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Aqueous Diffusion
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Aqueous diffusion of drugs is associated with large aqueous compartments such as the interstitial space and the cytosol.12,19
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In addition, aqueous diffusion describes drug movement across epithelial membrane tight junctions as well as endothelial cells that line blood vessels by means of aqueous pores.
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Under some circumstances relatively large molecules (molecular weight ~25,000) may pass through these pores.
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Aqueous diffusion is one type of passive diffusion.
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Lipid diffusion is the other type of passive diffusion.
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Passive
diffusion represents the most common and simplest
mechanism for drug absorption, depending only on a
concentration gradient.15,19 -
As noted earlier, Fick's law (of diffusion) describes passive diffusion in which drug molecules move from regions of higher to lower concentration.
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Fick's Law12
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Fick's Law describes passive movement molecules down its concentration gradient.
Flux (J) (molecules per unit time) = (C1 - C2) · (Area ·Permeability coefficient) / Thickness
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Where C1 is the higher concentration and C2 is the lower concentration
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Area = area across which diffusion occurs
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Permeability coefficient: drug mobility in the diffusion path
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For lipid diffusion, lipid: aqueous partition coefficient -- major determinant of drug mobility
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Partition coefficient reflects how easily the drug enters the lipid phase from the aqueous medium.
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Thickness: length of the diffusion path
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Aqueous diffusion describes movement of non-protein bound drugs as drugs associated with large plasma proteins e.g. albumin are not able to penetrate most aqueous pores.
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Drugs which carry a charge may have transport influences by local electric fields, such as the nephron's transtubular membrane potential.12
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The
diffusion of drugs through the lipid region of the membrane
bilayer represents the central limiting factor to the drug
reaching its site(s) of action.
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This conclusion is based on the numerous lipid barriers which separate body compartments.
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The lipid: aqueous partition coefficient described previously predicts how easily a drug moves between aqueous and lipid regions.
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Drugs that are weak acids or weak bases may either
gain or lose charge depending on local pH.
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This is an important consideration given that charged drugs are less likely to move easily through the lipid region of the membrane bilayer.12,19
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A charged drug associates with water molecules (hydrophilic) and movement into the lipid region is energetically unfavorable.
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The lipid soluble form of the drug is uncharged and the aqueous soluble form is charged.
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The ratio of these forms for a weak acid or weak base drug is described by the Henderson-Hasselbalch equation.
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Henderson-Hasselbalch equation: General form: log (protonated)/(unprotonated) = pKa-pH
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For drugs that are weak Acids: pKa = pH + log (concentration [HA] unionized)/concentration [A-]
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note that if [A-] = [HA] then pKa = pH + log (1) or (since log(1) = 0), pKa = pH
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For drugs that are weak Bases: pKa = pH + log (concentration [BH+] ionized)/concentration [B]
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note that if [B] = [BH+] then pKa = pH + log (1) or (since log(1) = 0), pKa = pH
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The lower the pH relative to the pKa the greater fraction of protonated drug is found.
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Recall that the protonated form of an acid is uncharged (neutral); however, protonated form of a base will be charged.
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As a result, a weak acid at acid pH will be more lipid-soluble because it is uncharged and uncharged molecules move more readily through a lipid (nonpolar) environment, like the cell membrane, compared to charged molecules
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Similarly a weak base at alkaline pH will be more lipid-soluble because at alkaline pH a proton will dissociate from molecule leaving it uncharged and thus free to move through lipid membrane structures.
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Attribution:
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Shukle P pKa and Drug Solubility: Absorption and Distribution - Pharmacokinetics (PK) | Lecturio May 20, 2019
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References
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