Drug Distribution.....

Bioavailability dependant on several things:

1. Route of administration
2. The drug’s ability to cross membranes
3. The drug’s binding to plasma proteins and intracellular component

Membrane Review:

1. Membranes separate the body in components
2. The ability of membranes to act as barriers is related to its structure
3. Lipid Soluable compounds (many drugs) pass through by becoming dissolved in the lipid bylayer.
4. Glucose, H20, electrolytes can’t pass on their own. They use pores.
5. In excitable tissues, the pores open and close.
   
   1. Movement occurs by:
   2. passive diffusion
   3. active transport
   4. facilitated diffusion
   5. endocytosis

Passive Diffusion Review:

1. No energy expended.
2. Weak acids and bases need to be in non-ionized form (no net charge).
3. Drugs can also move between cell junctions. BBB is exception.
4. Must be lipid soluable to pass through pores.
5. Osmosis is a special case of diffusion
   
   1. A drug dissolved in H2O will move with the water by “bulk flow”
   2. Usually limited to movement through gap junctions because size too large for pores.

Active Transport Review:

1. Requires energy and requires a transport protein
2. Drugs must be similar to some endogenous substance.
3. Can carry substances against a gradient
4. Some drugs may exert their effect by increasing or decreasing transport proteins.

Facilitated Diffusion Review:

1. Requires transport protein
2. Does not require energy
3. Very few drugs move this way

Endocytosis:

1. Drug gets engulfed by cell via invagination
2. Very few drugs move this way and only in certain cells.

Regulation of distribution determined by:

1. Lipid permeability
2. Blood flow
3. Binding to plasma proteins
4. Binding to subcellular components

Volume of Distribution (Vd) - is a calculation of where the drug is distributed.

Vd = amount of drug given (mg)

concentration in plasma (mg/ml)

Calculate the Vd and compare to the total amount of body H20 in a person.

-if Vd = total amount of body (approx. 42) is uniformly distributed

-if Vd is less than 42 – retained in plasma and probably bound to plasma proteins

-if Vd is more than 42 – concentrated in tissues

This is not a “real value” but tells you where the drug is being distributed.

Placental Transfer of Drugs

1. Some drugs cause congenital anomalies
2. Cross placenta by simple diffusion
3. Must be polar or lipid-insoluable Not to Enter
4. Must assume the fetus is subjected to all drugs taken by the mother to some extent. 

Factors influencing bioavailability

The absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one (i.e. F <100 %). Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation. Whether a drug is taken with or without food will also affect absorption, other drugs taken concurrently may alter absorption and first-pass metabolism, intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora. Disease states affecting liver metabolism or gastrointestinal function will also have an effect.

Other factors may include, but are not limited to:

• Physical properties of the drug (hydrophobicity, pKa, solubility)
• The drug formulation (immediate release, excipients used, manufacturing methods, modified release – delayed release, extended release, sustained release, etc.)
• Whether the formulation is administered in a fed or fasted state
• Gastric emptying rate
• Circadian differences
• Interactions with other drugs/foods:
  • Interactions with other drugs (e.g. antacids, alcohol, nicotine)
  • Interactions with other foods (e.g. grapefruit juice, pomello, cranberry juice, brassica vegetables)
• Transporters: Substrate of efflux transporters (e.g. P-glycoprotein)
• Health of the GI tract
• Enzyme induction/inhibition by other drugs/foods:
  • Enzyme induction (increased rate of metabolism), e.g. Phenytoin induces CYP1A2, CYP2C9, CYP2C19, and CYP3A4
  • Enzyme inhibition (decreased rate of metabolism), e.g. grapefruit juice inhibits CYP3A → higher nifedipine concentrations
• Individual variation in metabolic differences
  • Age: In general, drugs are metabolized more slowly in fetal, neonatal, and geriatric populations
  • Phenotypic differences, enterohepatic circulation, diet, gender
• Disease state
  • e.g. hepatic insufficiency, poor renal function

Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation). In clinical trials, inter-individual variation is a critical measurement used to assess the bioavailability differences from patient to patient in order to ensure predictable dosing.