08/28/2009 Pk Absorption (Clinical) Kuma

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Intravascular administration

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Intravenous
intraarterial

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Extravascular administration

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oral
sublingual
buccal
IM
SC
rectal
intraocular
topical
transdermal
inhaled
intraperitoneal
intrathecal
intraventriculr

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To enter the general systemic circulation, drug which is administered by any extravascular route must first be ...

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absorbded

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Absorption def.

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Definition = “the process by which unchanged drug proceeds from the site of administration to the site of measurement within the body” (usually blood)
Usually requires crossing one or more membranes
unchanged= parent drug is unaltered, it is not metabolized, or attached to anything
the drug must be active to be considered absorbed

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From a PK standpoint, absorption is defined as

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The rate at which a drug leaves its site of administration
The extent to which this occurs

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By definition, ----------- occurs when a drug is administered intravascularly

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No absorption

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Rate and extent are often ________ of each other

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independent

One may be altered while the other is unchanged

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Bioavailability (F)

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Bioavailability (F) = the extent of absorption of intact/unchanged drug from the site of administration into the systemic circulation
Expressed as the percent or fraction of an administered dose which achieves intact absorption
Ranges from 0 (no absorption), to 1.0 or 100% (complete intact absorption)
Complete absorption does not mean 100% bioavailability! (not all of the drug makes it to systemic circulation. It is metabolized along the way
Bioavailability does NOT reflect the rate of absorption
physical act of being absorbed does not equal bioavilability

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Calculation of bioavailability is based on a drug’s

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Area Under the Concentration-vs.-Time Curve (AUC)

Bioavailability is a numerical reflection of the extent of drug absorption

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What is the AUC ?

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The AUC may be based on concentrations in blood, plasma, serum, or any other biological fluid or tissue where drug concentrations are measured

magnitude of drug exposure (ie: how high the concentration, how long is the concentration is maintained

AUC is a reflection of the total magnitude of drug “exposure”
Includes peak concentration of drug after a dose, as well as how concentrations change over time
Expressed in units which incorporate both concentrations and time
Most common unit of measurement is mg•hr/L (rearranged from mg/L/hour)
AUC is directly proportional to a drug’s bioavailability

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AUC =

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Dose x F x S/Clearance

S= salt factor
Clearance is how quickly the drug is removed from the body

If other variables are held constant, a change in drug absorption will proportionately alter the AUC

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AUC is directly proportional to...

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bioavailability

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F%=

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[AUC oral * dose IV/ AUC iv * dose oral] * 100

If the same dose is given:
[AUC oral/AUC iv] * 100

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Absolute vs. relative bioavailbility

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In order to calculate the “absolute” bioavailability of an oral dose of drug, the AUC of an intravascular dose must first be determined
Differences in sizes of the oral and intravenous doses must be accounted for
If you don’t know F compared to an actual intravascular dose, only a “relative” F can be determined
e.g., the F of oral Drug A “relative” to oral Drug B

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Factors Affecting Membrane Passage

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1. Concentration gradients
2. Surface area of the membrane

3. Intrinsic drug permeability
Largely dictated by three factors:

4. Blood Flow

5. Protein binding

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In order for drugs to pass through membranes they must be..

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in solution

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net rate of penetration =

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P * SA * (C side 1-C side 2)

P= permeability
SA= surface area
(C side 1-C side 2) =concentraion difference

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Intrinsic drug permeability (membrane passage)

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Largely dictated by three factors:
Molecular size of the drug
Lipophilicity
Molecular charge (pKa, ionization state)
Un-ionized drugs are more lipophilic and are more rapidly absorbed from any site in the GI tract than are ionized drugs
Weak acids are generally more permeable and more rapidly absorbed at low pH, weak bases at higher pH

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Concentration gradients (membrane absorption)

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The body can be considered a “sink” for drug absorption
Concentrations of drug in the body are always relatively low compared to concentrations at the site of administration

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Surface area of the membrane (membrane absorption)

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Larger membranes allow for more rapid penetration of drugs which are absorbed by passive diffusion

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Blood flow (membrane absorption)

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Higher flow across the membrane facilitates diffusion and penetration of drugs which are otherwise freely permeable across the membrane

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Protein binding (membrane absorption)

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Only drugs not bound to plasma proteins or tissue components are thought to be capable of passively passing through membranes
The higher the unbound fraction of drug, the greater the potential for membrane penetration

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Factors Affecting GI Absorption

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1. Drug formulations
2. gastric emptying time
3. Intestinal transit time
4. Competing reactions within the GI tract
5. Hepatic extraction (“first pass effect”)
6. Alterations in gastrointestinal pH
7. Alterations in gastrointestinal blood flow
8. Gastrointestinal abnormalities or pathological conditions

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Drug formulations
(Gi absorprion)

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Drugs must be in solution in order to cross membranes

Drugs administered as liquids are generally absorbed more rapidly and fully

For solid dosage forms, dissolution rate is a critical factor which determines both rate and extent of absorption

Drug dissolution is influenced by many factors including:
Particle size
Smaller particles = greater surface area = more rapid dissolution
Drug solubility
Higher aqueous solubility = more rapid dissolution in GI tract
pH of the GI tract and pKa of drug in question
Note that pH which is favorable for drug dissolution may not favor permeability

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_________ form goes into solution

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ionized

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_________ form crosses membranes

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unionized

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However, absorption of acids is always actually much faster in the less acidic small intestine than from the stomach. How can this be?

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Permeability (as a function of pH)
An acid with pKa 4.2 will be ~94% un-ionized at gastric pH of 3 compared to ~6% un-ionized at pH of 6, a 16:1 ratio
Surface area
Surface Area of the Stomach ~ 1 m2
Surface Area of the Small Intestine ~ 200 m2
Blood flow
Blood flow to the stomach is estimated to be 0.15 L/min
Blood flow to the intestinal capillaries is estimated to be around 1.0 L/min

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Net rate of penetration for stomach and intestine

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Stomach = permeability (16) x surface area (1) x blood flow (0.15) = 2.4

Intestine = permeability (1) x surface area (200) x blood flow (1) = 200

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Gastric emptying time
(GI absorption)

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Since absorption of drugs is faster and more extensive from the small intestine than from the stomach…
The rate at which drugs are emptied from the stomach into the small intestine becomes a major rate-limiting factor in the rate of drug absorption
Food, especially fats, slows the rate of gastric emptying
Administration of drugs with food thus generally slows the rate of drug absorption
Concurrent administration of drugs which affect the rate of gastric emptying may also influence the rate of drug absorption
Drugs which are unstable at low pH may also have a decreased extent of absorption if the gastric emptying time is prolonged and the drugs are subjected to longer periods of low pH
Enhanced drug degradation occurs

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Intestinal transit time
(GI absorption)

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Increased speed of passage through the small intestine (i.e., decreased transit time) may result in a decreased extent of absorption for drugs which are not freely permeable through intestinal membranes, or for drugs which are poorly soluble

Conversely, the extent of absorption of such drugs may be increased by factors which increase intestinal transit time
Intestinal transit time may be affected by disease states, foods, and concurrent drugs

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Competing reactions within the GI tract
(GI absorption)

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Enzymatic and non-enzymatic reactions may occur after oral administration of drugs and may have important effects on drug absorption
These reactions largely affect the extent of absorption
Incomplete absorption caused by these reactions (or permeability problems) can sometimes be overcome by altering the dosage form or synthesizing more stable derivatives

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Hepatic extraction (“first pass effect”) (GI absorption)

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Metabolism of drug before it passes out of GI tract into systemic circulation

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If a patient is given metoclopramide what happens to GI absorption?

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this is a cholinergis so it increases gastric emptying time and therefore increase GI absorption

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If a patient is given Propantheline what happens to GI absorption?

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This is a anti-cholinergic therefore gastric emptying time is decreased and as a result GI absorption is decreased.

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Alterations in gastrointestinal blood flow
(GI absorption)

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May disrupt concentration gradients required for passive diffusion across membranes
May also affect function of the GI organs themselves

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Factors Affecting Absorption from Extravascular Sites

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Drugs injected into some extravascular sites (e.g. muscle, subcutaneous tissues) are actually administered into the interstitial spaces within tissues
Movement of drug from interstitial spaces into capillary blood is not generally limited by molecular weight of drug (if < 5000) or degree of ionization
Major rate-limiting factor is usually tissue perfusion with blood
Aqueous drugs are generally absorbed more rapidly than lipophilic drugs because they are more soluble in both interstitial fluids and blood
Larger drugs (M.W. > 20,000) are generally unable to cross capillary membranes
Access to bloodstream is usually through lymphatic drainage
Lymph flow is slow, therefore absorption from nonvascular parenteral sites can continue for many hours

Absorption of drugs from other sites (dermal, buccal, etc.) are generally the same as those influencing absorption from the GI tract or following injection into muscle/subcutaneous tissues

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dissolution rate determines

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For solid dosage forms, dissolution rate is a critical factor which determines both rate and extent of absorption

Drug dissolution is influenced by many factors including:
Particle size
Smaller particles = greater surface area = more rapid dissolution
Drug solubility
Higher aqueous solubility = more rapid dissolution in GI tract
pH of the GI tract and pKa of drug in question
Note that pH which is favorable for drug dissolution may not favor permeability