Membrane Transporters & Drug Response

Membrane Transporters & Drug Response

1. Definition, scope & pharmacological importance

• Membrane transport proteins are integral membrane proteins present in all organisms that control the influx of essential nutrients and ions and the efflux of cellular waste, environmental toxins, drugs, and other xenobiotics (G&G 14e Ch.4, p.79).
• ~2000 genes in the human genome (~7% of all genes) encode transporters or transporter-related proteins — a measure of their centrality to cellular homeostasis (G&G 14e Ch.4, p.79).
• All pharmacokinetic processes — absorption, distribution, metabolism, excretion (ADME) — fundamentally involve transport of drug across biological membranes; PK considerations in turn determine route, dose, latency, peak, duration and dosing frequency (KDT 8e Ch.2, p.15).
• Pharmacologists focus on transporters from two major superfamilies: ABC (ATP-binding cassette) and SLC (solute carrier) transporters (G&G 14e Ch.4, p.79).
• Four pharmacological dimensions of transporters (organising scheme of the chapter):
  • Pharmacokinetics — selective absorption and elimination in intestinal, renal and hepatic epithelia; tissue-specific distribution (drug targeting); protective barriers (G&G 14e Ch.4, p.79).
  • Pharmacodynamics — transporters are themselves drug targets (e.g. SERT for SSRIs; SGLT2 for gliflozins) (G&G 14e Ch.4, pp.79–80).
  • Drug resistance — efflux/influx transporters drive resistance to anticancer, antiviral and anticonvulsant drugs (G&G 14e Ch.4, p.80).
  • Adverse drug responses — transporters control cellular exposure to drugs and carcinogens and thereby mediate toxicity and drug–drug interactions (DDIs) (G&G 14e Ch.4, p.81).

The biological membrane — structural basis of transport

• A bilayer ~100 Å thick of phospholipid and cholesterol; polar head-groups (glyceryl-phosphate–ethanolamine/choline; cholesterol –OH) face the two surfaces, non-polar hydrocarbon chains are buried in the matrix — conferring high electrical resistance and relative impermeability (KDT 8e Ch.2, p.15).
• Extrinsic and intrinsic proteins are adsorbed on / span the bilayer; some intrinsic proteins surround fine aqueous pores; paracellular spaces/channels lie between epithelial/endothelial cells; surface glycoproteins/glycolipids carry sugars, aminosugars and sialic acids (KDT 8e Ch.2, p.16).
• The membrane is a dynamic fluid mosaic — proteins and lipids move laterally; some adsorbed proteins act as carriers, receptors, enzymes or signal transducers (KDT 8e Ch.2, p.16).