Block 4 Week 4

-Bulk flow transfer (i.e. in the bloodstream)
-Diffusional transfer (i.e. molecule by molecule, over short distances)

- diffusional characteristics
- lipid solubility affect ability to cross hydrophobic diffusion barriers

- diffusion through lipid (most common)
- diffusion through aqueous channels
- transmembrane carrier proteins (also very important and common)
- pinocytosis

- rate of absorption from the gut
- penetration into the brain and other tissues
- the extent of renal elimination

- They exist in unionized and ionized form.
- The ionized BH+ and A- cannot pass through the membrane unless there are special carriers.
- the uncharged form pass through lipids very well.
- This group could be very large depending on how large the difference between the two compartments are.

accelerates excretion of weak bases and retards that of weak acids

reduces excretion of weak bases and increases excretion of weak acids

-causes weakly acidic drugs to be extracted from the CNS into the plasma

causes weakly acidic drugs to become concentrated in the CNS, increasing their neurotoxicity
- ie can decrease plasma pH by administering carbonic anhydrase inhibitor, acetazolamide

- It is a the drug transporter responsible for multidrug resistance in neoplastic cells. Transport drugs OUT of the cell.
- present in renal tubular brush border membranes, in bile canaliculi, in astrocyte foot processes in brain microvessels and in the gastrointestinal tract
- plays an important part in absorption, distribution and elimination of many drugs

Examples:
- warfarin (non-steroidal anti-inflammatory drugs). binds to many acidic drugs.
- chlorpromazine (tricyclic antidepressents). bind to some basic drugs.

Factors:
- the concentration of free drug
- its affinity for the binding sites
- the concentration of protein

- 1.2 mmol/L. there are 2 binding sites on albumin.
- most drugs, the total plasma concentration required for clinical effect is much less than 1.2 mmol/L. binding site are far from saturated...unless multiple drugs and competitively bind.

In fat. Fat:water ratio is 10:1

1. most drugs have a low fat:water partition coefficient
2. body fat has low blood supply

Drug redistribution of drug released from fat over time. If LSD or marijuana, will get a "flashback high" every now and then.

- absorption from the site of administration
- distribution within the body
- metabolism
- excretion

if give drug orally, not going to achieve a systemic effect because after first pass through liver, it is cleared. So can give it through IV.

- gastric emptying rate (access of drug to increased intestinal surface area increases rate of absorption, remember Fick’s Law)
- gastrointestinal motility
- splanchnic blood flow
- particle size and formulation
- physicochemical factors

Tetracylcine binds strongly with Ca2+ and prevents absorption.

sotalol, warfarin and cyclophosphamide

Stereoselectivity- want to avoid toxicity that may be linked to one of the stereoisomers.

drug (substrate, “DH”), P450 enzyme, molecular oxygen (one will for into a hydroxyl group and another H20), NADPH and a flavoprotein (NADPH-P450 reductase)