Drug Absorption: Mechanisms, Factors, Lipid Solubility, pKa, First Pass Metabolism and Bioavailability

Drug absorption is transportation of drug from site of administration to plasma (blood)

Drugs administered by IV route skip absorption since they are injected directly to systemic circulation, drugs administered by most of the other routes like the oral route will be subjected to absorption

Mechanisms of drug absorption

Drug to be transported from site of administration to systemic circulation is by 4 ways:

• Passive diffusion :
  • In passive diffusion, drugs pass cell membrane by moving from area of high concentration to lower concentration
  • lipid soluble drugs move easily through membrane lipid bilayer whereas water soluble drugs penetrate through aqueous channels or pores
• Facilitated diffusion:
  • specialized transmembrane carrier proteins that facilitate the passage of drugs molecules
  • not require energy
  • can be saturated
  • can be inhibited by compounds that compete with carrier
• Active transport:
  • also require carrier proteins but it is energy dependent (requires ATP)
  • capable of moving drugs against concentration gradient
  • also saturable
  • selective for specific molecules the cell needs
• Endocytosis:
  • this type of absorption used to transport exceptionally large size drugs across cell membrane
  • involves engulfment of a drug by the cell membrane into the cell

Factors affecting drug absorption

Those include Factors related to the drug and factors related to the absorbing surface

Factors related to the drug include:

• molecular weight: the lower MW the better absorption, higher MW 1000 can’t absorbed
• drug dose : the higher the better
• drug formulations: like sustained release tablet which have many layers making it stays longer (slows absorption)
• local effects of the drug: like when putting adrenaline on the skin , leads to vasoconstriction and that lead to less absorption
• drug combination: two drugs that lead to increase absorption of each other like vit c increase absorption of iron (iron need to be in ferrous form to be absorbed which is the reduced form and vit c is reducing agent )
• lipid solubility of the drug: the more lipid soluble the better absorption
• The pKa and drug ionization: neutral drugs get absorbed easily.

Factors affecting absorbing surface:

• route of administration: IV is the fastest, then IM , then subcutaneous and inhalation , and oral is the slowest
• blood flow to the absorbing surface: the better blood flow to the absorbing surface , the better absorption
• total surface area available for absorption: intestine rich in microvilli and has 1000 fold the surface area of stomach , making absorption more efficient in intestine
• contact time at the absorption surface: if a drug moves fast through GI , it is not well absorbed, that happens in severe diarrhea and opposite is true
• presence of co factor: that helps the drug to enter like apoferritin system in intestine that helps the iron to be absorbed

Lipid solubility of the drug

General rules you have to know about lipid solubility of the drug:

• cell membrane is a phospholipid (lipid) so the drug that cross that membrane must be lipid soluble , so lipid dissolves in lipid and pass , but if drug is water soluble then can’t pass
• if drug get charge (ionized) become polar : is going to attract water molecules around it and make water shield around the drug , means it can’t cross too
• drugs that have neutral charge can pass easily because they would be fat soluble
• drug to have charge depend on PH of the medium that the drug put in: if we have acidic drug and put in basic medium , this lead to drug getting charged and can’t cross barriers , the opposite is true
• Most drugs are weak acids or weak bases

pKa

• pka is PH at which half of the drug is ionized and not absorbed and other half of non ionized and absorbed
• Examples
• pKa of aspirin is 3.5 : means if aspirin put in ph 3.5 this leads to half of aspirin not absorbed and other half absorbed
• Ph of stomach is 1.5, ph of intestine is 8.5 ; aspirin is acidic drug 3.5 , so if put in acidic environment it leads to better absorption
• Stomach ph is 1.5, aspirin 3.5 by subtracting them, we get 2 ph , which means 10 up to 2 which means 100: 1 absorption
• So in 3.5 ph aspirin 1: 1 absorbable: non absorbable
• In ph 1.5 it is 100: 1
• If we put aspirin in intestine 8.5 ph we get -5 and that 1: 100 000 , absorbable to non absorbable
• The questions come in form why aspirin cause stomach ulcer and not intestine, answer: because it is absorbed in stomach

Clinical significance of pKa

• Knowing the site of better absorption for the drug:
  • acidic pKa drug is better absorbed in the stomach
  • basic pKa drug is better absorbed in the intestine
• Treatment of drug toxicity:
  • Toxicity with acidic drugs could be treated by alkalinization of urine, which renders this drug more ionized in urine and less reabsorbable by kidney so it is excreted easily; example: if patient take a lot of aspirin (toxic dose) , this lead to aspirin when reaching urine would find urine is also acidic and help reabsorb the aspirin back , so we give patient effervescent that helps the urine to become alkaline to excrete aspirin effectively , aspirin in alkaline urine would be charged and excreted easily
  • toxicity with basic drugs could be treated by acidification of urine like amphetamine toxicity

Aspirin when absorbed into stomach it gets into stomach epithelial cells which have Ph of 7.4 which make the aspirin charged and gets trapped there, and can’t get diffused into blood until there is chemical processes that lead to aspirin losing charge and diffusing to blood but this take time and lead to aspirin diffusing little by little into circulation, This trapping of acidic aspirin inside the stomach cells might lead to ulcer, Ion trapping also true for other NSAIDs and that’s why they have bad effect on stomach

-Ion trapping of drugs in Breast milk: ph of breast milk is 7 , plasma is 7.4 , so milk to plasma is acidic , so if women take basic drug = not ionized in plasma but become ionized in breast milk so trapped in breast milk , so if alkaline drug would be trapped in breast milk and high plasma/milk ratio = problem to baby

First pass metabolism

• Metabolism of drugs that occur at site of administration or before reaching the systemic circulation, metabolism that occur after reaching systemic circulation is the main metabolism
• Examples: after oral administration drug is absorbed by intestine and into portal circulation and reaches liver where it undergoes first pass metabolism, lungs after inhalation, skin after topical administration
• Parenteral administration doesn’t undergo first pass metabolism
• Orally administrated drugs undergo first pass metabolism in the liver which either:
  • doesn’t metabolize the drug and give it all to systemic circulation like atenolol
  • partially metabolize the drug like morphine
  • metabolize all of the drug like lidocaine
• If liver metabolize all the drug once absorbed by intestine then oral route is not good for that drug, better to find another route like nitroglycerin which given sublingual
• If liver partially metabolize the drug, then increasing the drug dose might be a viable solution

Bioavailability

• After the drug gets absorbed, it reaches systemic circulation where it goes to its site of action
• Bioavailability Is the fraction of drug that reach systemic circulation after passing absorption and first pass metabolism
• Example: if you give 100 mg of a specific drug and only 40 mg reaches systemic circulation , that means bioavailability is 0.4 or 40%
• Bioavailability of IV drugs is 100% since they are injected directly to systemic circulation
• The oral dose of a medication is not the same as IV dose
• That is why doses are different for different routes, oral dose is more than IV dose just to count for the part that is not absorbed + the part that is first pass metabolized

Course Menu

This lecture is part of the Clinical Pharmacology Basic Principles Free Course; this course also include these lectures:

• Routes of drug administration
• Pharmacokinetics 101: Drug absorption
• Pharmacokinetics 101: Drug distribution
• Pharmacokinetics 101: Drug elimination
• Drug targets: Receptors, ion channels, enzymes and carrier molecules
• Pharmacodynamics 101: Agonist dose response curves
• Pharmacodynamics 101: Types of antagonists
• Drug factors affecting patient response
• Patient factors affecting response to drugs