principles of drug absorption

life of a drug

for a drug to exert its biological effect, it must:

• be transported by the body fluids

• traverse the required biological membrane barriers

• escape widespread distribution to unwanted areas

• endure metabolic attack (body’s mechanism to eliminate the drug)

• penetrate in adequate concentration to the sites of action

• interact in a specific fashion, causing an alteration of cellular function

life of a drug (short)

drugs must be ABSORBED first so that,

distribution (to the target tissues - via blood),

metabolism,

and excretion

can take place after the administration of a drug

general principles of drug absorption

body membranes generally classified into:

1. those composed of several layer of cells (ex: skin)

2. those composed of a single layer of cells (ex: intestinal epithelium)

3. those composed of less than one cell in thickness (ex: membrane of a single cell)

drug substance must pass more than one of these membrane types before it reaches its site of action

• most of the time, most of the layers of lipophilic in nature (oil loving)

drug penetration

drugs are thought to penetrate these biologic membranes in two general ways. what are they?

1. passive diffusion

2. through specialized transport mechanisms

what is diffusion?

process of mass transfer of individual molecules of a substance brought about by random molecular motion and associated with a driving force such as a concentration gradient

why is diffusion important?

• drug absorption: through the skin, gastric mucosa, etc.

• drug distribution: throughout the body, into tissues and organs

• drug elimination: various barriers for metabolism and excretion

• drug release: more important in topical semisolids and patches

what is passive diffusion?

used to describe the passage of (drug) molecules through a membrane which behaves inertly (i.e. membrane does not actively participate in the process)

• driven by the concentration gradient existing across the membrane

passive diffusion occurs primarily from a region of _____ drug concentration to a region of ______ drug concentration

high; low

is energy used in passive diffusion?

no, energy (ATP) is not used

• this happens spontaneously

Fick’s first law of diffusion

the rate of diffusion or transport across a membrane (dc/dt) is proportional to the difference in drug concentration on both sides of the membrane

• gastrointestinal absorption of most drugs from solution follow this law

• rate of absorption is dependent on drug concentration

• the magnitude of P (permeability coefficient) depends on

  • the diffusion coefficient of the drug (D)

  • the thickness (h) and the area of the absorbing membrane (S)

  • the partition coefficient of the drug (k)

select all that apply. for a drug mostly absorbed by passive diffusion, rate of absorption is directly proportional to ___________

a) diffusion coefficient

b) thickness of cellular membrane

c) melting point

d) molecular weight

e) surface area

a, e

• diffusion coefficient, D

• surface area, the higher the surface area, the higher the rate of drug absorption

what is part of GI tract?

stomach, intestine, colon, rectum, throat

absorption from GI tract

from high drug concentration in the lumen to lower drug concentration in the blood

passive diffusion depends on the surface area of the membrane available for drug absorption

• due to the presence of villi and microvilli, duodenum is the major site for drug absorption via passive diffusion

permeability and ionization

majority of the drugs are either weak - organic acids or bases

the degree of a drug’s ionization depends both on the pH of the solution and the pKa

Henderson-Hasselbalch Equation

for an acid

solve. Weak acid pKa = 4.0, pH 1.0

ALREADY THIS IS GOING TO BE UNIONIZED

pH = pKa + log ((ionized)/(unionized))

1 = 4 + log ((ionized)/(unionized))

1 - 4 = log ((ionized)/(unionized))

-3 = log ((ionized)/(unionized))

(flip)

3 = log ((unionized)/ionized))

10³ = 1000

MOSTLY UNIONIZED DRUG

Henderson-Hasselbalch Equation

for a base

solve. Weak base pKa = 7.0, pH 2.0

ALREADY THIS IS GOING TO BE IONIZED

pH = pKa + log ((unionized)/ionized))

2 = 7 + log ((unionized)/ionized))

2 - 7 = log ((unionized)/ionized))

-5 = log ((unionized)/ionized))

(flip)

5 = log ((ionized)/(unionized))

10^5 = 100,000

MOSTLY IONIZED DRUG

pH partition hypothesis

• drugs are absorbed from the GI tract by passive diffusion depending on the fraction of undissociated or unionized drug at the pH of the intestine

• the pKa of a drug molecules determines if the drug is going to be in unionized or ionized form in the biological fluids

• cell membranes are more permeable to the unionized forms of drug than to their ionized forms

• drug absorption is therefore a function of the pH of the intestine and pKa of the drug

for a weakly basic drug (pKa = 8.5), what will be the ionization in stomach?

a) higher

b) lower

c) no effect

a

• stomach is acidic

• base (drug) in acid (environment/stomach)= ionized

for a weakly basic drug (pKa = 8.5), absorption from the stomach will typically be ________

a) higher

b) lower

c) neither higher nor lower

b

• base in acid = ionized → permeability dec

for a weakly basic drug (pKa = 8.5), solubility in the stomach will typically be ________

a) higher

b) lower

c) neither higher nor lower

a

• base in acid = ionized → high solubility

which of the following will typically decrease the rate of drug absorption?

a) higher diffusion coefficient

b) higher thickness of the biological membrane

c) higher partition coefficient

d) lower thickness of the membrane

b

• P = DK/h

what are specialized transport mechanisms?

involves membrane components that may be enzymes or some other type of agent capable of forming a complex with the drug (or other agent) at the surface membrane

• the complex moves across the membrane, where the drug is released, with the carrier returning to the original surface

• this type of transfer seems to account for drugs that are:

  • lipid-insoluble and do not dissolve in the boundary

  • too large, which cannot flow or filter through the pores

the carrier will complex with the drug and carry the drug to the inside

what are two types of specialized transport mechanisms?

facilitated diffusion and active transport

what is facilitated diffusion?

specialized transport mechanism for movement of specific molecules

• a concentration gradient is required

• no energy is used. like ‘ordinary’ diffusion, it is entirely passive

• diffusion takes place with the aid of special channels and/or gates (carrier proteins)

• cell membrane contain special channel protein that provide hydrophilic passageways for certain ions and molecules

• diffusion through these channel proteins is called facilitated diffusion

• each carrier protein has its own shape and only allows one molecule (or one group of closely related molecules) to pass through. selection is by size, shape, and charge

is a concentration gradient required for facilitated diffusion?

yes, concentration gradient is required

is energy used in facilitated diffusion?

no, energy is not used. this is a type of passive diffusion

can any protein channel or gate work for any amino acid or glucose?

no, it’s very specific. there are special channels used for certain things. like there is a special channel dedicated to glucose only.

what is facilitated diffusion mainly used for?

the transport of drug molecules that are very polar, charged, and still small

what is active transport?

drug transport across the membrane against a concentration gradient

• transport is from a region of lower concentration to a region of higher concentration

• for ionized drug, transport is against an electrochemical potential gradient

• energy (via ATP breakdown) is required

despite there being a lot of Na+ on the outside of the cell, there is Na+ being pumped outwards. and despite there being a lot of K+ being on the inside of the cell, the very few K+ on the outside is being pumped inwards

for active transport, does the drug transport go against or with the concentration gradient?

goes against the concentration gradient

• it goes from lower concentration to higher concentration

for active transport, is energy required?

yes, energy is required (ATP breakdown)

active transport cont.

CONT

• occurs via transporter proteins in the cell membrane

• each transporter protein is specific to just one type of ion or molecule

• cells contain many different transporter proteins in their membranes

there is a carrier. when it sees a specialized molecule and attaches to the surface, it gives a signal to the inside. ATP is broken down and phosphorylates the channel protein (carrier), which gives the signal to open up. as the protein (carrier) is phosphorylated, it opens up (second image). then the specialized molecule can travel inside and the phosphorylation process breaks down and the channel (carrier) closes.