FDA Drug Approval Process

Pharmacokinetics

Upper therapeutic limit Lower therapeutic limit concentration

Therapeutic Window

Pharmacodynamics Effect of treatment

Graded response saturates and may be described by C is what comes from the PK analysis hence one then knows the treatment response from equation at left

Drug Entry

Table 8.1 Enteral routes mean the GI tract: buccal (mouth), sublingual (under the tongue), gastric (stomach), intestinally (small & large), and rectally Table 8.2

1. Prefer plasma drug concentration since it is quicker and not interfered by hemolysis and release of RBC proteins 2. Drug concentration as measured is usually the total plasma concentration or what is known as the unbound and bound drug concentration 3. Drug effect, distribution, and elimination is due to unbound drug concentration 4. fu is the fraction unbound = Cu/Ctotal and is usually constant so either Cu or Ctotal can be used in a PK analysis, just be sure to know what you are using, see equation 8.1 in the book

Splanchnic circulation (viscera or entrails) takes the drug from the GI tract directly to the liver for what is called first pass elimination, which can significantly reduce the amount of drug that is available for a given dose.

Diffusion through the lipid bilayer of the cell depends on the solubility of the drug. Environment is aqueous, lipid, then aqueous in the cell Standard way of describing the lipid solubility of a drug is by the logP which is also the octanol/water partition coefficient which is defined as: logP > 0 means the drug is more soluble in octanol than in water and are therefore called lipophilic drugs logP < 0 means the drug is less soluble in octanol than in water and are more hydrophilic Optimal logP for passive diffusion across the lipid bilayer of cells is around 2-3

Increasing lipophilicity

For capillary Pm see Fig 6.5 of the book Passive transport: rate = Pm S  C Carrier mediated Transport: Here C is Ctotal and note only the unbound drug is transported, bound drug is usually with albumin which is too big

Perfusion limited - Tissue membranes present no resistance to drug transport Permeability limited – membranes of the capillaries and cells limit transport

Perfusion rate limited Permeability- limited

Perfusion rate limited Permeability rate limited Now we will discuss the Krogh tissue cylinder model section 6. and the Renkin Crone model of section 6.4.3 in the book for finding the Pm of a solute across the capillary wall