Transporters and ADME

• What is the focus of the study material?

  F-GP
• What does ADME stand for?

  Absorption, Distribution, Metabolism, and Excretion
• What are the two superfamilies of transporters mentioned?

  • ATP-binding cassette (ABC)
  • Solute carriers (SLC)
• What is the role of Jadephen in the context of ADME?

  It is a multidrug transporter in the intestine.
• What processes are involved in ADME according to the study material?

  Net absorption, biliary excretion, slow distribution in the BBB, and renal clearance.
• What are the key transporters involved in ADME?

  1. ABC transporters: P-gp, BSEP, MRPs, BCRP (all efflux transporters)
  2. SLC transporters: Uptake - OATP1B1, OATP1B3, OCT1, OCT2, OAT2, OAT1; Efflux - MATE2, MATE2K
• What type of substrates do OATP and OAT transporters uptake?

  Organic anions.
• Which small organic cations are taken up by OCT1 and OCT2?

  Metformin and ciprofloxacin.
• How are transporters distributed on hepatic membranes?

  • Located on either apical (luminal) or basolateral (blood) side in polarized cells.
  • This spatial distribution affects their function in the organ.
• How does the location of P-gp in the gut affect drug exposure?

  P-gp is higher in the distal gut, affecting drug exposure based on permeability properties.
• How do highly soluble and permeable drugs behave in the duodenum?

  They are rapidly absorbed and less exposed to P-gp.
• What is the effect of slow-release formulations on P-gp exposure?

  • Slow-release formulations can increase exposure to P-gp.
  • This affects the drug's absorption and efficacy.
• What is the significance of co-expression with metabolic enzymes for transporters?

  It can influence the metabolism and efficacy of drugs.
• What is the role of P-gp in drug transport?

  • P-gp effluxes substrates into the lumen of the organ where it's expressed.
  • It has different effects on ADME at various locations.
• How does P-gp affect oral absorption in the intestine?

  • P-gp influences oral absorption in enterocytes.
  • It affects the area under the curve (AUC) of the drug.
• What is the role of P-gp in liver hepatocytes?

  • P-gp is involved in biliary elimination.
  • It affects the half-life (T½) and AUC of drugs.
• How does P-gp function in proximal tubular (PT) cells?

  • P-gp plays a role in renal excretion.
  • It influences the area under the curve (AUC) of drugs.
• What is the effect of P-gp at the blood-brain barrier (BBB)?

  • P-gp affects the distribution of drugs to the brain.
  • It influences the half-life (T½) of drugs.
• How can transporters be targeted in therapy?

  They can be targeted for drug interactions and efficacy improvements.
• What is the impact of probenecid on drug interactions?

  Probenecid interferes with tubular reabsorption in the kidney.
• What is the effect of metformin on hepatic uptake?

  Metformin has no effect on hepatic uptake.
• How are drugs metabolized by CYP3A4 related to transporters?

  They are often substrates for P-gp and can be influenced by transporters.
• What factors affect drug permeability in absorption?

  1. Internal efflux transporters
  2. Bile acids and dietary factors
  3. Drug formulation properties
• What happens when uptake transporters become saturated?

  AUC and Cmax do not correlate linearly with dose.
• How does renal excretion occur?

  It can occur passively or be mediated by transporters.
• How do transporters influence drug metabolism in the liver?

  • Transporters facilitate the uptake of drugs into hepatocytes.
  • They play a role in drug metabolism and elimination.
• What is the effect of probenecid on penicillin secretion?

  Probenecid inhibits tubular secretion of penicillin in the kidney.
• What is the effect of grapefruit juice on OATP transporters?

  Grapefruit juice inhibits OATP transporters.
• How do inducers affect drug absorption?

  Inducers can enhance the oral absorption of certain drugs.
• What is the relationship between P-gp and CYP3A4?

  P-gp and CYP3A4 often interact and influence drug metabolism and transport.
• What factors can modify transporter expression?

  • Extrinsic factors: drugs, environmental chemicals
  • Genetic polymorphisms affecting transporter genes