Physiological Factors and Drug Absorption | Pharmacokinetics

This article throws light upon the eight main physiological factors that affect the rate of drug absorption. The factors are: 1. Passage of Drug Molecule Across Membranes 2. pKa 3. pH – pka Partion Concept 4. pH-Partition Hypothesis 5. Active Transport 6. Facilitated Diffusion 7. Pinocytosis (Vesicular Transport) 8. Pore or Convective Transport.

Physiologic Factor # 1. Passage of Drug Molecule Across Membranes:

Before the drug reaches its site of action it has to cross the cellular membranes. The cell membranes are lipoprotein structures and are semi-permeable. Physiological properties of drug molecules influence the rate at which the drug passes the cell membrane. Many drugs contain both lipophilic and hydrophilic chemical constituents.

Those drugs which are more lipid soluble (Lipophilic) pass the membrane more easily than less lipid soluble or water soluble (hydrophilic) drugs. For weak electrolytes, such as weak acids and bases, the extent of ionization influences the rate of drug transfer.

The ionized moiety of drug contains a charge and is more water soluble than the non-ionized (Unionized) species of drug, which is more lipid soluble. The extent of ionization of a weak electrolyte will depend on both the pK_a of the drug and the pH of medium in which the drug is dissolved.

Physiologic Factor # 2. pK_a:

The pK_a is defined as the pH at which a drug is half ionized and half un-ionized. It plays an important role when considering the absorption and bioavailability of a drug across the membranes and in calculation of milk to plasma ratio or urine to plasma ratio. The following table shows the pK_a values of some drugs commonly used in the animal treatment.

Physiologic Factor # 3. pH – pk_a Partion Concept:

The following equation has been given by Henderson and Hasselbalch pertaining to weak acids and bases to describe the relationship between pH and pk_a:

For weak acids:

Rearrangement of the above equation gives,

Most drugs are weak organic acids or bases and exist in solution as both non- ionized and ionized forms. The non-ionized form is lipid soluble and can readily diffuse across the cell membrane to achieve the same equilibrium concentration on either side.

On the other hand the ionized portion of the drug is not soluble in lipid and can not diffuse through membrane. The degree of ionization of an organic electrolyte depends on its pka and pH of the environment.

Illustration of the effect of pH on distribution of Drugs:

Suppose, if the drug is acidic having pka-4.4, the gastric pH = 1.4 and plasma pH = 7.4.

Its absorption from g.i.t. will be as follows:

Another physicochemical property that influence the passage of a drug across a cell membrane is molecular size. Very small molecules like urea and small ions such as Na⁺, K⁺, and Li^– move across cell membranes rapidly as if the membrane contained pores.

In contrast, very large molecules, such as proteins, either do not traverse cell membranes or do so very poorly. Drugs which are tightly bound to proteins act as a macromolecule and do not cross cell membranes. This phenomenon occurs very often when drug binds to plasma proteins.

Physiologic Factor # 4. pH-Partition Hypothesis:

If the pH on side of a cell membrane differs from the pH on the other side of the membrane, then;

(i) The drug will ionize to different degrees on the respective sides of the membrane.

(ii) The total drug concentrations (ionized plus unionized drug) on either side of the membrane will be unequal.

(iii) The compartment in which the drug is more highly ionized will contain the greater total drug concentration.

Another factor that also influences the drug concentration on either side of the membrane is particular affinity of a drug for a tissue component, which would prevent the drug from freely moving back across the cell membrane.

Physiologic Factor # 5. Active Transport:

It is a carrier mediated specialized transport process which plays an important role in the renal and biliary secretion of many drugs and metabolites. A few lipid insoluble drugs are absorbed from the gastrointestinal tract by this process. In this process, a drug is transported against a concentration gradient i.e. the drug is transported from a lower concentration to a higher concentration.

Therefore, it requires energy and is also known as Up-Hill transport. In active transport process, the carrier binds the drug to form a carrier drug complex which shuttles the drug across the membrane and then dissociates the drug on the other-side of a membrane.

The carrier molecule may be highly selective for the drug molecule. If the drug structurally resembles a natural substrate that is actively transported, then it is likely to be actively transported by the same carrier mechanism. Therefore, drugs of similar structures may compete for the sites of absorption on the carrier.

Furthermore, carrier may become saturated if the drug concentration gets very high. A comparison between the rate of drug absorption and the concentration of drug at the absorption site is shown in Fig. 2.4. This figure evidence that for a drug absorbed by passive diffusion, the rate of absorption increases in a linear relationship to drug concentration.

In contrast, when a drug is absorbed by a carrier mediated process, the rate of drug absorption increases with drug concentration until the carrier molecules are completely saturated. At higher drug concentrations the rate of drug absorption remains constant.

Physiologic Factor # 6. Facilitated Diffusion:

It is also a carrier mediated transport system, differing from active transport in that drug moves along a concentration gradient (i.e., moves from a region of high drug concentration to lower drug concentration). Therefore, this system does not require energy input.

Since, this is a carrier involving process, it is saturable and structurally selective for the drug that shows competition kinetics for drug of similar structures. In terms of drug absorption, facilitated diffusion seems to play a very minor role.

Physiologic Factor # 7. Pinocytosis (Vesicular Transport):

It is a process of engulfment of large macromolecules. It is similar to phagocytosis by which the cell membrane invaginates to surround macromolecular material and then engulfs the material into the cell. The macromolecules remains within the cell as a vesicle or vaouole. Pinocytosis is the proposed process for absorption of the orally administered sabin polio vaccine and various large protein molecules.

Physiologic Factor # 8. Pore or Convective Transport:

Very small molecules such as urea, water and sugar are able to rapidly cross cell membranes as if the membrane contained channels or pores. However, such processes have never been directly observed by microscopy, the model of drug permeation through aqueous pores is used to explain renal excretion of drugs and uptake of drugs into the liver.