Pharmokinetics and membrane structure

Pharmokinetics

Study of drug movement in body

4 key parts of pharmokinetics

ADME

1) Absorption

2) Distribution

3) Metabolism

4) Excretion

Pharmodynamics

Physiological and biological effects if drugs on the Body

Drug absorption

The process by which a drug enters the bloodstream from its site of administration.

Transcellular

through cells

Paracellular

between cells, through tight junctions

What membrane must drugs cross after being orally administered

Intestinal epithelium

3 Membrane proteins

- Integral (spans across membrane)

- Peripheral (Present on external or internal side of membrane)

- Lipid anchored

5 functions or cell membrane

- Transport

- Enzymatic activity

- Signal Transduction

- Cell adhesion

- Receptor function

Substance polarity and membrane crossing

Highly polar substances are insoluble in membrane proteins and are unable to penetrate cell membranes

Drug lipid solubility and membrane crossing

The more lipid soluble the drug, the more readily it can dissolve in the membrane and diffuse through quickly

Vesicular transport

Materials move into or out of cell in vesicles

Passive diffusion

Major process for absorption, energy independent and non-saturable

How does molecule size effect passive diffusion

Larger molecules have more trouble passing through membrane

How does thickness of membrane effect drug absorption

A thicker membrane means it takes longer to pass, an example is the blood brain barrier

What is pore transport important in the process of

- Low molecular weight molecules

- Low molecular size molecules

- Generally water soluble drugs

Ion pair transport

When a substance with a charge combines with another to become neutralized, it then passes through the membrane and then dissociates back into its ion

Why are neutral complexes important in passive transport

Neutral substances have the required lipophilicity and aqueous solubility

Propanol ion pair transport

Propanol forms an ion pair with oleic acid

Facilitated transport

Rapid transport of materials down concentration gradient. NO ENERGY

Vitamin B12 and facilitated transport

Intrinsic factors (IF) forms a complex with B12 to aid in its movement through parietal cells

GLUT4 and facilitated transport

Insulin activates GLUT4 to aid in uptake of glucose from the blood stream

primary active transport

Active transport that relies directly on the hydrolysis of ATP.

2 examples of primary active transport

- Na/K pump

- Proton / Potassium exchanger

Sodium potassium pump

Uses energy of ATP hydrolysis to pump 3 Na out and 2K into the cell. Sodium goes to concentration of 10mM to 145mM, while potassium intracellular is 140mM and extracellular is 5mM

Proton Potassium exchanger

Found in the stomach, creates acid environment in the stomach, proton pump inhibitors are prescribed to stop ulcers and acid reflux

Organic anion transporter drug examples

pravastatin and atorvastin

Organic cation transporter drug examples

Diphenhydramine

ABC transporters

Transports small foreign molecules mainly out of cells (efflux pumps)

P-glycoprotein (P-gp)

An ABC transporter that pumps hydrophobic drugs, especially anti-cancer drugs out of cells

secondary active transport

Form of active transport that uses existing concentration gradients rather than ATP

Na+ / glucose transporter

A symport that uses potential energy of Na+ concentration gradient to pump glucose against its own gradient

Expulsion of protons in the kidneys

An example of anti port, protons are pumped out while sodium is pumped in

2 Transport mechanisms of Paracellular transport

1) Permeation through tight junctions (a little bigger than aqueous pores

2) Persorption

Persorption

Permeation of a drug through temporary openings formed by shedding of 2 neighbouring epithelial cells into the lumen

Pinocytosis

Cell uptake of fluid

Phagocytosis

Cell absorption/uptake of solid particulates

enterocytes

Important absorptive cells in the interstitial epithelial cells, their membranes limit drug movement

Membrane transport proteins

Facilitate passage of molecules into or out of the cell, 2 kinds and can use energy or be active in absence of energy

Uptake transporters

Transports drugs into the cell

Efflux transporters

Transports drugs out of the cell

How do drugs bearing similar parts to natural substrate impact membrane transport proteins

Can impact movement of natural drug and cause adverse side effects

Efflux transporter on apical membrane

Restrict the body's exposure to substrates

Efflux transporter on basolateral membrane

Enhance drug absorption

How does a drug respond if it is a substrate for an efflux pump on basolateral side and an uptake pump on luminal side

The two transporters could work together to either absorb and/or retain drug in the body

Transporter expression example: MRP2

MRP2 is an efflux pump that aids in bile excretion, if a drug such cyclosporin A inhibits it, there would be a large build of bile (hyperbilirubinemia)

3 changes in exposure of patients to drugs

1) Decreased uptake or secretion at clearance organs

2) Increased uptake3 or decreased efflux at target organs

3) Altered transport of endogenous compounds at target organs

SERT membrane transporter example

This transporter is a monoamine transporter and is a target for antidepressant drugs

Na+ / glucose transporter example

Type 2 diabetes drugs target this transporter to reduce renal reabsorption of glucose, thereby facilitating glucose elimination in the kidney

ABC transporter superfamily

Primary active transporters that mainly transport drugs to the outside of cells. Critical for development of multi drug resistance

SLC transporter superfamily

Secondary active transport / facilitated diffusers

OAT1 and OAT3

facilitate the uptake of drugs from blood into the renal tubular cells. Substrates include small hydrophilic anions such as decarboxylates and cyclic nucleotides

OATP family

Involved in drug absorption in the intestine and the uptake of drugs into the hepatocyte where they undergo metabolism. Transports large hydrophobic anions such as bile acids, thyroid hormones, prostaglandins, testosterone, and steroids

OCT1

Highly expressed in the liver where it enhances hepatic uptake of basic drugs like metformin

OCT2

Highly expressed in the kidney where it enhances uptake of its substrates into the renal tubular membrane from the blood

OCT3

found in liver, kidney, intestinal epithelial cells

PEPT transporters

Enhance the intertestinal absorption of peptide drugs.

Efflux ABC super family transporters

Present in all organisms, transports hydrophobic drugs, natural products, and peptides, facilitates removal of drugs by active transport. Also are a good defence mechanism.

Describe when efflux transporters work properly for defending from toxins

Few toxicants enter the cell, those that do are modified by oxidation and conjugation, these efflux pumps then extrude them

Describe when efflux transporters / cell are exposed to chemosensitizers

Transport gets inhibited and previously excluded chemicals can now enter the membrane

Describe topology of ABC transporters

- Consists of 2 domains, the transmembrane domain and nucleotide binding domains

- ATP binding causes dimerization of both units and causes transition of the TMD to change between inward and outward facing confirmations

Permeability glycoprotein (P-gp)

- Nonspecifc efflux pump with respect to substrates, exports neutral or positively charged hydrophobic molecules

- Ubiquitously expressed

- Highly expressed in tumour cells (stops sufficient anti-cancer drug accumulation)

Describe P-gp drug-drug mechanisms

Since they are so non-specific, these transporters have many substrates and inhibitors, have to be careful when taking multiple drugs

Multidrug resistant proteins (MRP)

- Efflux, Many isoforms, MRP1/2/4 are highly expressed in tumour cells

- MRP2 is in apical membrane in the kidney, liver and intestine, involved in excretion of bilirubin and glutathione.

- May also contribute to multi drug efflux by acting like P-gp to efflux unmodified xenobiotics

Breast Cancer Resistance Protein (BCRP)

- Efflux pump found in many tissues like intestinal membrane, liver, brain, and placenta

- Function is to limit drug accumulation like irinotecan and rosuvastatin, regulate BBB, and control oral bioavailability

BSEP

- Efflux, Bile Salt export pump, gene ABCB11, also known as sister P-gp

- Located in the duct membrane of hepatocytes

- transports bile acids and bile salts from hepatocytes to bile tubules

- Inhibiton cases toxic accumulation of bile salts in salts

Multidrug and toxin extrusion (MATE) family

- SLC transporter

- Efflux transporter with broad substrate specificity

- Exchange organic cations through electroneutral exchange with protons, complemental to OCT1/2

- Found on basolateral membrane of hepatocytes and proximal tubular cells