Chapter 3 PHARMACOKINETICS “What the body does to the drug” Lei Wang Department of Pharmacology

Absorption ：the movement of a drug from its site of administration into the circulation. Distribution ：the movement of a drug leaving the bloodstream and going into the organs and tissues. A D M E 2

Metabolism(Biotransformation) : chemical alteration of the drug structure mediated by enzyme, primarily in the liver. Excretion: the movement of drugs and their metabolites out of the body primarily by the kidneys. Elimination: the combination of metabolism and excretion. A D M E

Transmembrane Transport of Drugs Simple Diffusion Specialized Transport Filtration Facilitated Diffusion Active Transport

Simple Diffusion (Passive Diffusion ) Most drugs are transported across the membranes by passive diffusion Diffuses across the membrane in the direction of drug’s concentration gradient Diffusion rate is directly proportional to the gradient No need of energy No a carrier is involved

Simple Diffusion (Passive Diffusion ) Passive diffusion depends on the molecule's lipid solubility, size, degree of ionization, and the area of absorptive surface.

Cell Membrane Structure Simple Diffusion (Passive Diffusion) Cell Membrane Structure Biological membranes are bilayer, phospholipids matrices containing cholesterol, protein, and other constituent. The membranes are primarily lipid in nature.

“like dissolves like” a solute will dissolve best in a solvent that has a similar chemical structure to itself. Only lipid soluble drugs can dissolve in the lipid membrane and penetrate the membrane. Lipid soluble drugs Polar molecules and ions are not lipid soluble and cannot penetrate membranes by simple diffusion. Water soluble drug

Effect of pH on passive diffusion Simple Diffusion (Passive Diffusion) Effect of pH on passive diffusion Many drugs are weak acids or weak bases Weak acids and weak bases exist in solution as a mixture of ionized and un-ionized forms Weak Acid HA H+ + A- (unionized) (ionized) (cross membrane) Only the unionized (uncharged) form of a drug can cross cell membranes Ionized = Water soluble Nonionized = Lipid soluble

pKa : pH at which 50% of the drug is ionized and 50% is un-ionized. Simple Diffusion (Passive Diffusion) The proportion of unionized drug depends on the pKa (dissociation constant) of the drug and the environmental pH. pKa : pH at which 50% of the drug is ionized and 50% is un-ionized.

Handerson-Hasselbalch Equation Simple Diffusion (Passive Diffusion) Handerson-Hasselbalch Equation For acids (A)： For bases (B)：

Effect of the environment pH on the degree of ionization Simple Diffusion (Passive Diffusion) Effect of the environment pH on the degree of ionization A weak acid will be unionized when in an acidic environment, and a weak base will be unionized in a basic environment. A weak acid will be ionized when in a basic environment, and a weak base drug will be ionized in an acidic environment.

An alkaline drug is preferentially ionized in an acidic environment. Simple Diffusion (Passive Diffusion) In the stomach (pH 2.0)，which will be better absorbed, a weak acid (pK 6.8) or a weak base (pK 7.1)? A weak acid is most likely to be unionized when in an acidic environment An alkaline drug is preferentially ionized in an acidic environment. Weak acid

Most drugs are absorbed in the intestines Simple Diffusion (Passive Diffusion) Weak acids can also be absorbed more readily from the intestines than from the stomach, despite their greater ionization in the intestines The greater surface area in the intestines outweighs the influence of greater ionization in the intestines. Most drugs are absorbed in the intestines

Passive Tubular Reabsorption The reabsorption of drug from the lumen of the distal convoluted tubules into plasma occurs by simple diffusion. Urine pH determines the ionization state of a weak acid or base, and changes in urinary pH may markedly affect drug reabsorption and excretion. Passive reabsorption of lipid-soluble, unionized drug Passive Reabsorption Ionized or polar metabolite

Simple Diffusion (Passive Diffusion) Ion Trapping Ion trapping occurs with weak acids and weak bases if there is a difference in pH on two sides of a membrane. The ionized form of the drug will be trapped on one side of a membrane where the ionized form is predominant. Ionized form lipid Nonionized form

NH3 NH3 H+ H+ H+ PH 7.4 NH3 PH 7.0 H+ H+ H+ NH3 H+ NH3 NH3 NH3

Once the unionized basic drug crosses the cell membrane to enter the cell, it becomes ionized NH3 + H+ ⇌ NH4+ NH4+ PH 7.0 NH4+ NH4+ NH4+ NH4+ NH4+ NH4+ PH 7.4

Ion trapping results in basic drug’s accumulating in acidic bodily fluids and acidic drug’s accumulating in basic fluids. A- A- A- NH4+ NH4+ A- PH 7.0 NH4+ A- NH4+ NH4+ A- NH4+ PH 7.4

Filtration Filtration is passage of drugs through aqueous pores in the membrane or through paracellular spaces. Aqueous Diffusion

Filtration Aqueous Diffusion Water can cross cell membranes through aqueous pores. Bulk flow of water can carry with it drug molecules. Aqueous Diffusion Bulk Flow

membrane by this process. Aqueous Diffusion Only those drugs whose molecular size is smaller than the diameter of the pores may pass through the aqueous pores. Majority of cells have very small pores and drug with molecular weights (MW) exceeds 100 to 200 daltons are not able to penetrate. Aqueous diffusion is restricted to drugs with low molecular weights; many drugs are too large to penetrate the membrane by this process.

Paracellular Transport Filtration Paracellular Transport Passing through the intercellular space between the cells. Involved in capillaries. Capillaries (except those in brain) have large paracellular space and most drug can filter through these. Be limited to unbound drug. Be an important factor in filtration across glomerular membranes in the kidney.

Distribution Plasma Protein Binding

Glomerular Filtration Serum protein binding reduces filtration because plasma proteins are too large to be filtered.

Carrier-Mediated Membrane Transport Be specific for the substrate (selectivity) Carrier transport have arisen during evolution to carry naturally occurring molecules In reality very few drugs can cross the membrane by this method Be saturable. Competitively inhibited by analogues which utilize the same transporter.

Facilitated Diffusion It means the passage of drug across the biological membrane along the concentration gradient by the protein carrier mediated system also called as carrier mediated diffusion. Example: Cephalexin undergo facilitated diffusion by an oligopeptide transporter protein located in intestinal

Active Transport The process by which drugs pass across the biological membrane most often against their concentration gradient with the help of carriers along with the expenditure of energy. In all cells, active transport usually accumulates some molecules that the cell needs, such as ions, glucose and amino acids.

Characteristics of active transport are: Active Tubular Secretion Characteristics of active transport are: a. Saturability of the carrier b. Competition between substrates for the carrier penicillin penicillin penicillin penicillin probenecid probenecid Example: OATs OATs OATs OATs OATs OATs Penicillin and Probenecid Using acid pathway Decreasing excretion of penicillin Increasing action duration of penicillin

Transmembrane transport ADME Transmembrane transport Simple diffusion lipid solubility Ion trapping degree of ionization