Digestion
Digestion begins in the mouth with the secretion of saliva and its digestive enzymes. Food is formed into a bolus by the mechanical mastication and swallowed into the esophagus from where it enters the stomach through the action of peristalsis. Gastric juice contains hydrochloric acid and pepsin which would damage the walls of the stomach and mucus is secreted for protection. In the stomach further release of enzymes break down the food further and this is combined with the churning action of the stomach. The partially digested food enters the duodenum as a thick semi-liquid chyme. In the small intestine, the larger part of digestion takes place and this is helped by the secretions of bile, pancreatic juice and intestinal juice. The intestinal walls are lined with villi, and their epithelial cells is covered with numerous microvilli to improve the absorption of nutrients by increasing the surface area of the intestine.
Discovery and development of gastrointestinal lipase inhibitors
The lipase inhibitors lipstatin and orlistat act locally in the intestinal tract. They are minimally absorbed in the circulation because of their lipophilicity. Hence, they do not affect systemic lipases. 
The mechanism of lipase inhibitors in fat digestion is shown in figure 1. These inhibitors bind covalently as an ester to the serine hydroxyl group at the active site on pancreatic- and gastric lipases and form a stable complex.
This results in a conformational change in the enzyme which causes exposing of the catalytic active site. When the active site is exposed, the hydroxyl group on the serine residue is acylated. This leads to irreversible inactivation of the enzyme. 
The inactive lipase is incapable of hydrolysing fats into absorbable fatty acids and monoglycerides, therefore triglycerides are excreted undigested with faeces. With this mode of action calorie uptake from fat in food is limited, hence body weight is reduced. The main role of lipase inhibitors is therefore to inhibit lipases in the gastrointestinal tract, but they do not have significant activity against proteases, amylases or other digestive enzymes.