W4.4_Transporters Flashcards
What are transporters? Contrast passive and active transport. Explain how transporters work in the intestines.
- Integral transmembrane proteins that aid translocation of substances across membranes
- Passive transport (down a concentration gradient) vs Active transport (against a concentration gradient)
- Intestine: large macromolecules can’t be absorbed -> enzymes break them down into smaller absorbable molecules -> transporters aid absorption of nutrients
Describe the efficiency of solute carrier (SLC) transporters. State the breakdown products of sucrose, lactose, maltose, and proteins.
- Extremely efficient absorption
- Sucrase: sucrose -> glucose + fructose
- Lactase: lactose -> glucose + galactose
- Maltase: maltose -> glucose + glucose
- Proteins -> small peptides + amino acids
The below transporters are stated in transporter/gene form. Explain the properties and mechanism of SGLT1/SLC5A1, PepT1/SLC15A1, and OATP1B1/SLCO1B1.
- SGLT1/SLC5A1 (transporter/gene): Na+-dependent glucose transporter-1
- Glucose uptake energised by movement of Na+ ions down their electrochemical gradient into enterocyte
- Has 14 membrane-spanning regions
- PepT1/SLC15A1 transporter: transport small peptides into cell
- Energised by movement of H+ ions down their electrochemical gradient into enterocyte
- Has 12 membrane-spanning regions
- Exploited by drug designers (based on natural products, ex. peptide-based drugs)
- Antibiotics, angiotensin-converting enzyme (ACE) inhibitors, some prodrugs (ex. valacyclovir, valganciclovir) are PepT1 substrates
- OATP1B1/SLCO1B1: Organic Anion Transporting Polypeptide
- Involved in uptake of statins
- Inhibit liver HMG-CoA reductase -> reduces cholesterol synthesis in liver -> reduce plasma cholesterol level
What do ATP-Binding Casette (ABC) transporters do? Describe the properties of P-gp/ABCB1 and BCRP/ABCG2.
- May hinder absorption of drugs
- Hydrolyse ATP to energise transport of substrates against concentration gradient
- Usually causes efflux (transport substrates out of cells)
- P-gp/ABCB1: P-glycoprotein
- 2 transmembrane domains (TMDs) with 6 helices in each
- 2 nucleotide-binding domains (NBDs) in cytoplasmic region (intracellular facing) that hydrolyses ATP -> forms a pore in membrane
- BCRP/ABCG2: Breast Cancer Resistance Protein
- 1 TMD with 6 helices, 1 NBD in cytoplasmic region that hydrolyses ATP
- Two proteins combine to form a pore in membrane
Briefly explain the effects of ABC transporters in drug absorption.
- ABCB1 and ABCG2 are expressed in apical membrane of intestinal enterocytes -> reduce absorption of therapeutic drugs
- Many drugs are substrates of ABCB1 transporters (ex. ritonavir, cyclosporin A, tacrolimus, erythromycin, digoxin, loperamide, simvastatin, atorvastatin, lovastatin)
- Many anti-cancer drugs are ABCB1 substrates (ex. doxorubicin, daunorubicin, etoposide, vinblastine, vincristine, pacitaxel)
- Some drugs can inhibit P-gp activity -> reduce amount of drug the transporter can efflux out (ex. quinidine, itraconazole, verapamil)
- ABCG2 substrates (ex. Rosuvastatin, cimetidine, prazosin, sulfasalazine, topotecan, doxorubicin)
Explain the polypharmacy effect of P-glycoprotein inhibitors and substrates. What is the problem caused by the efflux mechanism in ABC transporters for anti-cancer drugs? How could the addition of P-gp modulator impact the pharmacokinetic effect of those anti-cancer drugs?
- P-glycoprotein inhibitors + substrates (ex. quinidine + digoxin) -> less efflux -> more digoxin reaches blood -> higher concentration and toxicity
- Problem for anti-cancer drugs: efflux causes drug not accumulating in tumour cells -> X therapeutic effect
(When accidentally leak into surrounding tissues during IV infusion -> chemotherapy extravasation) - Addition of P-gp modulator -> increase pharmacokinetic effect of anti-cancer drugs -> higher toxicity (ex. doxorubicin + valspodar)
