Ex. 2 L6: Drug Transporters Flashcards
Types of drug transport
Paracellular passive diffusion
Transcellular passive diffusion
Uptake transport
Endo/exocytosis
Efflux transport
Uptake and Efflux transport use
Carriers - matter of direction; transport take drugs in, efflux moves drugs out
Role of drug transporters in drug disposition
Substrate of one of the transporters
Several minutes after iv infusion
-A lot of drug present in liver
-A lot of drug starts in kidney because after it is metabolized it is excreted into the urine
Brain - do not see as much of the drug
Brain has endothelial cells w/transporters that pump drug out of the brain
-a lot of drug unable to reach brain
A lot of drugs metabolized in intestine - excreted into bile by action of P-glycoprotein
Find drug in feces
-
Efflux transporter
P-gp (P-glycoprotein)
Uptake Transporters
OATP (organic anion transporting protein)
PEPT1 (peptide transporter
Major drug transporters expressed in intestinal epithelia:
OATP
PEPTI
P-gp
Major drug transporters expressed in Hepatocytes
OATP
P-gp
Major drug transporters expressed in kidney proximal tubules
P-gp
Major drug transporters expressed in blood-brain barrier
P-gp
P-glycoprotein (P-gp)
Efflux transporter affecting permeability of drugs
Expression of P-glycoprotein leads to resistance to certain drugs
Also called MDR1 (multi-drug resistance I)
P-gp pumps drugs in the direction of eliminating them from the bodies
Expression of Pgp on cancer cells leads to resistance of many drugs - pumps them out - decreased internal cell count
Expressed on:
Brain
Liver
Kidney
Small intestine
Testis
P-gp tissue distribution
Expressed on the apical side
Transport drugs out of bodies or organs
Intestine - eliminates out of intestine
Hepatocyte - promotes elimination of drug into bile
BBB - pumps out of brain; protects brain
Kidney: Pump blood out of body and into urine
Pgp protects body from potentially toxic/harmful substances
Blood Brain Barrier (BBB)
Capillaries stick together
-Drugs can only cross endothelial cells through diffusion, or carrier mediated transport
-Drugs stick together through tight junction
P-glycoprotein in brain:
Body came up with efflux system to pump toxic molecule out of brain
-Expressed on apical membrane
Helpful drugs can go through membrane/capillaries by endo/exocytosis
Can cut through membrane using active transport system
Pgp substrates
Substrates vary greatly in their structure and functionality, ranging from small molecules such as organic cations, carbohydrates, amino acids, and some antibiotics to macromolecules such as polysaccharides
Pgp substrates: Anticancer agents
Paclitaxel
Topotecan
Etoposide
Pgp substrates: Anti-HIV agents
Indinavir
Ritonavir
Saquinavir
Pgp substrates: Immunosuppressants
Cyclosporine A
Tacroliums
Pgp substrates: Lipid-lowering agents
Lovastatin
Atorvastatin
Pgp substrates: Opiods
Loperamide
Pgp inhibitors:
Most of the inhibitors are also substrates for P-gp and are capable of competitively inhibiting P-gp function
Pgp inhibitors: Anti-HV agents
Lopinavir
Ritonavir
Saquinavir
Telaprevir
Tipranavir
Pgp inhibitors: Anti-infectives
Clarithromycin
Itraconazole
Pgp Inhibitors: Cardiovascular
Amiodarone
Carvedilol
Quinidine
Propafenone
Verapamil
Drug-Drug interaction via P-gp:
Monkey study radiolabeled N-desmethyl loperamide
loperamide: Peripherally acting opioid receptor agonist
Does not reach the brain because pgp is there to pump drug out of brain
When loperamide is present - Distribution in brain tissue
PGP in the liver
Hepatocytes - also major organs for bile production
Bile - bile hepatocyte - bile canaliculus
Bile eventually reaches small intestine
Hepatocytes get drug source from blood stream - drugs deliver through blood flow and reach hepatocytes
Portion of drug can be metabolized - metabolized portion can be excreted into the bile canaliculus
PGP (MDR1) is expressed on the bile canaliculus membrane of hepatocyte
Drugs reaching hepatocyte can be pumped into bile either as parent drug or metabolites
Inhibition of p-gp in liver leads to
Decreased drug concentration
P-gp in placenta
Pgp on apical membrane
Pumps drug out of blood - fetal tissue
Becomes part of system - there to pump blood out of fetal tissue to protect fetus
Pgp in placenta: inhibition leads to…
increased drug transfer across placenta
OATP (Organic anion transporting protein) superfamily
> 300 members with at least 11 OATPs expressed in human
Uptake transporters
OATP substrates:
Endogenous compounds: bilirubin, bile salts, steroid hormone metabolites (e.g. estradiol glucuronide)
Xenobiotics: fexofenadine, statins
Statins:
Inhibitors of 3-hydroxy-methyglutaryl coenzyme A (HMG-CoA) reductase in the liver
Cornerstone of lipid-lowering therapy to reduce the risk of coronary heart disease
Most statins are substrate of OATP1B1
Statins and OATP1B1
Life-threatening side effect: rhabdomyolysis
Cerivastatin withdrawn in 2001 due to increased risk of myopathy associated with higher doses and drug interactions
-During postmarketing surveillance, 52 deaths were reported, mainly from rhabdomyolysis and its resultant renal failure
Risks were higher in patients using fibrates, mainly gemfibrozilm and in patients using the highest (0.8mg/day) dose of cerivastatin
What are expected outcomes when OATP1B1 is inhibited?
Decrease amount of statin reaching hepatocytes (target)
Lower efficacy (due to decreased uptake by the target organ)
increase statin plasma concentration
(increased side effects (e.g. myopathy)
Drug-Drug interaction via OATP1B1
Gemfibrozil
-Lipid lowering agent
-OATP1B1 inhibitor
Gemfibrozil increases the incidence of statin-induced myopathy
Commonly combined with statin
Much greater statin exposure in presence of Gemfibrozil
increased exposure of statin can lead to statin induced myopathy
OATP1B1 genetic polymorphisms
OATP1B1 is inhibited
Intestinal drug transporters
PEPTI
On intestine
Pumps drug into hepatocytes helping during drug absorption
OATP
Also works as uptake transporter
Both work to pump drug into cell
Drug-Drug interaction via OATP
Fexofenadine
Fexofenadine is an OATP1A2 and OATP2B1 substrate
Grapefruit juice (GFJ) inhibits OATP
OATP - combined w/grapefruit juice inhibits OATP
-much decreased drug exposure and absorption
PEPT1 (Peptide transporter 1)
A peptide transporter in the small intestine
Uptake transporter
Substrates
-Dipeptides and tripeptides
B-lactam antibiotics
PepT1 can be utilized to improve oral absorption of drugs
Valacyclovir
-Significantly improve oral absorption because this becomes a substrate of PepT1
PEPT1: Valacyclovir
When administered at the same dose, valacyclovir leads to higher systemic exposure to acyclovir
Low exposure happens because acyclovir is not readily absorbed
^Same dose of valacyclovir:
-Better intestinal absorption
Leads to higher systemic exposure
