P-glycoprotein and Ion Trapping

What is the consequence of p-gp deficiency?

Increased penetration of drugs into the CNS

What two drugs are affected by p-gp deficiency?

Ivermectin

Ioperamide

What does the P-glycoprotein efflux transporter do?

It pushed out drugs that where lipophilic enough to pass a barrier like the blood-brain barrier

What happens if you block the P-glycoprotein efflux transporter?

The same amount of drug enters the CNS, but less of it is effluxed out

What breed has the most P-glycoprotein deficiency?

Collie

What should you consider doing before doing a high dose of ivermectin?

Genotyping the dog

What is ivermectin toxicity in a homozygous normal dog?

2mg/kg

What is ivermectin toxicity in a heterozygous mutation dog?

0.3mg/kg

What is ivermectin toxic dose in a homozygous mutation dog?

0.12 mg/kg

What is amphoteric mean?

Capable of being an acid and a base

What is pKa?

pH when 50% of drug is ionized

What favors the unionized from at pH>pKa?

Base

What favors the unionized form when pH<pKa?

Acid

What does the p-glycoprotein efflux pump do?

Active transport of drugs (efflux proteins)

What does the p-glycoprotein efflux pump do in the blood-brain barrier?

Secrete drug/toxin back into the capillary to reduce drug concentration in the CNS

What does the p-glycoprotein efflux pump do in the intestines/

Secrete drug/toxin back into lumen of intestine to decrease drug absorption

What does the p-glycoprotein efflux pump do in the liver?

Secrete drug/toxin into bile canaliculus to activate biliary secretion and enhance drug/toxin elimination

T/F some drugs are p-gp inhibitors and can decrease the rate of drug efflux?

True

What is ketoconazole used for?

It is a p-gp inhibitor

Concurrent administration with cyclosporine increases the oral absorption of cyclosporine

What does a genetic mutation resulting in decreased expression of p-gp cause?

Increased drug penetration to the brain resulting in CNS adverse effects. This is seen in ivermectin and loperamide

What are the consequences of p-gp deficiency?

Increased penetration of drugs into the CNS

Decreased elimination of drugs

Increased oral absorption of drugs

Decreased elimination of drugs due to p-gp deficiency causes what 3 effects?

Biliary secretion is reduced

Renal excretion is reduced

Can also lead to decreased metabolism

What is an example of a drug that is affected by reduced biliary secretion due to p-gp deficiency?

Vincristine

What is an example of a drug that has increased oral absorption due to p-gp deficiency?

Digoxin

An unionized drug is more what?

Lipid soluble

Why can you treat aspirin toxicity with IV fluids?

Administration of fluids will raise the urine pH causing more aspiring to be ionized in the urine and allow for more excretion instead of resorption in the kidneys