Drug Absorption & Bioavailability

Drug absorption

The movement of a drug from its site of administration into the bloodstream (central compartment)

Bioavailability

The fractional extent to which an administered dose of UNCHANGED drug reaches its site of action or biological fluid

Passive and facilitated diffusion, active transport, endocytosis or exocytosis

List the four mechanisms of absorption, for drugs by the GI tract.

Concentration gradient

The driving force for passive absorption of a drug is the _______ across a membrane separating two body compartments.

The drug moves from a region of high to low concentration.

Passive diffusion

Does not involve a carrier, is not saturable, and shows a low structural specificity.

Passive diffusion

The vast majority of drugs gain access to the body by this mechanism

Aqueous channels or pores

Water-soluble drugs penetrate the cell membrane through _________, whereas lipid-soluble drugs readily move across most biological membranes.

Facilitated diffusion

Drugs enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules.

Conformational changes

In facilitated diffusion, carrier proteins undergo ______, allowing the passage of drugs/endogenous molecules into the cells, moving from areas of high to low concentration.

Facilitated diffusion

A form of passive transport that does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier.

Active transport

This mode of drug entry involves specific carrier proteins. It is energy dependent and driven by the hydrolysis of ATP.

Active transport

This form of transport is capable of moving drugs against a concentration gradient, from a region of low to high concentration.

Selective, competitively inhibited

The process can be saturated. Active transport systems are _____ and may be ___________ by other cotransported substances.

Endocytosis & exocytosis

These types of drug delivery systems transport drugs of exceptionally large size across the cell membrane. Requires energy and it is saturable.

Endocytosis

Involves engulfment of a drug molecule by the cell membrane & transport into the cell by pinching off the drug-filled vesicle.

Exocytosis

Is the reverse of endocytosis and is used by cells to secrete many substances by a similar vesicle formation process.

Factors influencing absorption

Route of administration, internal environment, chemical characteristics, pH, blood flow to the absorption site, total surface area available for absorption, contact time at the absorption surface

Absorption

Transfer of a drug from site of administration to the bloodstream (via one of several mechanisms).

Rate & efficiency depends on the route of administration (which correlates to bioavailability; ex. IV = 100% BA)

Required to liberate the drug

For solid dosage forms, dissolution of the tablet or capsule is ___________.

• Rate of dissolution is the limiting factor

• After dissolution, the smaller the particle size, the more efficient it is absorbed

• Liquid formulations absorb more quickly

Is there a lack of absorption from the gut? Is p-glycoprotein present (pumps drug out)?

The rate & efficiency of drug absorption depends on… (environment)

P-glycoprotein

A multidrug transmembrane transporter protein responsible for transporting various molecules, including drugs, across all cell membranes.

Transporting drugs into bile for elimination

What is the function of p-glycoprotein in the liver?

Pumping drugs into urine for excretion

What is the function of p-glycoprotein in the kidneys?

Transporting drugs back into maternal blood, reducing fetal exposure to drugs

What is the function of p-glycoptoein in the placenta?

Transporting drugs into the intestinal lumen and reducing drug absorption into the blood.

What is the function of p-glycoprotein in the intestines?

Pumps drugs back into blood, limiting drug access to the brain.

What is the function of p-glycoprotein in the brain?

Reduces

In areas of high expression, p-glycoprotein ______ drug absorption. In addition to transporting many drugs out of cells, it is also associated with multidrug resistance.

Too hydrophilic, cannot cross lipid membrane. Too lipophilic, not soluble enough to cross lipid membrane to water layer.

The rate & efficiency of drug absorption depends on… (chemical characteristics)

faster

More lipid soluble and less water soluble drugs are absorbed…

Lipid soluble, uncharged, unionized

This type of drug will cross cell membranes rapidly.

Weak acids or weak bases

Most drugs are either…

Uncharged (ex. protonated H-Acid, deprotonated Base)

Drug passes through membranes more readily if it is…

Relative concentrations of the charged & uncharged forms

The effective concentration of the permeable form of each drug at its absorption site is determined by the…

Ionization constant, pKa

The ratio between the two forms (protonated/deprotonated) is determined by the pH at the site of the absorption.

It is also determined by the strength of the weak acid or base, which is represented by…

Lower

The _____ the pKa of a drug, the more acidic it is.

Higher

The _____ the pKa of the drug, the more basic it is.

HA & BH+

When pH is less than pKa, the protonated forms ___ & ____ predominate.

A- & B

When pH is greater than pKa, the deprotonated forms ____ & ____ predominate.

pH = pKa

When ______, [HA] = [A-] and [BH+] = [B]

protonated

At low pHs (acidic), molecules accept an H+, or are…

deprotonated

At high pHs (basic), molecules lose an H+, or are…

pH = pKa

When ______, the weak acid or base is 50% ionized.

pH = aka + log [unprotonated]/[protonated]

(ex. log [A-]/[HA]] & log [B]/[BH+]

Write out the HH equation.

Intesine

Because blood flow to this organ is much greater than flow to the stomach and has a large surface area, absorption from the ______ is favored over the stomach.

Not well absorbed

If a drug moves through the GI tract very quickly, as with severe diarrhea, it is…

Delays the rate of absorption

Anything that delays drug transport from the stomach to the intestine also…

Increases

Parasympathetic input _____ the rate of gastric emptying, whereas sympathetic input delays gastric emptying.

Dilutes

The presence of food in the stomach both ____ the drug & slows gastric emptying.

Bioavailability

Fraction of administered or unchanged drug that reaches the systemic circulation. Affected by route of administration, and chemical & physical properties.

BA = total drug non-IV / total drug IV *100

Calculation for all routes of administration except IV, IM, subcutaneous, and intradermal.

Bioavailability

Determined by comparing plasma levels of a drug after a particular route of administration with plasma drug levels achieved by IV injection.

When the drug is given orally, only part of the administered dose appears in the plasma.

Factors that influence bioavailability

Extent of absorption, rate of absorption, first-pass hepatic metabolism, solubility of the drug, chemical instability, nature of the drug formulation

Extent of absorption

• Fraction of drug absorbed across the gut wall

• Determined in part by physicochemical properties

• Size, ionization, metabolism in gut wall, transport

First pass hepatic metabolism

By the intestine or liver, limits the efficacy of many drugs when taken orally.

Drugs that exhibit high levels of this feature should be given in sufficient quantities to ensure that enough of the active drug reaches the target concentration.

F = f*(1-ER)

(F: systemic bioavailability, f: fraction absorbed, ER: extraction ratio)

Write out the equation for systemic bioavailability of a drug (F)

ER = CL(liver)/Q

(CL: clearance, Q: hepatic blood flow)

Effect of first-pass hepatic elimination on bioavailability is expressed as the extraction ratio, ER. Write the equation.

Rate and extent of absorption

Determined by the site of administration and the drug formulation. Affects clinical effectiveness of a drug.

Zero order

When the rate of absorption is independent of the amount of drug remaining in the gut

First order

When the drug is dissolved in the GI fluids, the rate is proportional to the GI fluid concentration

Very hydrophilic drugs

These types of drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes.

Very hydrophobic

Drugs that are _______ are also poorly absorbed, as they are insoluble in aqueous body fluids and cannot gain access to cells.

Largely hydrophobic & have some aqueous solubility.

For a drug to be readily absorbed….

This is one reason why many drugs are either weak acids or weak bases.

Penicillin G

This drug is unstable in the pH of gastric contents

Insulin

This drug is destroyed in the GI tract by degrative enzymes

Unrelated

Drug absorption may be altered by factors _____ to the chemistry of the drug.

• Particle size, salt form, crystal polymorphism, enteric coatings, excipients such as binders & dispersing agents

Bioequivalence

FDA definition; When two products are equal in the rate and extent to which the active pharmaceutical ingredient becomes available at the site(s) of drug action.

Pharmaceutical equivalent

FDA definition: Drug products in identical dosage forms & route(s) of administration that contain identical amounts of the identical active drug ingredient.

Therapeutic equivalence

FDA definition: Approved drug products that are pharmaceutical equivalents for which bioequivalence has been demonstrated, and they can be expected to have the same clinical effect & safety profile when administered to patients under the conditions specified in the labeling.