Drug Absorption II

• There are several mechanisms by which drugs move through the body and arrive at the intended site of action.

  • These mechanisms include:¹²

  • Aqueous Diffusion

  • Lipid Diffusion

  • Membrane Transporters (by active transport or by facilitated diffusion)

  • Endocytosis and Exocytosis¹² 

  • These mechanisms involve translocation of drugs across membranes.⁸ 

• Most of the time the drug directly crosses membranes in accord with certain drug and membrane intrinsic properties.

  • Since biological membranes have a lipid core, some drugs which are not lipid-soluble have difficulty crossing membranes.⁸   

    • These drugs may have a nonuniform electrical charge distribution, with one part of the molecule relatively more positive or negative compared to another part of molecule, i.e. a "polar molecule." 

      • An example of this principle is illustrated in a water molecule.⁸ 

        • Water Molecule Dipole Moment^16,8

          Image Attribution: Chegg  https://www.chegg.com/homework-help/questions-and-answers/polar-water-figure-shows-charge-distribution-water-molecule-dipole-moment-81-h-1045-h8-dis-q45173660 Note that the oxygen (O) is relatively negatively charged and so noted by the use of the designation δ- . By contrast, the hydrogen atoms (H) are relatively positively charged and designated by the term δ+ . These charges are not formal charges as for example in sodium ion (Na+) which is explicitly electron deficient.

       

      • This same principle of relative charge distribution can also be seen in complex molecules (drugs)

        • Examples of more complex, polar drugs include: gentamicin, cephaloglycin (a.k.a. cefaloglycin; a seldom used first-generation cephalosporin antibiotic), and floxuridine (5-fluorodeoxyuridine; an anticancer drug in the antimetabolite class, often used in the management of colorectal cancer).

      • Polar Drugs¹⁷ 

        Gentamicin Attribution: Chegg https://www.chegg.com/learn/topic/structure-of-gentamicin cLogP = -4.1 cLogP is a "partition coefficient", representing the drug concentration ratio in two different solvents. The "c" refers to "calculated" whereas log refers to logarithm and P refers to "partition". LogP is > 0 for lipophilic drugs and < 0 for hydrophilic (polar) drugs.	Cephaloglycin Attribution:   Fvasconcellos, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Cefaloglycin.svg cLogP = -3.0

      • Floxuridine Attribution: Edgar181, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Floxuridine.png cLogP = -1.2

      • Gentamicin and the origin of intramolecuar polarity.⁸

        • The OH (hydroxyl) groups tend to attract electrons, making this part of the molecule more negative compared to other parts of the molecule.⁸

        • Gentamicin, a polar antibiotic drug

          Image Attribution: ChemSpider  http://www.chemspider.com/Chemical-Structure.65329.html

     

    • Characterization of a drug as relatively nonpolar or polar may be based upon a drug's partition coefficient, the ratio of the drug concentration between two different solvents.

      • Usually one of the solvents is water and the other is a nonpolar solvent, typically octanol (n-octanol).

      • Consider the separatory funnel illustrated below in which an oil layer (clear) is separated from the water layer (green).

        • Separatory Funnel

          z

          Attribution: PRHaney, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Separatory_funnel_with_oil_and_colored_water.jpg

           

      • The partition coefficient, P, describes then the difference in solubility of the drug in non-mixing (immiscible) solvents: water vs. n-octanol (ontan-1-ol).¹⁸ 

        • The partition coefficient describes lipophilicity for neutral drugs or for the case in which the drug exists in a single form.

          • Partition Coefficient, P = [drug]n-octanol / [drug]water LogP = log 10 (Partition Coefficient) For example, if LogP = 1 then the ratio of drug concentration in the organic phase compared to the aqueous (water) phase = 10.

        • For those drugs that can exist as different species (different ionized states) depending on the pH, the distribution of the species between the n-octanol and water phases is described by a Distribution coefficient which takes into account the concentration of individual species in the two phases.¹⁸ 

        • LogP vs. LogD¹⁸ 

          LogD is appropriately used in describing lipophilicity of ionizable drugs, given that the pH dependency of the molecule in water is taken into account.

          LogP is the correct way of describing lipophilicity for neutral compounds.