Abstract
Hyperlipidemia is associated with disturbances in plasma lipoproteins. These changes were shown to modify the pharmacokinetics of some lipophilic lipoprotein-bound drugs with some of these changes being clinically significant. In this manuscript potential mechanisms that might be involved in hyperlipidemia-induced changes in drug pharmacokinetics such as modulation of p-glycoproteins and liver metabolising enzymes activities and/or expression were investigated. P-glycoprotein gene expression (MDR1A/B) and activity was assessed in porcine (LLC-PK1) and murine (NRK-52E) proximal tubular renal epithelial cells that were maintained in normolipidemic- or hyperlipidemic-serum containing media and was compared to expression levels in serum-deprived cells. Gene expression of low density lipoprotein receptor (LDLr) and MDR1A/B along with cytochrome P450 CYP3A2 and 2C11 were also investigated in hepatocytes from normolipidemic and hyperlipidemic rats using qRT-PCR. Hyperlipidemic serum did not affect MDR1A/B gene expression in LLC-PK1 and NRK-52E cells. However, it significantly reduced p-glycoprotein activity in rifampin-treated and non-treated LLC-PK1 cells. Interestingly, p-glycoprein gene expression was induced in LLC-PK1 and NRK-52E cell lines upon serum starvation. Moreover, hepatocytes from hyperlipidemic rat livers had reduced LDLr, MDR1A/B, and CYP2C11 mRNA levels compared to normolipidemic rats. It is concluded that hyperlipidemia-induced changes in drug pharmacokinetics might be attributed to modulation of drug efflux/uptake, metabolism and/or excretion. Further, p-glycoprotein gene expression is potentially inducible by serum starvation in renal proximal tubular cells, which might be a novel detoxification mechanism by which these cells adapt to stressful conditions.
Highlights
Hyperlipidemia is a disease state associated with disturbances in plasma lipoprotein levels
Though, hyperlipidemia-induced changes in drug pharmacokinetics is not limited to lipophilic drugs, there is an old report that shows it changes the pharmacokinetics of hydrophilic drugs such as atenolol extending its effects on drug pharmacokinetics beyond those expected based on simple protein-binding interactions [5]
The extent of upregulation was significantly lower in cells previously incubated with HL serum and equivalent to cells incubated with medium only
Summary
Hyperlipidemia is a disease state associated with disturbances in plasma lipoprotein levels. Since lipophilic drugs such as amiodarone and halofantrine bind to plasma lipoproteins, hyperlipidemia expectedly was shown to alter their pharmacokinetic profiles [1,2,3,4]. Pharmacokinetics alterations that are commonly produced by hyperlipidemia include decreased drug clearance and volume of distribution. These changes have been observed for several drugs including amiodarone and dronedarone [2, 6].
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