorption syndromes

Regional differences

Stomach

mechanical preparation

"flat" absorptive surface

 pH extreme

Rumenoreticulum

stratified squamous epithelium

pH varies with diet

metabolism by bacterial flora

significant volume of fluid compared to body water

Small Intestine

large absorptive surface

specialized absorptive functions

relatively neutral pH

Colon/Rectum

accessible

large absorptive surface

Intramuscular Administration

Advantages

More consistent absorption than oral or sub-cutaneous (below)

Depot or sustained effect possible (procaine penicillin G, methylprednisolone acetate, desoxycorticosterone pivalate)

Administration to unconscious, vomiting or fractious patients

Certainty of administration

Disadvantages

More difficult for owners (small patients)

Pain

Muscle Damage

Dose cannot be recovered.

Process

  1. Drug in suspension dissolves in tissue fluid (drug in solution only has to MIX with the tissue fluid).
  2. Drug in tissue fluid solution diffuses into capillaries
  3. Drug (in solution) in capillaries is carried to circulatory system.
ANY of these processes can be "rate limiting" for absorption.

Bolus injection roughly spherical

water soluble vehicle 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. 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, heat, cold, stress

Topical

Advantages

IF systemic therapy - easy painless application (e.g., mass medication of cattle)

IF 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

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. 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)

Intra-arterial

Advantages

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.

Disadvantages

Dose calculation is best guess.

Intra-arterial lines difficult to insert/maintain.

Dosing is still really systemic.

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.

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

Drug Distribution

Physiologic "spaces" (Figure)

Vascular space (plasma / plasma water + RBC's)

There is also "tissue 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)

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

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

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?

Elimination rate for drug is lower in spite of efficient hepatic metabolism / secretion

Volume of distribution of the drug is higher

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.)

Efficiency (rate)

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

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: Nephron

Nephron Animation

Glomerular filtration

passive elimination of drug dissolved in plasma water

ionized and unionized

NOT protein bound drug

Tubular secretion

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

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 - See Figure 1).

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 (See Figure 2).

Equation(s)

One compartment plot (Figure 6)

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.

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 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 7)

One compartment plot (Figure 7)

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

/hr, /min, hr-1, min-1

Figure 6: Determining the "pharmacokinetics" of the fish tank.

Figure 7: 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 X the 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 8: 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 itital dose of drug given to shorten the time to reach the steady-state concentrations.

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

/hr, /min, hr-1, min-1

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.

Figure 9.  Approach to steady state.  The figure represents a hypothetical situation in that the dose interval equals the drug half-life.

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.

Table 3: Two dose forms of the same drug are depicted. These two dose forms have equal bioavailability and they are bioequivalent.

Table 4: 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 10: 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:

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 time zero

mg/ml (or) mg/liter

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

F

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 concentration

hrs (or) minutes

The time that the Cmax (above) is achieved following a single non-intravenous dose of a drug. 

Vz

Volume of distribution

L/kg

The volume calculated using the intercept of the "z" portion of a curve and the Y axis.

Equation

Units

Application

hr-1, /hr, min-1, /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.

hr-1, /hr, min-1, /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).

5 x T1/2

hrs, min.

Five times the elimination half-life determines:

        97% of the time to reach steady state

        The time to eliminate 97% of the drug