Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

Abstract

Mixed micelles (MM) formed from glycocholic acid and lecithin are suited to solubilize lipophilic drugs for intravenous use. To test for possible drug‐drug interactions, the protein binding of a series of agents known to bind to different sites on albumin (diazepam, warfarin, ketoprofen, frusemide, probenecid) and additionally (prazosin, quinidine, propranolol) or exclusively (disopyramide) to alpha 1‐acid glycoprotein or to transcortin (prednisolone) was determined in the presence and absence of MM. Concentrations of MM, corresponding to the maximum possible plasma concentration achieved by injecting the highest clinical doses of MM into the systemic circulation, had little or no effect on the unbound fractions of drugs known to bind exclusively to albumin. Only at five times higher MM concentrations were the free fractions substantially increased (by up to 45%). Unbound fractions of drugs bound with high affinity but low capacity to alpha 1‐acid glycoprotein were increased between 50‐85% even at ‘therapeutic’ doses of MM. The present study suggests that drugs solubilized by MM should be given by slow injection or infusion to patients already receiving drugs which are highly bound to alpha 1‐acid glycoprotein.

Clinical pharmacokinetics of unbound docetaxel: role of polysorbate 80 and serum proteins

“…Alternatively, it cannot be excluded that this effect is the result of a displacement interaction caused by some (degradation) components of polysorbate 80. Similar observations have been reported for the binding of several other drugs that bind with high affinity but low capacity to AAG in the presence of structurally related mixed‐micellar systems 21 . It is interesting that the effect of polysorbate 80 appears to be biphasic both in vitro and in vivo, with a slight decrease in the f u at low concentrations of the vehicle.…”

“…Similar observations have been reported for the binding of several other drugs that bind with high affinity but low capacity to AAG in the presence of structurally related mixedmicellar systems. 21 It is interesting that the effect of polysorbate 80 appears to be biphasic both in vitro and in vivo, with a slight decrease in the f u at low concentrations of the vehicle. The mechanism underlying this phenomenon is unknown.…”

Stability of the Hsp90 Inhibitor 17AAG Hydroquinone and Prevention of Metal‐Catalyzed Oxidation

“…Lipophilic drugs are known to interact with HA38, 39 and it is possible that HA could sequester 17AAG or 17AAGH 2 in a hydrophobic interaction. The association of 17AAG and 17AAGH 2 with HA was measured by HPLC after incubation of either 17AAG or 17AAGH 2 (generated by NQO1 and NADH) with HA.…”

“…Many hydrophobic drugs can bind with HA38, 39 and HA is the primary protein in serum that binds acidic drugs 42. Previous studies using mouse models and membrane filtration suggested that >90% of 17AAG in mouse serum was protein bound 23.…”

Supramolecular Chiro-Biomedical Assays and Enantioselective HPLC Analyses for Evaluation of Profens as Non-Steroidal Anti-Inflammatory Drugs, Potential Anticancer Agents and Common Xenobiotics

“…Similarly, Bertucci [16] reported results of displacement chiral HPLC when noncovalent reversible binding of lithocholate to the second drug-binding cavity (site II) on the human serum albumin (HSA) induces an enhanced inhibition of ketoprofen, naproxen and surprofen enantioselective transport by this plasma drug carrier protein. In addition, Guentert et al [17] reported that mixed micelles formed from glycocholic acid and lecithin were well suited to solubilize ketoprofen and were preferentially bound to the plasma 1 -acid glycoprotein (AGP). However, Bielejewska et al [18] described use of the cholic acid and taurodeoxycholic acid as single and combined with native cyclodextrins (CDs) chiral selectors in HPLC and capillary electrophoresis (CE) systems which enabled highly selective enantioseparation of binaphtol atropoisomers.…”