PURPOSE: This investigation was performed to study the effects of Pluronic block copolymers and Cremophor EL on intestinal lipoprotein processing and to investigate a potential link between lipoprotein processing and P-glycoprotein. METHODS: Caco-2 cells were used to monitor changes in lipoprotein production and secretion following exposure to excipients. Effects on P-glycoprotein were monitored using cyclosporin A as a model substrate. RESULTS: A range of surfactants commonly used as pharmaceutical excipients in lipid-based oral drug delivery systems, including Pluronics block copolymers L81, P85, and F68 and Cremophor EL, inhibited intestinal lipoprotein secretion. The effects were concentration dependent and reversible. The mechanism of inhibition appears to be related to the assembly and secretion of lipoproteins rather than to initial intracellular triglyceride synthesis. A strong correlation was found between excipient-mediated inhibition of lipoprotein secretion and inhibition of P-glycoprotein efflux, implying a link between the two biochemical processes. CONCLUSION: The ability of such bioactive excipients to simultaneously manipulate different cellular processes must be considered in selecting excipients for oral drug delivery systems. Such information is particularly relevant when the drug is lipophilic, a candidate for P-glycoprotein efflux, and where intestinal lymphatic targeting via chylomicron stimulation is desirable.
PURPOSE: This investigation was performed to study the effects of Pluronic block copolymers and Cremophor EL on intestinal lipoprotein processing and to investigate a potential link between lipoprotein processing and P-glycoprotein. METHODS: Caco-2 cells were used to monitor changes in lipoprotein production and secretion following exposure to excipients. Effects on P-glycoprotein were monitored using cyclosporin A as a model substrate. RESULTS: A range of surfactants commonly used as pharmaceutical excipients in lipid-based oral drug delivery systems, including Pluronics block copolymers L81, P85, and F68 and Cremophor EL, inhibited intestinal lipoprotein secretion. The effects were concentration dependent and reversible. The mechanism of inhibition appears to be related to the assembly and secretion of lipoproteins rather than to initial intracellular triglyceride synthesis. A strong correlation was found between excipient-mediated inhibition of lipoprotein secretion and inhibition of P-glycoprotein efflux, implying a link between the two biochemical processes. CONCLUSION: The ability of such bioactive excipients to simultaneously manipulate different cellular processes must be considered in selecting excipients for oral drug delivery systems. Such information is particularly relevant when the drug is lipophilic, a candidate for P-glycoprotein efflux, and where intestinal lymphatic targeting via chylomicron stimulation is desirable.
Authors: K E Berge; H Tian; G A Graf; L Yu; N V Grishin; J Schultz; P Kwiterovich; B Shan; R Barnes; H H Hobbs Journal: Science Date: 2000-12-01 Impact factor: 47.728
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Authors: Cedar H A Boakye; Ketan Patel; Apurva R Patel; Henrique A M Faria; Valtencir Zucolotto; Stephen Safe; Mandip Singh Journal: Drug Deliv Transl Res Date: 2016-10 Impact factor: 4.617