The effect of increased lipoprotein levels on the pharmacokinetics of cyclosporine A in the laboratory rat

Abstract

The response of cyclosporine A (CyA) blood concentrations following changes in lipoprotein levels have been inconsistent. Some studies show increases in concentrations, whereas others have shown decreases. The intent of this study was to examine the effect of two rat models of increased lipoprotein on the pharmacokinetics of CyA. One was a simulated high fat content meal, in which 1% cholesterol in peanut oil was administered. The other was the poloxamer 407-induced model of hyperlipidemia. Rats in these two groups were compared to a group fasted overnight before the study. In rats given a simulated high fat meal, at most time points the mean blood and plasma concentrations were lower, though not significantly, compared to fasted animals. Oral lipid led to no significant changes in the measured pharmacokinetic parameters of blood or plasma area under the concentration vs time curve (AUC), clearance (CL), volume of distribution (Vd) or plasma unbound fraction. In the poloxamer 407-treated hyperlipidemic rats there were significant reductions in plasma unbound fraction plasma, Vd and terminal half-life, but not AUC or CL, compared to normolipidemic rats. In contrast, the CL, Vd and t1/2 in the oral lipid-fed rats were all significantly higher than the poloxamer 407 treated animals. Oral absolute bioavailability of CyA was unchanged by oral lipid. In humans and rats the pharmacokinetics of CyA in the face of increased lipoprotein levels do not correspond well to what is typically seen for other drugs that are known to bind to lipoproteins.

Pharmacokinetics of Human Immunodeficiency Virus Protease Inhibitor, Nelfinavir, in Poloxamer 407-Induced Hyperlipidemic Model Rats

“…19,20) The P407-induced hyperlipidemia rat model has been used for several PK studies of drugs having high binding charac- teristics to serum lipoproteins such as CyA, 28,29) amiodaron 30) or nifedipine 31) due to its convenience, reproducibility and lack of undesirable underlying pathological conditions. 32) Moreover, in the preliminary experiment, we checked the hepatic and renal function in P407-induced HL rat.…”

The Single Dose Poloxamer 407 Model of Hyperlipidemia; Systemic Effects on Lipids Assessed Using Pharmacokinetic Methods, and its Effects on Adipokines

“…P407 also causes indirect stimulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase which is involved in cholesterol biosynthesis (3,42). _________________________________________ Several groups have used the P407 model of HL for the study of HL on pharmacokinetics and pharmacodynamics of a variety of drugs (4,(7)(8)20,(22)(23)25,33,35). In most of these assessments, the pharmacokinetics of the drugs were studied after dosing at 24 or 36 h from the time of P407 i.p.…”

The induction of atherogenic dyslipidaemia in poloxamer 407-treated mice is not mediated through PPARα

“…Because this model is routinely utilized by numerous laboratories throughout the world, we continue to explore the mechanisms responsible for the atherogenic dyslipidemia produced in this model, as well as any changes that may occur in cell lipid, insulin, and glucose homeostasis. Examples of how researchers use this model include a) determining how the pharmacokinetics of specific drugs are altered in the context of atherogenic dyslipidemia (Brocks et al 2006), b) determining the immune response to oxidized LDLcholesterol produced in this model (Johnston & Zhou 2007), c) determining how the dyslipidemic state affects key enzymes of lipid metabolism (e.g., endothelial lipase) (T Ishida et al 2007;Personal Communication), and d) determining the hepatic production rate of triglycerides (Millar et al 2005). Thus, it is critical to develop a better understanding of the mechanisms behind the cell lipid, enzyme, and gene signaling pathways altered by P-407 in this mouse model of atherogenic dyslipidemia.…”