1. Plasma
lipid profile abnormalities in
hyperlipidemia can potentially alter the pharmacokinetics of a
drug in a complex manner. To evaluate these pharmacokinetic alterations in
hyperlipidemia and to determine the underlying mechanism(s),
poloxamer 407-induced hyperlipidemic rats (HL rats), a well-established animal model of
hyperlipidemia have been used. 2. In this review, we summarize findings on the pathophysiological and gene expression changes in
drug-metabolizing
enzymes and transporters in HL rats. We discuss pharmacokinetic changes in drugs metabolized primarily via hepatic
cytochrome P450 (CYPs) in terms of alterations in hepatic intrinsic clearance (CL'int), free fraction in plasma (fu) and hepatic blood flow rate (QH), depending on the hepatic excretion ratio, as well as drugs eliminated primarily by mechanisms other than hepatic CYPs. 3. For
lipoprotein-bound drugs, increased binding to
lipoproteins resulted in lower fu values and volumes of distribution, with some exceptions. Generally, slower non-renal clearance (or total body clearance) of drugs that are substrates of hepatic
CYP3A and
CYP2C is well explained by the following factors: alterations in CL'int (due to down-regulation of hepatic CYPs), decreased fu and/or possible decreased QH. 4. These consistent findings across studies in HL rats suggest more studies are needed at the clinical level for optimal
pharmacotherapies for
hyperlipidemia.