The potential of immobilized artificial membrane chromatography to predict human oral absorption.
The potential of immobilized artificial membrane (IAM) chromatography to estimate human oral absorption (%HOA) was investigated. For this purpose, retention indices on IAM stationary phases reported previously by our group or measured by other authors under similar conditions were used to model %HOA data, compiled from literature sources. Considering the pH gradient in gastrointestinal tract, the highest logkw(IAM) values were considered, obtained either at pH7.4 or 5.5, defined as logkw(IAM)(best). Non linear models were established upon introduction of additional parameters and after exclusion of drugs which are substrates either to efflux or uptake transporters. The best model included Abraham's hydrogen-bond acidity parameter, molecular weight as well as the positively and negatively charged molecular fractions. For reasons of comparison between IAM chromatography and traditional lipophilicity, corresponding models were derived by replacing IAM retention factors with octanol-water distribution coefficients (logD). An overexpression of electrostatic interactions with phosphate anions was observed in the case of IAM retention as expressed by the negative contribution of the positively charged fraction F(+). The same parameter is statistically significant also in the logD model, but with a positive sign, indicating the attraction of basic drugs in the negatively charged inner membrane. To validate the obtained models a blind test set of 22 structurally diverse drugs was used, whose logkw(IAM)(best) values were determined and analyzed in the present study under similar conditions. IAM retention factors were further compared with MDCK cell lines permeability data taken from literature for a set of validation drugs. The overexpression of electrostatic interactions with phosphate anions on IAM surface was also evident in respect to MDCK permeability. In contrast to the clear classification between drugs with high and poor (or intermediate) absorption provided by MDCK permeability, %HOA plotted versus both IAM and logD data result in a saturation curve with a smoother ascending line.
Laboratory of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis, Zografou 157 71, Athens, Greece; Laboratory of Inorganic and Analytical Chemistry, School of Chemical Engineering, National Technical University of Athens, Iroon Polytechniou 9, 157 80 Athens, Greece. Electronic address: ftsop@central.ntua.gr.
Fotios
F
Tsopelas
Laboratory of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis, Zografou 157 71, Athens, Greece.
Theodosia
T
Vallianatou
Laboratory of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis, Zografou 157 71, Athens, Greece.
Anna
A
Tsantili-Kakoulidou
D020003:1-Octanol / Q000737:chemistry; D000818:Animals; D002845:Chromatography / Q000295:instrumentation / Q000379:methods; D004285:Dogs; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D061985:Madin Darby Canine Kidney Cells; D008567:Membranes, Artificial; D008954:Models, Biological; D008970:Molecular Weight; D017711:Nonlinear Dynamics; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism; D055672:Static Electricity; D014867:Water / Q000737:chemistry
D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations; D014867:Water; D020003:1-Octanol
Electrostatic interactions; Human oral absorption; IAM.PC.DD2; Immobilized artificial membrane chromatography; Lornoxicam (PubChem CID: 54690031); MDCK; Meloxicam (PubChem CID: 54677470); Methylprednisolone (PubChem CID: 6741); Metoclopramide (PubChem CID: 4168); Minoxidil (PubChem CID: 4201); Nadolol (PubChem CID: 39147); Niflumic acid (PubChem CID: 4488); Octanol–water partitioning; Omeprazole (PubChem CID: 4594); Sulpiride (PubChem CID: 5355); Warfarin (PubChem CID: 54678486)