Pharmacokinetics: Absorption and ADMET

Objectives

• After this lesson, students should define pharmacokinetics
• After this lesson, students should know all the elements of pharmacokinetics
• After this lesson, students should understand ADMET

Absorption

• Absorption: The process where a chemical substance transports into systemic circulation across biological membranes.
• Biomembranes: These are fluid mosaics made of lipid bilayers and proteins.
• The lipid bilayer consists of phospholipids, cholesterol, and other lipids.
• The specific orientation of the lipid bilayer makes it lipophilic.

Physicochemical Properties Affecting Absorption:

• Aqueous solubility has an inverse relation to absorption.
• Absorption depends on lipid solubility and the partition coefficient.
• Absorption depends on Ionization and dissociation of drugs.

Aqueous Solubility

• Water solubility is needed in order to allow the drug to dissolve into gastric fluids.
• Water solubility is needed in order to approach the hydrophilic surface of biological membranes.
• The hydrophilic surfaces are covered by water molecules.
• Blood is the vehicle for drug distribution, and it is aqueous.
• Water is also the reaction medium of biological systems.
• The blood's water-soluble drug leads to a large volume of distribution.
• More water-soluble drugs lead to poor penetration into the CNS through the lipophilic blood-brain barrier.
• Very few drugs end up acting on the CNS.

Lipid Solubility and Partition Coefficient

• Biological membranes are predominantly lipophilic.
• Because of this, Lipophilic drugs are preferentially absorbed.
• Charged molecules are not able to penetrate the lipid bilayer.

Structural Features That Increase Lipophilicity:

• Aliphatic hydrocarbons increase lipophilicity.
• Aromatic hydrocarbons increase lipophilicity.
• Halogens and halogenate hydrocarbons increase lipophilicity.
• Ethers and esters increase lipophilicity.

Structural Features That Reduce Lipophilicity:

• Polar groups that contain Oxygen, Nitrogen and Sulfur.
• Sulfur is the most lipophilic of the polar groups.
• Groups that ionize at physiological pH such as carboxylates and amines.

Lipid Solubility and Partition Coefficient

• Taxol or paclitaxel is a mitotic inhibitor.
• Taxol or paclitaxel is used in cancer chemotherapy.
• Taxol and paclitaxel are lipophilic.
• Taxol and paclitaxel have good membrane penetration.
• Taxol and paclitaxel are trapped in the membrane.
• Taxol and paclitaxel require IV administration.
• Taxol and paclitaxel lack water solubility.
• Dosage forms get changed to fix that.
• Structural changes don't always solve all the problems
• The partition coefficient (P) measures the lipid solubility of drugs.
• P is the ratio of drug concentration in the octanol phase versus water phase.
• P = [Co]/[Cw]

LogP Values

• LogP > 2 indicates a lipophilic drug.
• LogP < 2 indicates a hydrophilic drug.
• LogP is only applied to neutral compounds.
• A low logP results in low penetration to the CNS.
• A high logP results in low water solubility.
• Drugs with high LogP are generally not suitable for oral administration.

Ionization and Dissociation of Drugs

• Ionization influences the site from which the drug will be absorbed.
• Ionization influences the extent to which the drug will be absorbed.
• The ionized form is hydrophilic and unabsorbed.
• The unionized form is lipophilic and absorbed.

Absorption of Ionizable Drugs

• The lipid solubility of the nonionized form of the drug
• The ratio of the nonionized form to the ionized form, depends on
  • The dissociation constant of the drug (pKa)
  • The pH of the medium in which it is in

Acids and Bases

• Acids donate protons.
• An Acid dissociates into H+ and a conjugate base(anion).
• Bases accept protons
• A Base accepts a proton to form a positively charged cation which is known as a conjugate acid.

pH Values in Various Body Components:

• Plasma pH value of 7.4
• Buccal cavity pH value is 6.2 – 7.2
• Stomach pH value is 1.0 – 3.6
• Small intestine pH value is 4.8 – 8.0
• Only the unionized form of a drug is able to partition across biological membranes.
• The unionized form is lipophilic.
• The ionized form is more water-soluble.
• The ionized form is required for drug administration and distribution in plasma.

Chemicals - expectations based on pKa.

• Acidic chemicals in the stomach (pH 1-3.6) are mainly unionized and absorbed.
• Acidic chemicals in the intestine (pH 8) are mainly ionized and not absorbed.
• Basic chemicals in the stomach are mainly ionized and not absorbed.
• Basic chemicals in the intestine are mainly unionized and absorbed.

Oral Administration and Absorption

• The drug must be in its lipophilic unionised form to partition out of the aqueous medium if the drug is to be absorbed through the mucosal membranes
• The partition co-efficient of the unionised form will also determine how much is absorbed.

Lipinski's Rule of Five

• Orally administered drugs must obey a certain set of rules
• Molecular weight less than 500 Dalton
• logP must be less than +5.
• No more than 10 hydrogen bond acceptors (HBA).
• No more than 5 hydrogen bond donors (HBD).
• The compounds Must not have more than 7 rotatable bonds

Lipinski's Rule Exceptions

• Polar drugs breaking the above rules are poorly absorbed; injection needed.
• Highly polar drugs can be absorbed from the digestive system using transport proteins.
• Transport proteins are in the membranes of cells lining the gut wall.
• Transporters move polar building blocks for biosynthetic pathways across cell membranes.
• If the drug resembles a building block, it gets transported across.
• Levodopa gets transported by the amino acid phenylalanine transport protein.

Acids and Bases -Key Points

• High pKa, the species is predominantly unionized, bad proton donor, weak acid.
• Low pKa, the species is predominantly ionized, good proton donor, strong acid.
• If pH < pKa by 2 units, 99% unionized
• If pH > pKa by 2 units, 99% ionized
• High pKa value: the species is predominantly ionized, good proton acceptor, and a strong base.
• Low pKa value: the species is predominantly unionized, bad proton acceptor, and a weak base.
• pH < pKa by 2 units, 99% ionized
• pH > pKa by 2 units, 99% unionized

Distribution

• Drug transport from administration point or absorption zone to the action sight, e.g., cardiac muscles.
• Drugs are mainly are routed through blood circulation.
• Blood's chemical/physical properties control the drug at its target location.
• Drug molecules bound to serum proteins cannot have pharmacological effect until released.

Distribution Patterns in Tissues

• The nature of tissue and the drug's lipid solubility determine the drug's distribution.
• Acids stay in plasma, while basic drugs pass and remain in tissue.
• Basic drugs have higher tissue distribution than acidic drugs.

Blood Brain Barrier

• Brain capillaries consist of tightly joined epithelial cells.
• Known as the BBB (Blood Brain Barrier).
• BBB is a thick and lipophilic environment,
• BBB Protects the brain from all dangerous compounds.
• Highly lipophilic drugs distribute to the CNS; diazepam is an example.
• Less lipophilic drugs get absorbed more slowly.
• Polar drugs cannot pass through the BBB.
• The BBB Also uses active transport which includes:
  • amino acids
  • sugars
  • nucleosides and small ions (Na+, Li⁺, Ca2+ & K+).

Plasma Protein Binding

• Many drugs bind to plasma proteins.
• Binding of Plasma protein binding is reversible, this gives prolonged drug time.
• Protein binding affects action duration.
  • solubility
  • biodistribution
  • interaction with other drugs.

Tissue Depots

• Lipid-soluble compounds distribute into neutral fat cells.
• This forms what are called lipid depots.
• Example: thiopental barbital ultrashort acting general anesthetic.

Excretion

• Defined as the process by which unwanted substances get removed.
• Glomerular filtration excretes small, unbound drug molecules.
• Tubular secretion actively transfers bound & unbound molecules.
• Water, amino acids, salts, and glucose are returned by tubular reabsorption, as well as drug molecules.
• Reabsorption of acidic and basic compounds depends on urine pH.