Passive Lipoidal Diffusion and Carrier-Mediated Cell Uptake Are Both Important Mechanisms of Membrane Permeation in Drug Disposition

Abstract

Recently, it has been proposed that drug permeation is essentially carrier-mediated only and that passive lipoidal diffusion is negligible. This opposes the prevailing hypothesis of drug permeation through biological membranes, which integrates the contribution of multiple permeation mechanisms, including both carrier-mediated and passive lipoidal diffusion, depending on the compound's properties, membrane properties, and solution properties. The prevailing hypothesis of drug permeation continues to be successful for application and prediction in drug development. Proponents of the carrier-mediated only concept argue against passive lipoidal diffusion. However, the arguments are not supported by broad pharmaceutics literature. The carrier-mediated only concept lacks substantial supporting evidence and successful applications in drug development.

How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion

“…Quoting from a recent example Smith et al (2014): “Additional recent ( sic ) data (Xu et al, 1998) from fluorine NMR studies on uptake of modified nucleosides (L-FMAU) into erythrocytes (biological systems that include transporters) provide clear indication ( sic ) of two different mechanism ( sic ) governing uptake of L-FMAU in erythrocytes: facilitated transport via nucleoside transporter and non-facilitated diffusion.” In fact, they do not. What Xu et al (1998) actually showed was that some of the uptake of the nucleoside was inhibited by an inosine analog, considered to be an inhibitor of “the” nucleoside transporter, but the rest of the uptake was not affected either by thiol reagents or by uracil (a substrate for a nucleobase—rather than nucleoside—transporter).…”

“…Note that dependent variables cannot be stated as causes; only independent variables or parameters play these roles (Kell and Westerhoff, 1986). Many of the correlations given (e.g., Smith et al, 2014) (and they always seem to be given in log.-log. space) have points that are two orders of magnitude apart in one axis.…”

“…As part of an ongoing discussion of the importance of transporters in drug distribution that we (Dobson and Kell, 2008; Dobson et al, 2009a,b; Kell and Dobson, 2009; Kell et al, 2011, 2013; Lanthaler et al, 2011; Kell, 2013; Kell and Goodacre, 2014) and others (e.g., Sai and Tsuji, 2004; Shitara et al, 2006; Anderson and Thwaites, 2010; Franke et al, 2010; Giacomini et al, 2010, 2013; Lai et al, 2010; Burckhardt and Burckhardt, 2011; Fromm and Kim, 2011; König, 2011; Mruk et al, 2011; Nies et al, 2011; Thompson, 2011; Tirona, 2011; Zolk and Fromm, 2011; Degorter et al, 2012; Mandery et al, 2012; Riedmaier et al, 2012; Sprowl et al, 2012; Chu et al, 2013b; Estudante et al, 2013; Giacomini and Huang, 2013; Hagenbuch and Stieger, 2013; König et al, 2013; Schlessinger et al, 2013a,b; Tamai and Nakanishi, 2013; Lai and Hsiao, 2014; Sprowl and Sparreboom, 2014) have been highlighting, Smith and colleagues recently published a review (Smith et al, 2014) that claims that the hypothesis that drugs are usually transported into cells via protein carriers is “not a sound scientific principle and lacks experimental evidence.” Smith et al (2014) set out their arguments in considerable detail, and this allows us, in the present publication, to present a contrary view and rehearse the core arguments that pertain to the mechanism(s) of drug and xenobiotic transport across biological membranes.…”

“…The abstract of the Smith article (Smith et al, 2014) (“Recently, it has been proposed that drug permeation is essentially carrier-mediated only and that passive lipoidal diffusion is negligible”) recognizes that we imply a dominant role for transporter-mediated uptake of drugs into cells (note the titles of Dobson and Kell, 2008; Dobson et al, 2009a; Kell and Dobson, 2009; Kell et al, 2011, 2013). We do not assert that carrier-mediated transport is the only means by which drugs and other xenobiotics gain access to cells, nor do we seek to invalidate passive lipoidal diffusion as an alternate mechanism.…”

The Role of Protein-Protein and Protein-Membrane Interactions on P450 Function

“…Drugs enter cells via active and passive transport processes through lipid membranes and inside cells; both transport modes significantly contribute to the final drug disposition (Smith et al, 2014). Besides the mentioned processes, membrane partitioning, nonspecific protein binding, and biotransformation dominantly contribute to drug disposition in a cell (Anzenbacher and Anzenbacherova, 2001;Guengerich, 2006;Balaz, 2009;Seddon et al, 2009;Lucio et al, 2010;Endo et al, 2011;Nagar and Korzekwa, 2012).…”