title: Effect of sodium bicarbonate as a pharmaceutical formulation excipient on the interaction of fluvastatin with membrane phospholipids.
abstract: Excipients in the pharmaceutical formulation of oral drugs are notably employed to improve drug stability. However, they can affect drug absorption and bioavailability. Passive transport through intestinal cell walls is the main absorption mechanism of drugs and, thus, involves an interaction with the membrane lipids. Therefore in this work, the effect of the excipient NaHCO(3) on the interaction of the anticholesterolemic drug fluvastatin sodium (FS) with membrane phospholipids was investigated by (1)H NMR and FTIR spectroscopy. Sodium bicarbonate is often combined with fluvastatin for oral delivery to prevent its degradation. We have used model DMPC/DMPS membranes to mimic the phospholipid content of gut cell membranes. The results presented in this work show a 100% affinity of FS for the membrane phospholipids that is not modified by the presence of the excipient. However, NaHCO(3) is shown to change the interaction mechanism of the drug. According to our data, FS enters the DMPC/DMPS bilayer interface by interacting with the lipids' polar headgroups and burying its aromatic moieties into the apolar core. Moreover, lipid segregation takes place between the anionic and zwitterionic lipids in the membranes due to a preferential interaction of FS with phosphatidylserines. The excipient counteracts this favored interaction without affecting the drug affinity and location in the bilayer. This work illustrates that preferential interactions with lipids can be involved in passive drug permeation mechanisms and gives evidence of a possible nonpassive role of certain excipients in the interaction of drugs with membrane lipids.
authors.affiliation: Department of Chemistry, Pharmaqam/NanoQAM, Université du Québec à Montréal, P.O. Box 8888, Downtown Station, Montreal, QC, H3C 3P8, Canada.
authors.forename: Germain
authors.initials: G
authors.lastname: Larocque
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Arnold
authors.forename: Etienne
authors.initials: E
authors.lastname: Chartrand
authors.forename: Yves
authors.initials: Y
authors.lastname: Mouget
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marcotte
mesh_terms: D000924:Anticholesteremic Agents / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry / Q000378:metabolism; D005079:Excipients / Q000737:chemistry*; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000378:metabolism*; D000077340:Fluvastatin; D007211:Indoles / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D017693:Sodium Bicarbonate / Q000737:chemistry / Q000494:pharmacology*; D017550:Spectroscopy, Fourier Transform Infrared; D014494:Unithiol / Q000737:chemistry / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D005079:Excipients; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D010743:Phospholipids; D014494:Unithiol; D000077340:Fluvastatin; D017693:Sodium Bicarbonate; D004134:Dimyristoylphosphatidylcholine
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