Carrier-Mediated Uptake of Nicotinic Acid by Rat Intestinal Brush-Border Membrane Vesicles and Relation to Monocarboxylic Acid Transport

The intestinal transport of [¹⁴C] nicotinic acid was investigated at 27 °C by using brush-border membrane vesicles (BBMV) isolated from the rat small intestine. The osmolarity sensitive uptake by BBMV showed a remarkable overshoot phenomenon in the presence of an inward-directed H⁺ gradient (pH_in = 7.5, pH_out = 6.0). In contrast, the imposition of a Na+ gradient ([Na⁺]in = 0 mM, [Na⁺]out = 100 mM) had no stimulatory effect on the uptake of [¹⁴C]nicotinic acid. The remarkable pH-dependence of the initial uptake showing an increase of the uptake rate with decreasing the extra-vesicular pH disappeared completely in the presence of a structural analogue, isonicotinic acid, at pH below 6.5. In the presence of a H⁺ gradient, the initial uptake of [¹⁴C]nicotinic acid was saturable with the apparent K_t of 4.43 mM and J_max of 2.55 nmol/mg protein/15 s. The uptake was increased by the imposition of an inside-positive membrane potential and was significantly inhibited by monocarboxylic acids such as benzoic acid, salicylic acid, acetic acid, propionic acid, valproic acid and L-lactic acids as well as two isomers (isonicotinic acid and picolinic acid). The uptake was not inhibited by nicotinamide, nicotinyl alcohol, D-glucose, p-aminohippuric acid, glycyl-L-proline, succinic acid and an exchange transport inhibitor. From these results it was concluded that nicotinic acid is transported through the intestinal brush-border membrane by a carrier-mediated system and the system can recognize some acidic drugs with a monocarboxylic group. The pH dependent intestinal uptake of nicotinic acid can be ascribed to the proton-coupled and active carrier-mediated transport mechanism rather than a simple diffusion of the undissociated nicotinic acid to follow a pH-partition hypothesis.