1-40 Drug Transport

Question 1

Pharmacokinectics

Answer 1

Drug transport 1. Absorption 2. Distribution 3. Metabolism 4. Elimination

Question 2

Factors involved in drug transport

Answer 2

membrane barriers molecular transport mech chemical & physical properties (pKa, pH of bio environment, lipid solubility, others…)

Question 3

Membrane barriers to drug transport (3)

Answer 3

1. epithelial cells: intestinal lining (infolding helps increase surface area to enhance opportunity for absorption, many transporters on lumen side to pick up nutrient/drug), renal tubules (elimination), intra-hepatic biliary (elimination) 2. vascular endothelial cells: peripheral capillaries (distribut), BBB (endothelial cell barrier is tough to cross, distribut) 3. cell (plasma) membranes: hepatocytes (capillaries to transport receptors on interstitial space side of hepatocyte then metabolism happens, and then put waste in to bile canaliculus(epithelial barrier) ), other cells (site of action)

Question 4

Epitherlial barrier basics

Answer 4

sheets/monolayers of epithelial cells, joined by tight junction

TJ: make cells impenatrable-ish and seperates cells into apical/basolateral levels

Apical membrane: faces the lumen, above the tight junction, microvilli/brush border

Basolateral membrane: faces the interstitium, below the tight junction

asymmetric distirubiton of membrane proteins between the apical vs basolateral, this facilitates protein movment to appropriate places (lumen to interstitium: absorption; interstitum to lume: secretion)

cellular pathway: movement through the cells

paracellular pathway: movement through the tight junctions, some epitherlia are leaky (low resistance ex: small intestine, proximal renal tubule) some are tight (high resistance ex: colon, renal collecting duct)

Question 5

Endothelial barrier basics

Answer 5

Types: continuous (snug connection/tight junctions, arranged can be tight or loose, very little spaces between cells, BBB, lymph node, muscle),

fenestrated (holes or windows between cells, more leaky, typical capilary within organs like GI tract, kidney glomerus)

sinusoidal (incomplete barriers with large holes/gaps, found in liver spleen and bone marrow where whole cells have to go in/out)

Question 6

BBB endotherlial barrier

Answer 6

Regular CONTINUOUS tight junction endothelial capillary PLUS glia cells surround the endothelial cells to form an extra protection layer

Question 7

Types of drug transport (5)

Answer 7

1. passive diffusion

• lipid diffusion: free diffusion through membrane, rate of transport is proportional to concentration gradient and lipid solubility (measured as partition coefficient, D), common mode of drug transport)
• aqueous diffusion: water soluble drugs can cros epi/endo barriers through fenestration or paracellular jxns, small drugs may pass through aquaporins or aquaglyeroporins, protein bound drugs cant cross typical epi/endothelial barriers, may “leak” from sinosoidal capillaries)

2. active transport

• primary active (ABC tranpsorters)
• secondary active (SLC transporters)
• facilitated diffusion (SLC transporters)

3. transcellular

• across epitherlial
• across endothelial
• cellular transport

4. paracellular
5. transcytosis

Question 8

Cell membrane barrier: pH dependence

Answer 8

• most drugs in clinical use are weak acids and bases
• they exist in ionized and non ionized forms
• non-ionized form is more lipid soluble and preferentially penetrates lipid membranes
• propotion of ionized to nonion forms determined with H-H equation: log(protonated/nonprotonated) = pKa molecule - pH fluid

Question 9

Transporters across cell membranes (drugs)

Answer 9

1. ATP Binding Cassette tranpsorters (ABC): mediate primary active transport by hydrolyzing ATP
   
   • some genes mediate anti cancer drug resistance, can pump cancer drugs right out of cells through p-glycoprotein transporter
2. Solute Carreir Transporters (SLC): done use active energy but use gradients
   
   • mediate co-transport & facilitated diffusion
   • opperate via alternating access
   • can be saturated
   • neurotransimtter transporters: norep, dopamine, seotonin get re-uptaken into pre-synaptic neuron (SSRI, inhibit a SLC for serotonin)

Question 10

p-glycoprotein acts to:

Answer 10

1. eliminate drugs from the brain
2. reduce GI absorption
3. excrete drugs in bile and urine

Unfortunately: also expressed on cancer cells which can then pump out chemotherapy :( leading to relapse/resistance