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Evidence for a saturable component in isoniazid transfer across rat small intestine in vitro

It is well known that isoniazid is a drug that is rapidly absorbed after oral administration (Genazzani et al 1966; Gelber et a1 1969). As a weak base it is probably absorbed mainly in the small intestine (Schanker 1961). Studying isoniazid transport across rat small intestine in vitro, Barley et al (1972) concluded that the drug was transported by passive diffusion. However, its good water solubility and the almost total dissociation of its hydrazine moiety (pKa = 10.8) at physiological pH cannot be regarded as favourable for penetration through lipid barriers like intestinal epithelium by passive diffusion. Since Barley et al (1972) based their conclusion on experiments with a limited number of relatively high isoniazid concentrations, we have reexamined the problem of intestinal transfer of isoniazid using a wider range of concentrations (0.5-50 mM) and a modified perfusion technique of rat small intestine in vitro. An everted isolated segment of the rat proximal ileum, approximately 10 cm long was suspended in 70 ml phosphate buffer (KH2PO4/NazHPO4. 12H2, pH = 6.0) representing the mucosal compartment into which isoniazid was introduced at the beginning of the experiment. Continuous bubbling by air ensured mixing of the entire volume of this Compartment. The serosal side of the segment was continuously washed by Ringer solution from a reservoir (volume 500 ml) by means of a peristaltic pump (Desaga Resomat 14700, Dibbern, FRG) at a rate of 3.5 ml min-1. The solution in the reservoir was continuously mixed by means of a magnetic mixer assuring a constant concentration in all of the system. The temperature of both solutions was maintained at 37 “C thermostatically. The concentrations of isoniazid in the serosal compartment were continuously recorded for 10 min after