P-glycoprotein and Ion Trapping

What is the p-glycoprotein efflux pump?

Active transporter of drugs in the blood brain barrier, intestines, and liver

Where is the p-glycoprotein efflux pump found?

Blood-brain barrier

Intestines

Liver

What are the main effects of the p-glycoprotein efflux pump?

Decrease drug absorption

Keep drug concentration/exposure in the CNS low

Enhance drug/toxin elimination

Where does the p-glycoprotein pump secrete drugs/toxins?

Into the lumen of capillaries

Into the lumen of the intestines

Into the bile canaliculus

How do some drugs decrease the rate of drug efflux?

By acting as p-glycoprotein efflux pump inhibitors

What is an example of a p-glycoprotein efflux pump inhibitor?

Ketoconazole

What reasons can cause p-glycoprotein efflux pumps' efficiency to decrease?

Drugs that act as inhibitors

Genetic mutations

What does a mutation in the gene coding of p-glycoprotein efflux pumps cause?

Decreased expression of functional pumps and increased sensitivity to some drugs

What are potential consequences of a p-glycoprotein efflux pump deficiency?

Increased penetration of drugs into the CNS

Decreased elimination of drugs

Increased oral absorption of drugs

What dog breed has the frequency of p-glycoprotein efflux pump deficiency?

Collie

What are the top four dog breeds affected by p-glycoprotein efflux pump deficiency?

Collie

Long-haired Whippet

Australian Shepherd

Mini Australian Shepherd

Many drugs are weak whats?

Acids or bases

What are acids?

Proton donors

What are bases?

Proton acceptors

What is it called when a substance is capable of acting as an acid and a base?

Amphoteric

What does amphoteric mean?

Capable of acting as an acid and a base

Ionized drugs have poor what?

Lipid solubility

What is a drug's pKa?

pH at which 50% of the drug is ionized

When does an acid favor the unionized form?

pH < pKa

When does a base favor the unionized form?

pH > pKa

Does an acid or a base favor ionization when pH is lower than pKa?

Base

What does a solution's pH equal?

-log (H+ concentration)

When an acid or base is unionized, what happens?

It favors diffusion

When pH changes by 1, how much does the H+ concentration change?

10x

Unionized drugs are more _____ than ionized drugs

Lipid soluble

What is more capable of diffusion, ionized or unionized drugs?

Unionized

Why are ionized drugs unable to diffuse easily?

Positive/negative charge

Poor lipid solubility

What does "acid-acid" help us remember?

An acid in a more acidic environment favors the unionized form and diffusion

What does "base-base" help us remember?

A base in a more basic environment favors the unionized form and diffusion

What is ion trapping?

Differential drug accumulation in tissue compartments with different pH's due to drug ionization