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
• hyperlipidemic rats
• drug-metabolizing enzymes
• transporters
• protein binding

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) [No. 2012R1A1A1005896 and 2015R1C1A1A01051599] and by the Research Fund, 2017 of The Catholic University of Korea.