Modeling of intestinal drug absorption: roles of transporters and metabolic enzymes (for the Gillette Review Series).

The absorption of drugs via the oral route is a subject of intense and continuous investigation in the pharmaceutical industry since good bioavailability implies that the drug is able to reach the systemic circulation by mouth. Oral dry absorption is affected by both drug properties and the physiology of the gastrointestinal tract (GIT), or patient properties, including drug dissolution from the dosage form, the manner in which drug interacts with the aqueous environment and membrane, permeation across membrane, and irreversible removal by first-pass organs such as the intestine, liver, and lung (Martinez and Amidon, 2002). The purpose of this minireview is to highlight the processes governing drug bioavailability when the drug is already in solution, and emphasizes the roles of intestinal transporters and metabolism on oral bioavailability. The description of physical models for drug dissolution on drug absorption (Higuchi, 1967) or hepatic modeling (Pang and Chiba, 1994; Pang et al., 1998; Abu-Zahra and Pang, 2000), however, is beyond the scope of this work. The intestine, in addition to the liver, is an important tissue that regulates the extent of absorption of orally administered drugs, since the intestine and liver are involved in first-pass removal (Gibaldi et al., 1971; Rowland, 1972). The majority of drug absorption occurs at the small intestine because of the large surface area since the presence of villi and microvilli increases the absorptive area manyfold. The duodenum and jejunum possess the greatest surface areas due to the highest concentration of villi and microvilli in these regions, and surface area is least for the ileum (Magee and Dalley, 1986). The circulation of the intestine is unique in that the intestine is the anterior or portal tissue that regulates the flow of substrates to the liver. The intestinal venous blood constitutes the majority of the blood supply to the liver, accounting for 75% of total liver blood flow. For drugs that are highly cleared by the intestine, the contribution of the liver or lung to drug metabolism will become reduced, whereas for drugs that are poorly extracted by the intestine, the substrate is able to reach the next organs, the liver and the lung, for removal (Gugler et al., 1975; Xu et al., 1989; Hirayama et al., 1990). The concentration of drug entering the intestine (Xu et al., 1989; Hirayama and Pang, 1990) and the intestinal flow rate (Chen and Pang, 1997) alter the rate of drug delivery and affect the degree of saturability of intestinal enzymes. These ultimately affect the rates of intestinal and hepatic first-pass metabolism. Additionally, variables such as other drugs or food that alter the transit times within the gastrointestinal tract further modulate the absorption of substrates by the intestine (Welling, 1984; Kimura and Higaki, 2002).