Screening of Antihyperlipidemic Drugs

Introduction & screening cascade

• Definition — Screening of antihyperlipidemic drugs is the systematic in-vitro → ex-vivo → in-vivo evaluation of a candidate's ability to lower atherogenic lipids (total cholesterol, LDL-C, VLDL, triglycerides), raise HDL-C, and/or retard atherosclerotic plaque, benchmarked against an established reference (standard) drug.
• Three-target rationale — Hyperlipidaemia arises from increased gut absorption, enhanced endogenous synthesis, or inadequate serum clearance — so assays are built to interrogate each lever (block synthesis, decrease absorption, or enhance clearance).
• Endpoint anchor — Lipoproteins span chylomicrons → VLDL → IDL → LDL → HDL; VLDL/LDL (especially oxidised LDL, taken up by macrophage scavenger receptors) are atherogenic, HDL drives reverse cholesterol transport — so an anti-atherosclerotic drug should reduce VLDL + LDL and/or raise HDL.
• Species choice is model-defining — For fibrates rats/mice suffice; for LDL-lowering compounds use hamster, guinea pig or rabbit, because rodent lipoprotein biology differs from humans (mice are HDL-dominant and lack CETP).
• Historical anchor — Experimental atherosclerosis was first induced in cholesterol-fed rabbits by Saltykow (1908) and Ignatowski (1909); dietary cholesterol was identified as the responsible stimulus.

• Tier 1 — in-vitro target assays — fast, cheap, IC₅₀-driven — isolated HMG-CoA-reductase, squalene synthase/epoxidase, LXR/PPAR ligand-binding, cholestyramine bile-acid binding, Cu²⁺-induced LDL oxidation (TBARS).
• Tier 2 — cell-based — ¹⁴C-acetate → cholesterol in hepatocytes / HepG2; labelled-LDL internalisation into HepG2; macrophage cholesterol-efflux assays.
• Tier 3 — acute in-vivo lipaemia — days-scale synthesis/clearance screens — Triton WR-1339, fructose-induced hypertriglyceridaemia, IV Intralipid tolerance, hypolipidaemic activity in normolipaemic rats / Syrian hamsters.
• Tier 4 — chronic diet/genetic atherosclerosis — weeks–months, measure plaque not just serum lipids — cholesterol-fed rabbit, hyperlipidaemic hamster, apoE^-/- and LDLR^-/- mice, WHHL rabbit, balloon-injury.
• Interpretive principle — acute artificial models (e.g. Triton) are simple but artificial — a positive result must be validated by an orthogonal method (e.g. ex-vivo liver cholesterol-synthesis measurement).