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Lack of predictability of classical animal models for hypolipidemic activity: a good time for mice?
1Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, MI 48105, USA. kraus01@aa.wl.com
Abstract:
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.
Insights
Genetic mouse models are improving the study of hypolipidemic drugs. These models better predict how drugs like statins and fibrates will work in humans, advancing dyslipidemia research.
Area of Science:
- Pharmacology
- Genetics
- Biochemistry
Background:
- Classical animal models often fail to predict human responses to hypolipidemic drugs.
- Established drugs like statins and fibrates show limited efficacy in traditional models such as rats and hamsters.
- Existing models do not fully recapitulate human lipid metabolism, hindering drug development.
Purpose of the Study:
- To evaluate the utility of genetically modified mouse models for studying hypolipidemic drugs.
- To determine if these novel models can better predict human drug responses compared to classical models.
- To explore the application of these models in characterizing new hypolipidemic compounds.
Main Methods:
- Utilizing genetically engineered mice with specific human genes or disrupted genes.
- Re-examining the effects of established hypolipidemic drugs (statins, fibrates) in these models.
- Screening for novel compounds targeting specific human lipid parameters like Lp(a) and cholesterol in LDL receptor-deficient mice.
Main Results:
- Genetically modified mice exhibit drug responses mirroring those seen in humans, such as HDL elevation with fenofibrate in mice expressing the human apo A-I gene.
- These models allow for the study of drug action on human-specific targets, like lowering human Lp(a).
- The models facilitate the identification of compounds effective in scenarios lacking LDL receptors.
Conclusions:
- Genetically modified mouse models offer a more focused approach to examining drug action in dyslipidemia.
- These advanced models provide improved prediction of hypolipidemic drug efficacy in humans.
- The use of these models is crucial for the development and characterization of novel therapeutic agents for lipid disorders.