Pharmacokinetics : Membrane Transport Of Drugs

Pharmacokinetics

Pharmacokinetics is defined as the quantitative study of a drug’s entry, passage through, and exit from the body. The pharmacokinetic properties of the drug determine its concentration at the site of action, which in turn affects the intensity of response. The route of administration, dosage, latency of onset, time of peak action, duration of action, and frequency of drug administration are thus determined by pharmacokinetic considerations.

Table of Contents

All the pharmacokinetic processes involve transport of the drug across biological membranes.

Membrane transport of drugs

Biological membrane is a bilayer of phospholipid and cholesterol molecules that is roughly 100 Å thick. The nonpolar hydrocarbon chains are embedded in the matrix to form a continuous sheet, and the polar groups of these molecules—glyceryl phosphate attached to ethanolamine/choline or the hydroxyl group of cholesterol—are oriented at the two surfaces.

As a result, the membrane gains high electrical resistance and relative impermeability. Protein molecules, both intrinsic and extrinsic, are adsorbed on the lipid bilayer. Depending on the type of cell or organelle, different membranes have different specific lipid and protein compositions.

The following methods are used to transport drugs across membranes: (a) passive diffusion and filtration (b) specialized transport

Passive diffusion

The concentration gradient of the drugs causes them to diffuse across the membrane; the membrane is not actively involved in this process. Drugs that dissolve in lipids are known as lipid-soluble drugs, and the rate of transport of these drugs is directly proportional to their lipid: water partition coefficient. Diffusion is accelerated by higher concentrations and concentration differences.

There is also influence of pH in the membrane transport, most drugs are weak electrolytes, meaning their ionization is pH-dependent. In contrast, strong electrolytes are nearly completely ionized at both acidic and alkaline pH . The equation describes the ionization of a weak acid HA.

pH = pKa + log [A^–] / [HA]

The acidic dissociation constant of a weak electrolyte’s negative logarithm is represented by the symbol pKa. It is the same number as the pH at which a medicine has 50% ionization. Weakly acidic drugs ionize more at alkaline pH, resulting in a 10-fold change in ionization, if pH is raised by one scale.

Due to lipid insoluble ions, weakly basic and weakly acidic drugs are distributed differently on the two sides when weakly basic drugs ionize more at acidic pH levels. Lipid soluble non-electrolytes easily cross biological membranes and their transport is pH dependent.

Filtration

Drugs are filtered when they pass through paracellular gaps or aqueous pores in membranes. If the solvent is hydrodynamically flowing under an osmotic or hydrostatic pressure gradient, as is the case across the majority of capillaries, including glomeruli, this process can be expedited. Drugs that are lipid-insoluble can pass through biological membranes by filtering through them if their molecular size is smaller than the pore diameter.

The majority of cells (intestinal mucosa, RBC, etc.) have extremely tiny pores (4 Å), making it impossible for medications with MW > 100 or 200 to pass through. However, most medications, including albumin, can pass through the large paracellular spaces (40 Å) found in capillaries (apart from those in the brain). Therefore, blood flow through capillaries determines the rate at which drugs diffuse through them, not the drug’s lipid solubility or the medium’s pH.

Specialized transport

Specialized transport can occur through a carrier transport or through pinocytosis.

Carrier transport

Transmembrane proteins, which are found in cell membranes, facilitate the passage of ions, nutrients, metabolites, and foreign substances. Unlike channels that permit finite ion passage, these transporters combine transiently with their substrate, go through conformational changes, and then dissociate, returning to its original state. Carrier transport is slower than channel flux, substrate-specific, saturable, and competitively inhibited by analogs. Depending on the amount of energy needed, there are two types: facilitated diffusion and active transport,

Facilitated diffusion

As a member of the super-family of solute carrier (SLC) transporters, the transporter functions in a passive manner without requiring energy and moving the substrate in the direction of its electrochemical gradient, that is, from a concentration that is higher to one that is lower. It only helps a poorly diffusible substrate to permeate, such as when glucose is taken up by the glucose transporter GLUT 4 and enters muscle and fat cells.

Active transport

It moves the solute against its electrochemical gradient (low to high), needs energy, and is inhibited by metabolic poisons. As a result, the solute accumulates selectively on one side of the membrane. Drugs like levodopa and methyl dopa that are associated with normal metabolites can use the transport mechanisms intended for them. Depending on where the driving force comes from, active transportation can be either primary or secondary.

Primary active transport: Energy is obtained directly by the hydrolysis of ATP.

Secondary active transport: In this type of active transport effected by another set of SLC transporters, the energy required to pump one solute is derived from the downward movement of another solute.

Pinocytosis

Pinocytosis is the process of transporting particulate matter across cells using vesicles. This applies to proteins and other big molecules, and contribute little to transport of most drugs, except vitamin B12 which is absorbed rom the gut after binding to an intrinsic factor which is a protein.

Conclusion

Pharmacokinetics is the study of a drug’s entry, passage, and exit from the body. It determines the drug’s concentration at the site of action, which affects the intensity of response. The route of administration, dosage, latency of onset, time of peak action, duration of action, and frequency of drug administration are all determined by pharmacokinetic considerations. Drugs are transported across biological membranes, which are a bilayer of phospholipid and cholesterol molecules. Passive diffusion and filtration are methods used to transport drugs across membranes. Specialized transport can occur through carrier transport or through pinocytosis.

Frequently asked questions

What are the factors affecting drug transport across the cell membrane?

Drugs diffuse across a cell membrane from a region of high concentration (eg, gastrointestinal fluids) to one of low concentration (eg, blood). Diffusion rate is directly proportional to the gradient but also depends on the molecule’s lipid solubility, size, degree of ionization, and the area of absorptive surface

What is the most common method of drug transport across biological membranes?

Passive diffusion is most common method of drug transport across biological membranes.

What is the mechanism of drug transport across membrane?

Drug transporters are membrane proteins that regulate drug absorption, distribution, and excretion. Drugs, endogenous molecules, and toxins are transported across membranes via ATP hydrolysis or ion/concentration gradients.

Pharmacokinetics : Membrane Transport of Drugs