PHARMACOKINETICS: ABSORPTION

ABSORPTION 

Absorption is the transfer of a drug from its site of administration to the bloodstream via one of several mechanisms. The rate and efficiency of absorption depend on both factors in the environment where the drug is absorbed and the drug’s chemical characteristics and route of administration (which influence its bioavailability). For IV delivery, absorption is complete. That is, the total dose of drug administered reaches the systemic circulation (100% bioavailability). Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability. 

A. Mechanisms of absorption of drugs from the GI tract 

Depending on their chemical properties, drugs may be absorbed from the GI tract by passive diffusion, facilitated diffusion, active transport, or endocytosis. 

1. Passive diffusion: The driving force for passive absorption of a drug is the concentration gradient across a membrane separating two body compartments. In other words, the drug moves from a region of high concentration to one of lower concentration. Passive diffusion does not involve a carrier, is not saturable, and shows a low structural specificity. The vast majority of drugs gain access to the body by this mechanism. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores, whereas lipid-soluble drugs readily move across most biologic membranes due to their solubility in the membrane lipid bilayers. 

2. Facilitated diffusion: Other agents can enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. These carrier proteins undergo conformational changes, allowing the passage of drugs or endogenous molecules into the interior of cells and moving them from an area of high concentration to an area of low concentration. This process is known as facilitated diffusion. It does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier.

3. Active transport: This mode of drug entry also involves specific carrier proteins that span the membrane. A few drugs that closely resemble the structure of naturally occurring metabolites are actively transported across cell membranes using these specific carrier proteins. Energy-dependent active transport is driven by the hydrolysis of adenosine triphosphate. It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of higher drug concentration. The process shows saturation kinetics for the carrier, much in the same way that an enzyme-catalyzed reaction shows a maximal velocity at high substrate levels where all the active sites are filled with substrate.Active transport systems are selective and may be competitively inhibited by other cotransported substances.

4. Endocytosis and exocytosis: These types of drug delivery systems transport drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug filled vesicle. Exocytosis is the reverse of endocytosis and is used by cells to secrete many substances by a similar vesicle formation process. Vitamin B12 is transported across the gut wall by endocytosis, whereas certain neurotransmitters (for example, norepinephrine) are stored in intracellular membrane-bound vesicles in the nerve terminal and are released by exocytosis.

    

Factors influencing absorption 

1. Aqueous solubility: Drugs given in solid form must dissolve in the aqueous biophase before they are absorbed. For poorly water soluble drugs (aspirin, griseofulvin) rate of dissolution governs rate of absorption. Ketoconazole dissolves at low pH: gastric acid is needed for its absorption. Obviously, a drug given as watery solution is absorbed faster than when the same is given in solid form or as oily solution.

2. Blood flow: Blood circulation removes the drug from the site of absorption and maintains the concentration gradient across the absorbing surface. Increased blood flow hastens drug absorption just as wind hastens drying of clothes.

3. Concentration: Passive diffusion depends on concentration gradient; drug given as concentrated solution is absorbed faster than from dilute solution.

4. Total surface area available for absorption: With a surface rich in brush borders containing microvilli, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient.

5. Contact time at the absorption surface: If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. 

6. Dosageform: This affects drug absorption, because each route has its own peculiarities. 

Oral: Nonionized lipid soluble drugs, e.g. ethanol are readily absorbed from stomach as well as intestine at rates proportional to their lipid : water partition coefficient. Acidic drugs, e.g. salicylates, barbiturates, etc. are predominantly unionized in the acid gastric juice and are absorbed from stomach, while basic drugs, e.g. morphine, quinine, etc. are largely ionized and are absorbed only on reaching the duodenum.

Presence of food dilutes the drug and retards absorption. Further, certain drugs form poorly absorbed complexes with food constituents, e.g. tetracyclines with calcium present in milk; moreover food delays gastric emptying. Thus, most drugs are absorbed better if taken in empty stomach. However, there are some exceptions, e.g. fatty food greatly enhances lumefantrine absorption. Highly ionized drugs, e.g. gentamicin, neostigmine are poorly absorbed when given orally.

Subcutaneous and Intramuscular: By these routes the drug is deposited directly in the vicinity of the capillaries. Lipid soluble drugs pass readily across the whole surface of the capillary endothelium. Capillaries having large paracellular spaces do not obstruct absorption of even large lipid insoluble molecules or ions. Thus, many drugs not absorbed orally are absorbed parenterally. Absorption from s.c. site is slower than that from i.m. site, but both are generally faster and more consistent/ predictable than oral absorption. Application of heat and muscular exercise accelerate drug absorption by increasing blood flow, while vasoconstrictors.

Topical sites: Systemic absorption after topical application depends primarily on lipid solubility of drugs. However, only few drugs significantly penetrate intact skin.

7. Effect of pH on drug absorption: Most drugs are either weak acids or weak bases. Acidic drugs (HA) release a proton (H+), causing a charged anion (A–) to form.

 

Weak bases (RNH3+) can also release an H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (RNH2):

 

A drug passes through membranes more readily if it is uncharged. Thus, for a weak acid, the uncharged, protonated HA can permeate through membranes, and A– cannot. For a weak base, the uncharged form, RNH2, penetrates through the cell membrane, but RNH3+, the protonated form, does not. Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa. [Note: The pKa is a measure of the strength of the interaction of a compound with a proton. The lower the pKa of a drug, the more acidic it is. Conversely, the higher the pKa, the more basic is the drug.] Distribution equilibrium is achieved when the permeable form of a drug achieves an equal concentration in all body water spaces. [Note: Highly lipid-soluble drugs rapidly cross membranes and often enter tissues at a rate determined by blood flow.]

  

5. Expression of P-glycoprotein: P-glycoprotein is a multidrug transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. It is expressed throughout the body, and its functions include:  

• In the liver: transporting drugs into bile for elimination 

• In kidneys: pumping drugs into urine for excretion 

• In the placenta: transporting drugs back into maternal blood, thereby reducing fetal exposure to drugs 

• In the intestines: transporting drugs into the intestinal lumen and reducing drug absorption into the blood 

• In the brain capillaries: pumping drugs back into blood, limiting drug access to the brain Thus, in areas of high expression, P-glycoprotein reduces drug absorption. In addition to transporting many drugs out of cells, it is also associated with multi drug resistance.

Bioavailability

Bioavailability is the fraction of administered drug that reaches the systemic circulation. For example, if 100 mg of a drug are administered orally, and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7, or 70 percent. Determining bioavailability is important for calculating drug dosages for non-intravenous routes of administration. The route by which a drug is administered, as well as the chemical and physical properties of the agent, affects its bioavailability.  

Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with plasma drug levels achieved by IV injection, in which the total agent rapidly enters the circulation. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, the area under the curve (AUC) can be measured. This curve reflects the extent of absorption of the drug. [Note: By definition, this is 100 percent for drugs delivered intravenously.] Bioavailability of a drug administered orally is the ratio of the area calculated for oral administration compared with the area calculated for IV injection if doses are equivalent.

 

 Factors that influence bioavailability: In contrast to IV administration, which confers 100% bioavailability, oral administration of a drug often involves first-pass metabolism. This biotransformation, in addition to the drug’s chemical and physical characteristics, determines the amount of the agent that reaches the circulation and at what rate.  

a. First-pass hepatic metabolism: When a drug is absorbed across the GI tract, it first enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug that gains access to the systemic circulation is decreased. [Note: First-pass metabolism by the intestine or liver limits the efficacy of many drugs when taken orally. For example, more than 90 percent of nitroglycerin is cleared during a single passage through the liver, which is the primary reason why this agent is administered via the sublingual route]. Drugs that exhibit high first-pass metabolism should be given in sufficient quantities to ensure that enough of the active drug reaches the target concentration. 

 

b. Solubility of the drug: Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes. Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions. This is one reason why many drugs are either weak acids or weak bases.

Bioequivalence: 

Oral formulations of a drug from different manufacturers or different batches from the same manufacturer may have the same amount of the drug (chemically equivalent) but may not yield the same blood levels—biologically inequivalent.  Two preparations of a drug are considered bioequivalent when the rate and extent of bioavailability of the active drug from them is not significantly different under suitable test conditions.