Cyclosporine Lipophilic drugs

These two prehepatic systems have been shown to contribute to the limited oral bioavailability of many lipophilic drugs including cyclosporine [8], terfenadine [9], saquinavir [10], midazolam [11], tacrolimus [12], atorvastatin [13], and others. 

The ability of lipid vehicles (either in the pharmaceutical formulation or in food) to enhance the absorption of lipophilic drugs has been well known for many years. Recently, successful bioavailability enhancement utilizing lipid-based formulations has been accomplished with the immunosuppressive agent cyclosporine A (Neoral, Novartis Pharmaceuticals Corporation, East Hanover, NJ), and for the two HIV protease inhibitors ritonavir (Norvir, Abbott Laboratories, IL) and saquinavir (Fortovase, Roche Pharmaceuticals, Nutley, NJ). Consequently, considerable interest in lipid-based formulations has been aroused. 

Cyclosporine (CY) is an example of a lipophilic drug that is predominantly bound to lipoproteins in plasma, has a low extraction ratio (EH < 0.3), and a volume of distribution of about 3.9 L/kg [155], Both the CL and VD of low extraction ratio highly bound drugs such as CY are highly dependent on the unbound fraction present in plasma. It might be expected that an increase in the concentration of plasma lipoproteins would result in a decreased unbound fraction of CY and therefore decreased CL and VD. In support of this hypothesis, an inverse linear relationship has been shown between cyclosporine CL and the level of TRL-TG, TRL-CH, and LDL-TG in uremic patients [155],... 

In recent years there has been an increased interest in the utility of lipid-based delivery systems to enhance oral bioavailability (4). It is generally known that membrane permeability is directly correlated to a drug s water-lipid partition coefficient however, the systemic availability of highly lipophilic drugs is impeded by their low aqueous solubility. In an effort to improve this solubility-limited bio-availabiliy,formulators have turned to the use of lipid excipients to solubilize the compounds before oral administration. Several formulations are currently on the market, for example, Sandimmun/Neoral (cyclosporin microemulsion), Norvir (ritonavir), and Fortovase (saquinavir)... 

The new cyclosporine formulation (Sandimmun Neoral, Novartis Pharmaceuticals Corporation, East Hanover, NJ) is a self-microemulsifying drug delivery system, which consists of the drug in a lipophilic solvent (corn oil), hydrophilic cosolvent (propylene glycol) surfactant and an antioxidant [37]. Upon contact with GI fluids, Sandimmun Neoral readily forms a homogenous, monophasic microemulsion, which allows the absorption of the drug molecules. Unlike Sandimmun, the formation of this microemulsion is independent of bile salt activity, and indeed, studies have shown that the absorption of cyclosporine from the new formulation is much less dependent on bile flow [38] and is unaffected by food intake [39],... 

Drugs that are highly lipophilic by their own nature, e.g., taxanes, epothilones, and cyclosporins, can only be used therapeutically by the addition of possibly toxic solubilizing agents (e.g., Cremophor EL) in complex pharmaceutical formulations [97-99]. One of several feasible means of obtaining nontoxic parenterally applicable formulations of such drugs is their incorporation into the bilayer matrix of phospholipid liposomes. 

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