The enteral drug administration involves three primary routes: oral, sublingual, and buccal. Oral ingestion is the most prevalent, safe, economical, and convenient method for drug administration. However, it has certain drawbacks, including limited absorption due to the drug's low water solubility or poor membrane permeability, possible emesis from GI mucosa irritation, destruction of drugs by digestive enzymes or low gastric pH, and irregular absorption along with food or other drugs.

Drugs in the GI tract may undergo metabolism before reaching the systemic circulation, mediated by the intestinal microbiome, mucosa, or liver enzymes. Absorption is influenced by factors such as absorption surface area, blood flow, the drug's physical state and concentration, and its aqueous solubility. Many drugs are absorbed by passive diffusion, favoring nonionized, lipophilic forms. Despite weak acids being better absorbed from the stomach and weak bases from the intestine, the large surface area of the small intestine allows for a greater drug absorption rate than the stomach.

The gastric emptying rate, affected by various factors like food caloric content, fluid volume, osmolality, temperature, pH, diurnal and interindividual variation, metabolic state, and ambient temperature, influences drug absorption. Estrogen also affects gastric emptying in women; emptying is slower for premenopausal women and for those on estrogen replacement therapy.

Certain drugs are administered with an enteric coating to prevent destruction by gastric secretions or to reduce gastric irritation.

Controlled-release preparations, designed for slow, uniform absorption, are advantageous for reducing administration frequency, maintaining overnight therapeutic effects, and decreasing undesired effects. They are particularly suitable for drugs with short half-lives or in specific patient groups, such as those receiving antiepileptic or antipsychotic agents.

The sublingual and buccal administration methods enable the direct diffusion of a drug into the bloodstream, bypassing the GI tract and enhancing absorption. These routes also bypass the first-pass effect in the liver, which can significantly increase the bioavailability of certain drugs. The venous drainage from the mouth leads directly to the superior vena cava, protecting the drug from premature metabolism and ensuring its rapid effectiveness upon reaching the heart and arterial system. For instance, sublingual nitroglycerin is used in the management of angina, and buccal midazolam is employed in the emergency treatment of epileptic seizures in children.