Pharmacokinetic alterations in poloxamer 407-induced hyperlipidemic rats

Abstract

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 (f_u) and hepatic blood flow rate (Q_H), 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 f_u 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 f_u and/or possible decreased Q_H. 4. These consistent findings across studies in HL rats suggest more studies are needed at the clinical level for optimal pharmacotherapies for hyperlipidemia.

Keywords: Pharmacokinetics; drug-metabolizing enzymes; hyperlipidemic rats; protein binding; transporters.