Gastrointestinal absorption of drugs: methods and studies

Physico-chemical descriptors of drug molecules are often not adequate in pr edicting their oral bioavailability. In vitro methods can be useful in eval uating some of the different factors contributing to bioavailability. While physical parameters such as drug solubility may effect oral bioavailabilit y, in most cases, the major determining factors are likely to be metabolism , and absorption at the intestinal level. Metabolism may be preabsorptive, as with peptides, or during absorption, particularly as a result of the act ivity of the intracellular enzyme CYP3A4. Absorption may be transcellular ( membrane diffusion, carrier-mediated, endocytosis) or paracellular, while p -glycoprotein activity in the apical cell membrane may limit bioavailabilit y by expelling drugs from the mucosal cells. Knowledge of the absorption me chanism is important in determining formulation strategies. The different i n vitro techniques used to study absorption have advantages and disadvantag es. Ussing chambers can be useful to measure bidirectional transport, but m ost studies use simple salt media, and full tissue viability is doubtful. C aco-2 cell monolayers are human cells, but the system is static, and gives very low rates of transport, and exagerated enhancement of the paracellular route compared with small intestine. The rat everted gut sac incubated in tissue culture medium maintains tissue viability and gives reliable data, a lthough it is a closed system. In situ perfusion gives no information on ev ents at the cellular level, and absorption may be reduced by anaesthesia an d surgical manipulation. In vivo perfusion in man, with multichannel tubes, gives valuable data, but is not practical for screening. Pharmacokinetic m odelling can also give useful data such as the existence of different absor ption sites. Permeability values from the literature show that for small hy drophilic molecules, which pass by the paracellular route, the improved eve rted sac gives values close to those for humans, while values with Caco-2 c ells are orders of magnitude lower. (C) Elsevier, Paris.