Pharmacokinetics: Membrane Transport, Absorption and Distribution of Drugs
Systemic diagram for Pharmacokinetic process
All pharmacokinetic processes involve transport of the drug across biological membranes.
Biological membrane
This is a bilayer (about 100 Å thick) of phospholipid and cholesterol molecules, the polar groups (glyceryl phosphate attached to ethanolamine/choline or hydroxyl group of cholesterol) of these are oriented at the two surfaces and the nonpolar hydrocarbon chains are embedded in the matrix to form a continuous sheet. Extrinsic and intrinsic protein molecules are adsorbed on the lipid bilayer
Glycoproteins or glycolipids are formed on the surface by attachment to polymeric sugars,
amino sugars or sialic acids.The specific lipid and protein composition of different membranes differs according to the cell or the organelle type. The proteins are able to freely float through the membrane: associate and organize or vice versa. Some of the intrinsic ones, which extend through the full thickness of the membrane, surround fine
aqueous pores. Paracellular spaces or channels also exist between certain epithelial/endothelial cells.
Other adsorbed proteins have enzymatic, carrier, receptor or signal transduction properties.
Lipid molecules also are capable of lateral movement. Thus, biological membranes are highly dynamic structures.
Drugs are transported across the membranes by:
(a) Passive diffusion and filtration
(b) Specialized transport
Passive diffusion
The drug diffuses across the membrane in the direction of its concentration gradient, the
membrane playing no active role in the process. This is the most important mechanism for
majority of drugs; drugs are foreign substances (xenobiotics), and specialized mechanisms are developed by the body primarily for normal metabolites.
Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the membrane the rate of transport being proportional to the lipid : water partition coefficient of the drug. A more lipid-soluble drug attains higher concentration in the membrane and diffuses quickly. Also, greater the difference in the concentration of the
drug on the two sides of the membrane, faster is its diffusion.
Influence of pH Most drugs are weak electrolytes,
i.e. their ionization is pH dependent
(contrast strong electrolytes that are nearly completely ionized at acidic as well as alkaline
pH).
The ionization of a weak acid HA is given by the equation:
[A¯ ]
pH = pKa + log —–— ...(1)
[HA]
pKa is the negative logarithm of acidic dissociation constant of the weak electrolyte. If the
concentration of ionized drug [A¯ ] is equal to concentration of unionized drug [HA], then
[A¯ ]
—–— = 1
[HA]
since log 1 is 0, under this condition
pH = pKa
Thus, pKa is numerically equal to the pH at which the drug is 50% ionized. If pH is increased by 1 scale, then—
log [A¯ ]/[HA] = 1 or [A¯ ]/[HA] = 10
Similarly, if pH is reduced by 1 scale, then—
[A¯ ]/[HA] = 1/10
Thus, weakly acidic drugs, which form salts with cations, e.g. sod. phenobarbitone, sod.
sulfadiazine, pot. penicillin-V, etc. ionize more at alkaline pH and 1 scale change in pH causes 10 fold change in ionization. Weakly basic drugs, which form salts with anions, e.g. atropine sulfate, ephedrine HCl, chloroquine phosphate, etc. conversely ionize more at acidic pH. Ions being lipid insoluble, do not diffuse and a pH difference across a membrane can cause differential distribution of weakly acidic and weakly basic drugs on the two sides
Implications of this consideration are:
(a) Acidic drugs, e.g. aspirin (pKa 3.5) are largely unionized at acid gastric pH and are absorbed from stomach, while bases, e.g. atropine (pKa 10) are largely ionized and are absorbed only when they reach the intestines.
(b) The unionized form of acidic drugs which crosses the surface membrane of gastric mucosal cell, reverts to the ionized form within the cell (pH 7.0) and then only slowly passes to the extracellular fluid. This is called ion trapping, i.e. a weak electrolyte crossing a membrane to encounter a pH from which it is not able to escape easily. This may contribute to gastric mucosal cell damage caused by aspirin.
(c) Basic drugs attain higher concentration intracellularly (pH 7.0 vs 7.4 of plasma).
(d) Acidic drugs are ionized more in alkaline urine—do not back diffuse in the kidney tubules
and are excreted faster. Accordingly, basic drugs are excreted faster if urine is acidified.
Lipid-soluble nonelectrolytes (e.g. ethanol, diethyl-ether) readily cross biological membranes
and their transport is pH independent.
Filtration
Filtration is passage of drugs through aqueous pores in the membrane or through paracellular spaces. This can be accelerated if hydrodynamic flow of the solvent is occurring under hydrostatic or osmotic pressure gradient, e.g. across most capillaries including glomeruli. Lipid-insoluble drugs cross biological membranes by filtration if their molecular size is smaller than the diameter of the pores . Majority of cells (intestinal mucosa, RBC, etc.) have very small pores (4 Å) and drugs with MW > 100 or 200 are not able to penetrate. However, capillaries (except those in brain) have large paracellular spaces (40 Å) and
most drugs (even albumin) can filter through these. As such, diffusion of drugs across capillaries is dependent on rate of blood flow through them rather than on lipid solubility of
the drug or pH of the medium.
Specialized transport
This can be carrier mediated or by pinocytosis.
Carrier transport
All cell membranes express a host of transmembrane proteins which serve as carriers or
transporters for physiologically important ions, nutrients, metabolites, transmitters, etc. across the membrane. At some sites, certain transporters also translocate xenobiotics, including drugs and their metabolites.
In contrast to channels, which open for a finite time and allow passage of specific ions, transporters combine transiently with their substrate (ion or organic compound)—undergo a conformational change carrying the substrate to the other side of the membrane where the substrate dissociates and the transporter returns back to its original state....
Illustration of different types of carrier mediated transport across biological membrane
ABC—ATP-binding cassettee transporter; SLC—Solute carrier transporter; M—Membrane
A. Facilitated diffusion: the carrier (SLC) binds and moves the poorly diffusible substrate along its concentration gradient (high to low) and does not require energy
B. Primary active transport: the carrier (ABC) derives energy directly by hydrolysing ATP and moves the substrate against its concentration gradient (low to high)
C. Symport: the carrier moves the substrate ‘A’ against its concentration gradient by utilizing energy from downhill movement of another substrate ‘B’ in the same direction
D. Antiport: the carrier moves the substrate ‘A’ against its concentration gradient and is energized by the downhill movement of another substrate ‘B’ in the opposite direction..
