GASTROINTESTINAL PHYSIOLOGY

• Drugs, via drug delivery systems, are most often administered to human subjects by the oral route. Compared to other routes of drug administration, especially the intravenous route, the oral route is unusually complex with respect to the physicochemical conditions existing at the absorption site. Therefore, before we discuss how the biopharmaceutical properties of a drug in a dosage form can affect the availability and action of that drug, it is prudent to review gastrointestinal physiology.

Processes occurring along with drug absorption when drug molecules travel down the gastrointestinal tract and the factors that affect drug absorption.

Biologic Membrane

• The prevalent view of the gastrointestinal membrane is that it consists of a bimolecular lipoid layer covered on each side by protein, with the lipid molecule oriented perpendicular to the cell surface. The lipid layer is interrupted by small, water-filled pores with a radius of approximately 4 Å. A molecule with a radius of 4 Å or less can easily pass through these water-filled pores. Thus, membranes have a specialized transport system to assist the passage of water-soluble material and ions through the lipid interior, a process sometimes termed “convective absorption.”

• When permeation through the membrane occurs, the permeating substance is considered to have transferred from solution in the luminal aqueous phase to the lipid membrane phase, then to the aqueous phase on the other side of the membrane.

• Biologic membranes differ from a polymeric membrane in that they are composed of small amphipathic molecules, phospholipids, and cholesterol. The protein layer associated with membranes is hydrophobic in nature. Therefore, biologic membranes have a hydrophilic exterior and a hydrophobic interior.

Biologic Membrane

• Cholesterol is a major component of most mammalian biologic membranes, and its removal renders the membrane highly permeable. Cholesterol complexes with phospholipids, and its presence reduces the permeability of the membrane to water, cations, glycerides, and glucose.

• In addition to biopharmaceutical factors, several physiologic factors can also affect the rate and extent of gastrointestinal absorption. These factors are as follows: properties of epithelial cells, segmental activity of the bowel, degree of vascularity, effective absorbing surface area per unit length of gut, surface and interfacial tensions, electrolyte content and their concentration in luminal fluid, enzymatic activity in the luminal contents, and gastric emptying rate of the drug from stomach.

Sequence of events in drug absorption from formulations of solid dosage forms.

Basic structure of an animal cell membrane.

Mechanisms of Drug Absorption1) Passive Diffusion

• The transfer of most drugs across a biologic membrane occurs by passive diffusion, a natural tendency for molecules to move from a higher concentration to a lower concentration. This movement of drug molecules is caused by the kinetic energy of the molecules. The rate of diffusion depends on the magnitude of the concentration gradient across the membrane.

• The greater the concentration of drug at the absorption site, the faster is the rate of absorption.

Mechanisms of Drug Absorption1) Passive Diffusion

• A major source of variation is membrane permeability, which depends on the lipophilicity of the drug molecule. This is often characterized by its partition between oil and water. The lipid solubility of a drug, therefore, is a very important physicochemical property governing the rate of transfer through a variety of biologic membrane barriers.

• Although most drugs are absorbed from the gastrointestinal tract by passive diffusion, some drugs of therapeutic interest and some chemicals of nutritional value, such as amino acids, dipeptides and tripeptides, glucose, and folic acid, are absorbed by the action of transporter proteins (i.e., a carrier-mediated transport mechanism).

• The usual requirement for active transport is structural similarities between the drug and the substrate normally transported across the membrane. Active transport differs from passive diffusion in the following ways: 1) The transport of the drug occurs against a concentration gradient; 2) the transport mechanism can become saturated at high drug concentration; and 3) a specificity for a certain molecular structure can promote competition in the presence of a similarly structured compound. This, in turn, can decrease the absorption of a drug.

Mechanisms of Drug Absorption1) Carrier-Mediated or Active Transport

Mechanisms of Drug Absorption1) Carrier-Mediated or Active Transport

PHYSICOCHEMICAL FACTORS AFFECTING DRUG ABSORPTION

• The pH-Partition Hypothesis on Drug Absorption

1. The gastrointestinal and other biologic membranes act like lipid barriers.

2. The un-ionized form of the acidic or basic drug is preferentially absorbed.

3. Most drugs are absorbed by passive diffusion.

4. The rate of drug absorption and amount of drug absorbed are related to the drug’s oil–water partition coefficient (i.e., the more lipophilic the drug the faster is its absorption).

5. Weak acidic and neutral drugs are absorbed from the stomach, but basic drugs are not.

• When a drug is administered intravenously, it is immediately available to body fluids for distribution to the site of action. However, all extravascular routes, such as oral, intramuscular, sublingual, buccal, subcutaneous, dermal, rectal, and nasal routes, can influence the overall therapeutic activity of the drug, primarily because of its dissolution rate, a step that is necessary for a drug to be available in a solution form. When a drug is administered orally in a dosage form such as a tablet, capsule, or suspension, the rate of absorption across the biologic membrane frequently is controlled by the slowest step in the following sequence:

PHYSICOCHEMICAL FACTORS AFFECTING DRUG ABSORPTION

For very weak acids, pK a values greater than 8.0 are predominantly un-ionized at all pH values between 1.0 and 8.0. Profound changes in the un-ionized fraction occur with pH for an acid with a pKa value that lies within the range of 2.0 to 8.0. Although the fraction un-ionized of even strong acids increases with hydrogen ion concentration, the absolute value remains low at most pH values shown.

Estimation of Drug Absorption

• An antibiotic EMUMYCINE has a pKa of 4. What would be its main absorption site?

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Biopharmaceutical Drug Classification

• CLASS I DRUGS (HIGH SOLUBILITY AND HIGH PERMEABILITY

• CLASS II DRUGS (LOW SOLUBILITY AND HIGH PERMEABILITY)

• CLASS III DRUGS (HIGH SOLUBILITY AND LOW PERMEABILITY)

• CLASS IV DRUGS (LOW SOLUBILITY AND LOW PERMEABILITY)

Efflux Transporters• More recently (33–37), the role of efflux transporters in influencing

the permeability and the overall bioavailability of drugs has emerged and gained considerable attention. Among these transporters is P-gp, which is expressed on the luminal surface of normal intestinal mucosa. Unlike absorptive transporters that increase the uptake of a substrate from intestinal lumen, P-gp impedes uptake by returning the portion of drug entering the mucosa back to the lumen in a concentration-dependent manner. Two types of P-gp have been observed in mammals: drug-transporting P-gp and phospholipid transporting P-gp.

• The localization suggests that P-gp functionally can protect the body against toxic xenobiotics by excreting these compounds into bile, urine, and the intestinal lumen and by preventing their accumulation in brain and testes. Thus, P-gp can have a significant role in drug absorption and disposition in human and animals. An increasing number of drugs have been shown to be substrate for P-gp.

Prodrugs

• Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacologic effect. In both drug discovery and development, prodrugs have become an established tool for improving physiochemical, biopharmaceutical, or pharmacokinetic properties of pharmacologically active agents. The rationale behind the use of a prodrug is generally to optimize absorption, distribution, metabolism, and excretion (ADME) processes.

• Prodrugs are usually designed to improve oral bioavailability due to poor absorption from the gastrointestinal tract. Prodrugs are now an established concept to overcome barriers to a drug’s usefulness. About 5% to 7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend.

Type of Prodrugs• Hard Prodrug: A hard prodrug is a biologically active compound

with a high lipid solubility or high water solubility having a long biologic half-life.

• Soft Prodrug: A soft drug is a biologically active compound that is biotransformed in vivo in a rapid and predictable manner into nontoxic moieties.

• Carrier-Linked Prodrug: A carrier-linked prodrug is a compound that contains an active drug linked to a carrier group that can be removed enzymatically. These prodrugs are generally esters or amides, and such a prodrug would have greatly modified lipophilicity due to the attached carrier. The active drug is realized by hydrolytic cleavage either chemically or enzymatically.

• Mutual Prodrug: Two, usually synergistic, drugs are attached to each other. A bipartite or tripartite prodrug is one in which the carrier is a synergistic drug with the drug to which it is linked.

Major Objectives of Prodrug Design

• IMPROVED BIOAVAILABILITY • IMPROVED AQUEOUS SOLUBILITY • IMPROVED PASSIVE INTESTINAL ABSORPTION • PROTECTION AGAINST FAST METABOLISM• IMPROVEMENT OF TASTE AND ODOR• CHANGE OF PHYSICAL FORM OF API• REDUCTİON OF PAIN ON INJECTION

A simplified representative illustration of the prodrug concept.

• The drug–promoiety is the prodrug that is typically pharmacologically inactive. In broad terms, the barrier can be thought of as any liability or limitation of a parent drug that prevents optimal (bio)pharmaceutical or pharmacokinetic performance, and which has to be overcome for the development of a marketable drug. The drug and promoiety are covalently linked via bioreversible groups that are chemically or enzymatically labile, such as those shown here. The ‘ideal’ prodrug yields the parent drug with high recovery ratios, with the promoiety being non-toxic

Common functional groups on parent drugs that are amenable to prodrug design (shown in green)

• Most prodrug approaches require a ‘synthetic handle’ on the drug, which are typically heteroatomic groups.

Examples: Prodrugs for improved lipophilicity or permeability

Examples: Prodrugs for improved aqueous solubility

Other selected examples• Capecitabine (Xeloda) is a prodrug that has reduced gastrointestinal toxicity

and high tumour selectivity. The enzymatic bioconversion pathway initiates in the liver, where human carboxylesterases 1 and 2 (CES1 and CES2) cleave the ester bond of the carbamate142. This is followed by a fast, spontaneous decarboxylation reaction resulting in 5′-deoxy‑5-fluorocytidine (5′-dFCyd)144. Generation of the parent drug continues in the liver, and to some extent in tumours, by cytidine deaminase (CDA), which converts 5′-dFCyd to 5′-deoxyuridine (5′-dFUrd). Finally, thymidine phosphorylase (dThdPase; also known as ECGF1) liberates the active drug 5′‑fluorouracil in tumours7,144