Absorption

Absorption

Bioavailability is the fraction of an ingested dose of a drug that is absorbed into the systemic circulation, compared with the same dose of the com-pound injected intravenously, which is directly injected into the systemic circulation. Bioavailability of a drug is determined during new product development.

Bioequivalence, on the other hand, is a comparison of relative bio-availability of two dosage forms in terms of the rate and extent of the drug levels achieved in the systemic circulation and the maximum drug concentration reached. Generic drugs are required to satisfy statistical cri-teria of bioequivalence to the branded version before they can be considered equivalent.

In the case of oral dosage forms, drug bioavailability depends on the rate and extent of drug absorption from the GI tract. Drug absorption from the gut depends on many factors, such as the drug’s solubility and intrinsic dis-solution rate in the GI fluids, which are influenced by GI pH and motility, and the drug’s particle size and surface area. Thus, an interplay of physico-chemical properties of the drug and physiological properties of the GI tract determines the outcome of factors that determine drug absorption.

Drug absorption is affected not only by the properties of drug and its dosage forms but also by the nature of the biological membranes. Drugs pass through living membranes by the following processes (Figure 4.4):

1. Passive diffusion

a. Simple diffusion

b. Facilitated diffusion

i. Channel-mediated transport

ii. Carrier-mediated transport

2. Active transport

Passive diffusion can also be classified as paracellular or transcellular, depending on the route of drug absorption across the epithelial cell barrier. The surface lining of the GI tract consists of epithelial cells attached to each other by tight junctions formed through their membranes. Drug transport across the tight junctions between cells is known as paracellular transport. It involves both diffusion and the convective flow of water accompany-ing water-soluble drug molecules. Drug transport by absorption into the

Figure 4.4 An illustration of the main transport processes across cellular membranes.

epithelial cell from the gut’s lumen side, followed by release of the drug molecule from the epithelial membrane on the other side of the epithelial cell into the systemic circulation, is known as transcellular transport.

Passive transport

Passive transport can be divided into simple diffusion, carrier-mediated dif-fusion, and channel-mediated diffusion (Figure 4.4).

Simple diffusion

Biological membranes are lipoidal in nature; that is, they are made of lipid bilayers, with hydrophobic tails in the center and hydrophilic heads fac-ing the aqueous environment on either side. Therefore, hydrophobic lipid-soluble drugs of low molecular weight can pass through membranes by simple diffusion. Passive transport by simple diffusion is driven by differ-ences in drug concentration on the two sides of the membrane. In intestinal absorption, for example, the drug travels by passive transport from a region of high concentration in the GI tract to a region of low concentration in the systemic circulation. Given the instantaneous dilution of the absorbed drug once it reaches the bloodstream, sink conditions are essentially maintained at all times.

Carrier-mediated transport

Carrier-mediated transport is a passive diffusion process that involves facil-itation or increase of diffusion rate by the involvement of a carrier protein embedded in the biological membrane. It differs from active transport in that the drug moves along a concentration gradient (i.e., from a region of high concentration to the one of low concentration) and that this system does not require energy input; that is, the carrier does not use energy, such as adenosine triphosphate (ATP), to transport the drug. Carrier-mediated transport is saturable, structurally selective for the drug, and shows com-petition kinetics for drugs of similar structures. Carrier-mediated transport does not require the substrate to be lipophilic: both hydrophilic and lipo-philic solutes can be transported in this manner.

Amino acid transporters, oligopeptide transporters, glucose transport-ers, lactic acid transporters, phosphate transporters, bile acid transporters, and other transporters facilitate drug transport across the GI tract, espe-cially the small intestine. Transporters are specific proteins in the biological membranes that transport the molecules (e.g., glucose) across the mem-brane. Transporters bind to the molecule, transport the molecule across the membrane, and then release it on the other side. The transporter remains unchanged after the process.

Channel-mediated transport

A fraction of the cell membrane is composed of aqueous-filled pores or channels, which are continuous across the membrane. These pores offer a pathway parallel to the diffusion pathway through the lipid bilayer. Channel-mediated transport (also known as port or convective transport) plays an important role in the transport of ions and charged drugs, espe-cially in the case of renal excretion and hepatic uptake of drugs. Certain transport proteins may form an open channel across the lipid membrane of the cell. Small molecules, including drugs, move more rapidly through the channel by diffusion than by simple diffusion across the membrane due to facilitation by the solvent and if their diffusion rate in the solvent is higher than in the lipoidal membrane.

Fick’s laws of diffusion in drug absorption

Transport of a drug by diffusion across a membrane such as the GI mucosa is represented by Fick’s law equation:

where:

M is the amount of drug in the gut compartment at time t

D_m is the diffusion coefficient or diffusivity of the drug in intestinal membrane

S_membrane is the surface area of the membrane

K_{membrane/intestinal ⋅fluid} is the partition coefficient of the drug between the membrane and the aqueous intestinal fluid

h_membrane is the membrane’s thickness

C_gut is the drug concentration in the gut or intestinal compartment

C_plasma is the drug concentration in plasma compartment

Since the absorbed drug is instantaneously diluted and rapidly removed from the absorption site by the systemic circulation, C_plasma → 0. Therefore, Equation 4.26 becomes:

The left-hand side of Equation 4.27 can be converted into concentration units, since:

C_gut = M/V

On the right-hand side of the equation, the diffusion coefficient, membrane area, partition coefficient, and membrane thickness can be combined to yield a permeability coefficient.

where C_gut and P_gut are the concentration and permeability coefficient, respectively, for drug passage from intestine to plasma. Similarly, C_plasma and P_plasma are the concentration and permeability coefficient, respectively, for the reverse passage of drug from plasma to intestine. These equations demonstrate that the ratio of absorption rates in the intestine-to-plasma and the plasma-to-intestine directions depends on the ratio of permeability coefficients, drug concentrations, and volumes of drug distribution.

Active transport

Active transport involves the use of transmembrane proteins that require the use of cellular energy (usually ATP) to actively pump substances into or out of the cell. In active transport, the molecules usually move from regions of low concentration to those of high concentration. The most well-known active transport system is the sodium–potassium–ATPase pump (Na⁺/K⁺ ATPase), which maintains an imbalance of sodium and potassium ions inside and outside the membrane, respectively, for neuronal signal transmission. The Na⁺/K⁺ pump is an antiport; it transports K⁺ into the cell and Na⁺ out of the cell at the same time, with no expenditure of ATP. Other active trans-port systems include the sodium–hydrogen ion pump of the GI tract, which maintains gastric acidity while absorbing sodium ions, and the calcium ion pump, which helps maintain a low concentration of calcium in the cytosol.