23 Drug Transporters

What is drug transport?

Movement of drugs through biological membranes

Drug movement through cells is known as what?

Transcellular transport

Drug movement between cells is known as what?

Paracellular transport

What allows some drugs to move unaided?

Favorable physicochemical properties such as lipophilicity → passive transcellular diffusion

Why do many drugs require transporters?

They lack properties for passive diffusion and need facilitated transcellular movement

What aspects of a drug can transporters alter?

Pharmacokinetics, safety, and efficacy

Which types of transporters move substances against a concentration gradient?

Active transporters

What characterizes active transporters?

ATP-dependent, move drugs against concentration gradient

What characterizes passive transporters?

Facilitate transport down concentration gradient and have no effect at equilibrium

What is a transporter substrate?

A drug that is transported by a specific protein

What is a transporter inhibitor?

A drug that blocks transporter activity

Why does transporter inhibition matter clinically

It alters drug levels and causes drug-drug interactions

What type of transporter is P-glycoprotein (P-gp)?

Efflux pump

Where is P-gp widely expressed?

Intestine, brain, liver, kidney

What is the main function of P-gp?

Eliminates drugs from cells via efflux

P-glycoprotein primarily limits what?

Oral absorption, renal excretion, and biliary excretion

What does P-gp inhibition cause?

Increased drug exposure

What is the primary role of OATP1B1?

Uptakes drugs from blood into hepatocytes

Why is OATP1B1 important for clearance?

It enables hepatic uptake for metabolism and elimination

What does genetic polymorphism in OATP1B1 cause?

Altered statin PK → increased myopathy risk

What is the function of PEPT1?

Influx transporter that absorbs peptides and peptide-like drugs

Why is PEPT1 important for valacyclovir?

Determines conversion to acyclovir by controlling absorption

How does disease affect transporters?

Chronic diseases alter expression via cytokines like IL-6

What is the function of the BBB?

Separates CNS from circulating blood

Why is paracellular transport restricted at the BBB?

Tight junctions between endothelial cells

Which drugs can cross the BBB despite efflux?

Small, lipophilic, uncharged drugs

What happens to drugs with poor physicochemical properties at the BBB?

Efflux systems keep CNS levels low

What does P-gp do at the BBB?

Limits drug entry into the brain via active efflux

What happens when P-gp at the BBB is inhibited (e.g., cyclosporine)?

Increased CNS exposure to P-gp substrates

What are common P-gp substrates?

Digoxin, loperamide, irinotecan, doxorubicin, vinblastine, paclitaxel, fexofenadine

What are common P-gp inhibitors?

Cyclosporine, quinidine, verapamil, clarithromycin, amitriptyline, ritonavir

What is the effect of P-gp in the intestinal epithelium?

Reduces oral absorption by pumping drugs back into the lumen

What is the effect of P-gp in the kidney?

Secretes drugs into urine; inhibition increases plasma levels

What does P-gp do in the liver?

Mediates biliary excretion

Why does ritonavir increase exposure of certain drugs?

It is a potent P-gp inhibitor (“PK booster”)

What does OATP1B1 transport?

Statins, repaglinide, valsartan, olmesartan, bilirubin glucuronide, bile acids

What occurs with OATP1B1 inhibition?

Increased plasma statin levels → increased myopathy risk

What does PEPT1 transport?

Cephalexin, valacyclovir, enalapril, captopril, peptides

What is the role of bacterial porin channels?

Allow antibiotics to enter bacteria

How do mutated porins contribute to resistance?

Reduced antibiotic uptake → resistance

What is the function of bacterial efflux pumps?

Remove antibiotics from bacterial cells → lower intracellular levels

How do defective efflux pumps affect susceptibility?

Increase intracellular drug levels → increased susceptibility