Pharmacokinetics: Drug absorption, Distribution, and Elimination Flashcards
Involves absorption of the drug from aqueous solution in the stomach or intestinal lumen across GI epithelial membranes into the plasma
The oral route (enteric drug absorption)
What are the two types of drug absorption across GI membranes?
Active transport and Passive transport
Drugs bind to a protein carrier in the membrane with a high degree of structural specificity in
Active Transport
Transport system is commonly linked to ATP consumption and can thus transport against a concentration gradient
Active Transport
The active transport system is readily
-Limits the amount of drug that can be transported
Saturated
More common than active transport, since the system is less selective with regard to what drugs can be transported
Passive transport
The passive transport system is not readily saturatable because it does not depend on a
Protein carrier
In passive transport, drugs will only move
Down a concentration gradient
“Water loving” drugs that form hydrogen bonds with aqueous solvents.
❖ Usually possess a net charge that makes it difficult to pass through a lipid membrane
Hydrophilic Drugs
The only hydrophilic drugs that can pass through protein pores and be passively transported across biological membranes are those that are
Small (MW less than 100)
Have no net charge at physiological pH and can therefore pass through biological membranes more easily than hydrophilic drugs
Hydrophobic (Lipophilic) Drugs
Best predictor of drug entry into the body
Lipid-To-Water Partition Coefficient (P)
Will pass more readily through the GI epithelial membranes
Drug with higher P value
Only uncharged drugs can move passively across
-Why the distinction between weak acids and bases is so important
GI membranes
The distribution of unprotonated to protonated drug can be determined from the
pKa and ambient pH
A very important predictor of drug absorption when we know the pH at the site of absorption
pKa
At equilibrium, the total drug concentration (uncharged + charged) will be higher in the compartment with the greater degree of
pH-dependent ionization
Are not absorbed into the plasma from the stomach, but instead must wait until they enter the intestine where the pH is elevated
Weak Bases
What is the pH of the intestines?
5.3-5.4
The more blood flow at a site, the more efficiently drug absorption occurs at that
Site
Present a 500-times greater surface area for absorption than that of the stomach
Intestinal Vili
As a result of this large surface area and a high rate of blood flow, is considered to be the most efficient area of drug absorption
Intestine
Defined as the fraction (often given as a %) of orally administered drug that gains access to the systemic circulation in a chemically unaltered form
Oral Bioavailability (%F)
What are 4 factors that decrease oral bioavailability?
First-pass hepatic transformation, hydrophilicity, metabolic and pH instability, and Physical properties of the drug preparation
When a drug is absorbed along the intestine, the portal circulation brings it to the liver before it reaches the systemic circulation. Many drugs are chemically altered (i.e., metabolized) in this hepatic pass, thereby inactivating a significant fraction of the drug
First-Pass hepatic metabolism
Most important factor unrelated to drug formulation itself
First-pass metabolism
If a drug is too hydrophilic, it will never gain access to the body and will thus have a low
Bioavailability
When two drug preparations differ to the point that their bioavailabilities also differ, they are said to be
Bioinequivalent
Most common in hydrophobic drugs that are poorly water soluble (e.g., steroids)
Bioinequivalence
Arises when the bioinequivalence of two drug preparations leads to a difference in therapeutic outcome
Therapeutic inequivalence
The most important determinant of whether bioinequivalence leads to therapeutic inequivalence is the
Therapeutic index
One major reason for use of the intravenous (IV) route is increased
Speed of action (Ex: anti-arrythmics)
Trapped in the plasma because their large size precludes entry into other water compartments, like the IF
High molecular weight drugs
Smaller size permits entry into the IF, but the drugs cannot passively cross cell membranes to enter the ICF
Hydrophilic Low Molecular Weight (LMW) Drugs
Can enter all three compartments (plasma, IF, and ICF) and thus swim in the biggest pool
Hydrophobic LMW Drugs
Distribute only in the plasma because the drug-protein complexes cannot enter the IF or ICF
Drugs that bind to plasma proteins
Most drugs that bind to plasma proteins bind to
Albumin
Drug molecules that bind to albumin are inert, since only the free form of the drug is
Pharmacologically active
Bind strongly to albumin
Anionic Hydrophobic Drugs
Do not bind strongly to albumin
Hydrophilic drugs
Premised on the fact that:
- The body is a single compartment into which drug distributes uniformly.
- The drug concentration in that compartment is the same as the plasma concentration
Vd
A dilution space normalized to body size and also indicative of a drugs tendency to distribute beyond the vascular space into tissues
Vd
If the Vd is greater than 42L (total body water volume) than the drug must be
Tissue bound
Body lipid content can impact distribution (e.g., a lipophilic drug will have a higher Vd in an
Obese person
Drugs are eliminated from the body in which two primary ways?
- ) Drug metabolism
2. ) Renal elimination
For renal elimination, what are the three partitioning events?
- ) Glomerular filtration
- ) Tubular secretion
- ) Tubular reabsorption
How much filtrate is there from each 600 mL/min of renal plasma flow in a healthy adult?
125 mL/min (GFR = 125 mL/min)
A non-saturatable process
Glomerular filtration
In glomerular filtration, only free (non-protein-bound) drug can be filtered, with drug pKa and lipophilicity having
No effect
Drug moves from the blood to the lumen of the proximal nephron tubule by an active transport mechanism in
Tubular secretion
Tubular secretion has two separate carrier-mediated systems for
Acids and bases
Characterized by saturable protein carriers with little specificity for drug structure
Tubular secretion
What kinds of drugs can be secreted by tubular secretion?
Drugs that were free or protein-bound
By the time the drug reaches the lumen of the distal nephron tubule, its concentration is
Very high
The drug then diffuses passively back out of the nephron lumen into the blood. This is called
Tubular reabsorption
The only drugs that can undergo tubular reabsorption are
Free and unionized drugs
In other words, pH partitioning occurs during
Tubular reabsorption
Alkalinizes the urine and increases anionic (acidic) clearance
Bicarbonate
Acidifies the urine and increases cationic (basic) clearance
Ammonium Chloride (NH4Cl)
Refers to the volume of some biological fluid (e.g., plasma) from which, over a specified interval of time, all drug present is removed
Clearance
Clearance mechanisms typically follow
First order kinetics
The time it takes for the plasma concentration or the amount of drug in the body to be reduced by one-half (50%)
Half-life (t 1/2)
