Screening of Antihyperlipidemic Drugs

Screening of Antihyperlipidemic Drugs

1. Definition, rationale & the three-target framework

• Screening of antihyperlipidemic drugs = the systematic in-vitro → ex-vivo → in-vivo evaluation of a candidate compound's ability to lower plasma atherogenic lipids (total cholesterol, LDL-C, VLDL, triglycerides), raise HDL-C, and/or retard atherosclerotic plaque formation, benchmarked against an established reference (standard) drug (Vogel 4e V3 Part X, pp.2227–8).
• Pathophysiologic premise for the assays: elevated lipid levels — especially hypercholesterolaemia — arise from one (or more) of three processes: (i) increased absorption from the gut, (ii) enhanced endogenous synthesis, or (iii) inadequate clearance from serum. Therefore there are three feasible ways to reduce hyperlipidaemia — block endogenous synthesis, decrease absorption, or enhance clearance — and screening assays are built to interrogate each (Vogel 4e V3 Part X, p.2228).
• These three levers can be evaluated in normal animals without artificial diets, because clinically used lipid-lowering compounds — PPARα agonists (fibrates), cholesterol-absorption inhibitors (ezetimibe), bile-acid sequestrants, and HMG-CoA-reductase inhibitors (statins) — are all active in the normolipaemic model, then further profiled with mechanism-specific tests (Vogel 4e V3 Part X, p.2228).
• Lipoprotein taxonomy anchoring the endpoints: lipoproteins are divided into six classes — chylomicrons, chylomicron remnants, VLDL, IDL, LDL, HDL. HDL promotes reverse cholesterol transport (removal from peripheral cells → delivery to liver), so raising HDL is desirable; high VLDL/LDL is atherogenic. LDL — especially in its oxidised form — is taken up by macrophages via a scavenger mechanism. Hence an antiatherosclerotic drug should reduce VLDL + LDL and/or elevate HDL (Vogel 4e V3 Part X, p.2229).
• Choosing the right species is model-defining: for fibrates, rats and mice are appropriate; for LDL-lowering compounds, hamster, guinea pig and rabbit (because rodents' lipoprotein biology differs from humans) (Vogel 4e V3 Part X, p.2228).
• Historical anchor: experimental atherosclerosis was first successfully induced in rabbits by Saltykow (1908) and Ignatowski (1909); dietary cholesterol was subsequently identified as the responsible stimulus (Vogel 4e V3 Part X, p.2207).