Lack of predictability of classical animal models for hypolipidemic activity: a good time for mice?
Hypolipidemic drugs that are efficacious in man are not always active in classical animal models of dyslipidemia. Inhibitors of HMG-CoA reductase (statins) do not lower plasma cholesterol in rats, but yet this species was alone in providing activity for fibrate-type drugs. Nicotinic acid possesses many desirable features with regard to clinical use, but most of these actions are lacking in rats and monkeys. The metabolism of low density lipoproteins in hamsters is widely thought to be similar to that in humans, yet neither statins or fibrates lower plasma lipids in these species. With the advent of mouse models expressing specific human genes (or disruption of genes) it is now possible to re-examine the effect of established drugs and to characterize new hypolipidemic compounds with respect to site and mechanism of action. Drug responses observed in humans are now being seen in such mouse models (e.g. HDL elevation with fenofibrate in mice with the human apo A-I gene). Moreover, mice are now being screened for compounds that lower plasma (human) Lp(a), or lower plasma cholesterol in the absence of LDL receptors. It is proposed that these new genetic mouse models may afford a more focused examination of drug action and provide, for new compounds, better prediction of the human response.
Krause
B R
BR
Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, MI 48105, USA. kraus01@aa.wl.com
Princen
H M
HM
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood*; D008074:Lipoproteins / Q000097:blood*; D051379:Mice; D009525:Niacin / Q000031:analogs & derivatives
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008055:Lipids; D008074:Lipoproteins; D009525:Niacin