To be absorbed, a drug given orally must survive encounters with low pH and numerous gastrointestinal (GI) secretions, including potentially degrading enzymes. Peptide drugs (eg, insulin) are particularly susceptible to degradation and are not given orally. Absorption of oral drugs involves transport across membranes of the epithelial cells in the GI tract. Absorption is affected by
Differences in luminal pH along the GI tract
Surface area per luminal volume
Presence of bile and mucus
The nature of epithelial membranes
The oral mucosa has a thin epithelium and rich vascularity, which favor absorption; however, contact is usually too brief for substantial absorption. A drug placed between the gums and cheek (buccal administration) or under the tongue (sublingual administration) is retained longer, enhancing absorption.
The stomach is normally the first organ in which intense contact between a drug given orally and GI fluids occurs (for review, see [ 1 General reference Drug absorption is determined by the drug’s physicochemical properties, formulation, and route of administration. Dosage forms (eg, tablets, capsules, solutions), consisting of the drug plus... read more ]). Although the stomach has a relatively large epithelial surface, its thick mucous layer and short transit time limit drug absorption. These properties of the stomach can influence drug formulation and behavior. Because most absorption occurs in the small intestine, gastric emptying is often the rate-limiting step. Food, especially fatty food, slows gastric emptying (and rate of drug absorption), explaining why taking some drugs on an empty stomach speeds absorption. Drugs that affect gastric emptying (eg, parasympatholytic drugs) affect the absorption rate of other drugs. Food may enhance the extent of absorption for poorly soluble drugs (eg, griseofulvin), reduce it for drugs degraded in the stomach (eg, penicillin G), or have little or no effect.
The small intestine has the largest surface area for drug absorption in the GI tract, and its membranes are more permeable than those in the stomach. For these reasons, most drugs are absorbed primarily in the small intestine, and acids, despite their ability as un-ionized drugs to readily cross membranes, are absorbed faster in the intestine than in the stomach (for review, see [ 1 General reference Drug absorption is determined by the drug’s physicochemical properties, formulation, and route of administration. Dosage forms (eg, tablets, capsules, solutions), consisting of the drug plus... read more ]). The intraluminal pH is 4 to 5 in the duodenum but becomes progressively more alkaline, approaching 8 in the lower ileum. GI microflora may reduce absorption. Decreased blood flow (eg, in shock) may lower the concentration gradient across the intestinal mucosa and reduce absorption by passive diffusion.
Intestinal transit time can influence drug absorption, particularly for drugs that are absorbed by active transport (eg, B vitamins), that dissolve slowly (eg, griseofulvin), or that are polar (ie, with low lipid solubility; eg, many antibiotics).
To maximize adherence, clinicians should prescribe oral suspensions and chewable tablets for children < 8 years of age. In adolescents and adults, most drugs are given orally as tablets or capsules primarily for convenience, economy, stability, and patient acceptance. Because solid drug forms must dissolve before absorption can occur, dissolution rate determines availability of the drug for absorption. Dissolution, if slower than absorption, becomes the rate-limiting step. Manipulating the formulation (ie, the drug’s form as salt, crystal, or hydrate) can change the dissolution rate and thus control overall absorption.
1. Vertzoni M, Augustijns P, Grimm M, et al: Impact of regional differences along the gastrointestinal tract of healthy adults on oral drug absorption: An UNGAP review. Eur J Pharm Sci 134:153-175, 2019. doi:10.1016/j.ejps.2019.04.013
To achieve the desired therapeutic objective, the drug product must deliver the active drug at an optimal rate and amount.
FACTORS INFLUENCING DRUG ABSORPTION AND BIOAVAILABILITY
Biopharmaceutic Considerations in Dosage Form Design
To achieve the desired therapeutic objective, the drug product must deliver the active drug at an optimal rate and amount. By proper biopharmaceutic design, the rate and extent of drug absorption (also called as bioavailability) or the systemic delivery of drug to the body can be varied from rapid and complete absorption to slow and sustained absorption depending upon the desired therapeutic objective. The chain of events that occur following administration of a solid dosage form such as a tablet or a capsule until its absorption into systemic circulation are depicted in Fig. 2.14.
Fig. 2.14. Sequence of events in the absorption of drugs from orally administered solid dosage forms
The process consists of four steps:
1. Disintegration of the drug product.
2. Deaggregation and subsequent release of the drug.
3. Dissolution of the drug in the aqueous fluids at the absorption site.
4. Absorption i.e. movement of the dissolved drug through the GI membrane into the systemic circulation and away from the absorption site
As illustrated in Fig. 2.14, the drug may also dissolve before disintegration or deaggregation of the dosage form, and before or after reaching the absorption site. Unless the drug goes into solution, it cannot be absorbed into the systemic circulation.
In a series of kinetic or rate processes, the rate at which the drug reaches the systemic circulation is determined by the slowest of the various steps involved in the sequence. Such a step is called as the rate-determining or rate-limiting step (RDS). The rate and extent of drug absorption from its dosage form can be influenced by a number of factors in all these steps. The various factors that influence drug absorption (also called as biopharmaceutic factors in the dosage form design) can be classified as shown in Table 2.2.
TABLE 2.2.
Factors influencing GI Absorption of a Drug from its Dosage Form
A. PHARMACEUTICAL FACTORS: include factors relating to the physicochemical properties of the drug, and dosage form characteristics and pharmaceutical ingredients
I. Physicochemical Properties of Drug Substances
1. Drug solubility and dissolution rate
2. Particle size and effective surface area
3. Polymorphism and amorphism
4. Pseudopolymorphism (hydrates/solvates)
5. Salt form of the drug
6. Lipophilicity of the drug
7. pKa of the drug and gastrointestinal pH
8. Drug stability
9. Stereochemical nature of the drug
II. Dosage Form Characteristics and Pharmaceutical Ingredients (Pharmaco-technical Factors)
1. Disintegration time (tablets/capsules)
2. Dissolution time
3. Manufacturing variables
4. Pharmaceutical ingredients (excipients/adjuvants)
5. Nature and type of dosage form
6. Product age and storage conditions
B. PATIENT RELATED FACTORS: include factors relating to the anatomical, physiological and pathological characteristics of the patient
1. Age
2. Gastric emptying time
3. Intestinal transit time
4. Gastrointestinal pH
5. Disease states
6. Blood flow through the GIT
7. Gastrointestinal contents:
a. Other drugs
b. Food
c. Fluids
d. Other normal GI contents
8. Presystemic metabolism by:
a. Luminal enzymes
b. Gut wall enzymes
c. Bacterial enzymes
d. Hepatic enzymes