Drug Absorption & Bioavailability

PHARMACOKINETICS (ADME)

❏ “ADME”: absorption, distribution, metabolism, excretion

❏ definition: the manner in which the body handles a drug

❏ examines the rate at which drug concentrations change in the body by observing

1. input processes
   • absorption: movement of drug into the body from the site of administration
2. output processes: responsible for drug delivery and removal from the body
   • distribution: movement of drug from intravascular to extravascular compartment
   • metabolism: chemical transformation of drug
   • elimination: removal of drug from the body

 ABSORPTION

 Absorption:

The absorption is the transportation of the drug across the biological membranes into systemic circulation via portal vein. There are different mechanisms for a drug to be transported across a biological membrane:

• Passive (simple) diffusion
• Filteration/pore/paracellular
• Facilitated diffusion
• Active transport
• Electrochemical/ionic diffusion
• Ion pair transport.
• Endocytosis/Pinocytosis

❏ most drugs are absorbed into the systemic circulation via passive diffusion

❏ absorption rate and amount depends on

• local blood flow at admininstration site (eg. sublingual vessels provide significant blood flow therefore rapid absorption)
• lipid solubility: greater lipid solubility = increased rate of diffusion through membranes (e.g. anesthetics are very lipid soluble therefore have a rapid onset of action)
• molecular size: small size, water soluble drugs can pass through channels in membranes, large molecules cannot (e.g. aminoglycosides are large molecules and are not absorbed through intestinal mucosa and are therefore not orally active)
• local pH and drug ionization: charged molecules do not cross membranes (e.g. lactulose ionizes ammonia to ammonium and keeps it in the bowel)
• total surface area for absorption: the small intestine has villi which increase the surface area for absorption, and hence is the primary site of absorption for most oral drugs

Drug Transportation Mechanism:

     1. Simple (Passive) Diffusion

• The major role for the transportation of the drugs across the cell membrane is simple (passive) diffusion.
• The substances move across a membrane according to a concentration gradient (High to Lower).
• The concentration gradient is the factor that determines the route and rate of the diffusion.
• No energy is required.
• There is no special transport (carrier) protein.
• No saturation.
• The concentration gradient and the lipid solubility of the drug are the two main factors that determine the diffusion rate (speed) of the drug.
• Molecular weight of the high lipophilic drugs is not important as much as in the drugs that are soluble in water, BUT MW OVER 1000 is generally restrictive!!!

    2. Filteration/Paracellular Transport

•  The simple diffusion of the drugs with high solubility in water occurs via the aqueous pores (4 A^o) found on the cell membrane (i.e. caffeine, ascorbic acid, acetylsalicylic acid, nicotinamide, urea, glucose).
• Aqueous pores do not play a major role in the simple diffusion of the drugs across the cell membrane.
• Wt should less then 100 dalton.
• In case of capillaries (except brain), pore size is extent to 40 A^o to filter large molecules. E.g., albumine.
• Capillary absorption/filteration is important on Renal excretion, removal of drug from CSF, and entry of drug into lever.

    Rate of filteraion = N R²  A (dC)/η h

Where, N = no. of pores; R = radius; A = area; dC = conc. Gradient; η = viscosity; h = thicknes

3. Facilitated diffusion

•  Require a carrier protein/system (PERMIASE) to transport the drug across the membrane.
• Net flux of drug molecules is from the high concentration to low concentration.
• No energy is required.
• Saturable
• Polar drugs. E.g., trasport of glucose (GLUTs) and amino acids
• Trasport of Vit B 12 [intrinsic factor-1 (IF-1)-glycoprotein]

4. Active transport

•  The transportation of the drug molecules across the cell membrane against a concentration or an electrochemical gradient.
• It requires energy (ATP) and a special transporter (carrier) protein.
• There is «transport maximum» for the substances (the rate of active transport depends on the drug concentration in the enviroment).
• Due to energy dependent process, it is inihibited by metabolic poisons like cyanide, fluoride.
• g., L-dopa (alfa-amino acid transport), 5FU (pyrimidine trnasport), ACEIs (peptide transport).

5. Electrochemical Diffusion

•  Downhill process, depends upon conc. Gradients.
• Union>Anion>Cation

6. Ionpair Transport

• Quaternary ammonium compouns and Sulfonic acids drugs are ionized at all pH media. Therefore, they transport via ion-pair system.
• Endogeneous mucin (anionic) neutralized the cations and transport across to the membrane.

7. Pinocytosis/Cell Engulfing

• The drugs which have MW over 900 can be transported by pinocytosis.
• It requires energy.
• The drug molecule holds on the cell membrane and then surrounded with plasma membrane and inserted into the cell within small
• g., Sabin polio vaccin, Fat soluble Vit. (A,D,E,K) and Neurotransmitter uptake.
• Neurotransmitter release/secretion is a exocytosis process

 Bioavailability

•  “In which extent (rate) the body benefits from the drug” is known as bioavailability.
• IV. dose has 100 % Bioavailability
• For the orally administered drugs, bioavailability (systemic bioavailability) is the “fraction of unchanged drug that reaches to the systemic circulation from the administration site (after passing through the liver)”.
• Bioequivalence: When a preparation/formulation of a drug by different company has similar bioavailability, its called bioequivalent.

Relative B. A. (%) = [(AUC)o/(AUC)iv] x 100

F (%) =  (PC_Oral/Pc_iv) x 100

Mass_{(absorbed/iv)} = Mass_{(administeed/oral)} x (F/100)

 First Pass Metabolism Effect

❏ metabolism of orally administered drug in the liver before it reaches the systemic circulation

❏ significant first pass metabolism limits a drug’s bioavailability

❏ drugs with a high first-pass effect include: chlorpromazine, levodopa, morphine, propranolol, lidocaine, hydralazine, nortriptyline, and organic nitrates

❏ drugs with low hepatic extraction (little or no first pass effect) include: diazepam, digoxin, phenylbutazone, phenytoin, theophylline, tolbutamide, warfarin

Factors Affecting Drug Absorption and Bioavailibility

1. A) Drug-Related Factors

• Molecular size:
  • There is a negative relationship between the molecular size and the absorption rate of the drugs. If the molecular size increases, absorption rate decreases.
  • Micronization (0.1 um) reduces the particle size for better absorption. E.g., Greseofulvin, Aspirin, Spiranolactone, and Chloramphenicol.
• Lipid solubility:
  • A parameter of the lipid solubility is called “lipid-water partition coefficient (Ko/w)”.
  • If a lipid-water partition coefficient of a molecule is high, then the lipid solubility of the molecule is high. And Absorption rate is higher in lipid soluble drugs.
  • g., Phenylbutazone, Thiopental
• Degree of ionization/ pKa:
  • The lipid-water partition coefficient of an ionized drug molecule decreases.
  • The acidic drugs are unionised in acidic media and allow to absorb, and Basic drugs are unionized in basic media and allow to absorb.
  • Degree of ionization is determined by “Handersen-Hasselbach equation”
    • For weak acids: pH-pKa = log (ionized drug /unionized drug)
    • For weak bases: pH-pKa = log (unionized drug / ionized drug)

*pKa – the value of pH in which drugs have 50 % ionised and 50% unionised.

• According to the equation, for weak acid drugs: if you increase the acidity of the medium (decrease the pH), the unionized form of the drug molecule increases so the absorption rate increases.
• The closer the pKa value to the pH of the body fluids (generally 7.4), the greater is the change in ionization degree

FOR WEAK ACID DRUGS

• ION TRAPPING:
  • The distribution of a drug between two compartments separated by a membrane that allows simple diffusion depends on the pH difference between these compartments.
  • At steady state, the concentration of unionized form of the drug molecules are the same; however the concentration of ionized form will not be equal at both sides because of the pH difference at both sides.
  • e. accumulation of basic drugs in the milk (trapped)
• Dosage form:
  • Disintegration: Breaking up of the drug molecules into smaller pieces after administration (mostly oral) is called disintegration.
  • Dissolution: Entering of the solid drug into a solvent to form a solution is called dissolution.
  • Solution forms of a drug molecule (liquid dosage forms) are absorbed faster compared to unsolved (solid) forms of the same drug.
  • High aqueous soluble drugs has high dissoultion rate and have higher absorption rate.
  • Dissolution rate directly proportion to the Kw/o.
• Chemical nature (Salt/organic forms, crystal forms, solvate form etc.):
  • Salt formations: Salt forms of weak acids (Na+, K+, Ca2+ compounds) and weak base (HCl, HBr compounds) drugs are more easily absorbed compared to their original (free) forms.
  • Crystal forms: Amorphous structure of a drug has a higher dissolution rate compared to its crystalline structure.
  • Solvate form: The hydrates are more soluble in water compared to other solvates.
• Particle size:
  • Decreasing the particle size of the drug fastens its dissolution so increases the absorption rate.
• Complex formation:
  • The solubility of some low-soluble drug molecules can be increased by formation a complex with another drug molecule.
• The pharmacological effect of the drug:
  • Effect on blood flow (vasoconstrictors, vasodilators, some cardiac drugs) in the absorption site,
  • transition time of the drug in GI tract (drugs effecting the GI motility).
• Concentration of the drug:
  • Higher the concentration of the drug at the administration site, higher the absorption rate of that drug.

B) Site Of Application Related Factors

• Blood flow (at site of application):
  • If the blood flow is high at the site of application, it causes an increase in absorption rate.
• Area of absorption:
• If the surface area that allows the absorption of the drug molecules is wide, then absorption rate from that surface becomes high