Uptake of ibuprofen, indomethacin and ketoprofen into isolated rabbit parietal cells

In the United States and other countries, non-steroidal anti-inflammatory d rugs (NSAIDs) can be purchased without a prescription. Due to their widespr ead use, the drugs' most common side effect, gastric toxicity, becomes a mo re serious concern. Gastric toxicity can occur directly by contact with muc ous membranes or indirectly by the inhibition of prostaglandin production i n the gastric mucosa. We have studied the uptake of NSAIDs in gastric tissu e, specifically parietal cells removed from the rabbit stomach. New Zealand White rabbits were killed and then used to harvest parietal cel ls. The purified cells were used to study the uptake of ibuprofen, indometh acin and ketoprofen (NSAIDs) over time and under different experimental con ditions. The effects of concentration were investigated for all three NSAIDs. In add ition, indomethacin and ibuprofen were used to investigate the mechanism of uptake. Studies were determined for the effects of varied extracellular pH from pH 6 to 8, and inhibitory conditions from depressed temperature (5 de grees C), metabolic inhibitors (sodium azide and 2,4-dinitro-phenol), an io nophore (nigericin) and a sodium free support medium. The interaction of NS AIDs with lysed parietal cells was investigated also. Initial rate data indicated that Michaelis-Menten kinetics were apparent; h owever, poor solubility of all three NSAIDs prevented complete characteriza tion of the inclusion of a passive transport mechanism. Uptake showed a sta tistically significant increase (P = 0.01 to 0.05) as pH decreased, also su ggesting contribution from a passive mechanism. Studies with inhibitors sho wed minimal effects. However, uptake at equilibrium for the ionophore, nige ricin, showed a 10-fold increase over the control for ibuprofen (P = 0.005) and a 1.4-fold increase for indomethacin (P = 0.04). Depressed temperature (5 degrees C) increased the initial rate and uptake at equilibrium 2.1- an d 2.2-fold, respectively, for ibuprofen (P < 0.01). For indomethacin depres sed temperature increased the initial rate and uptake at equilibrium 2.7- a nd 5.2-fold, respectively (P < 0.01). The increases at 5 degrees C suggests that adsorption may be an important uptake component. Experiments with lys ed parietal cells showed a non-specific uptake phenomenon, suggesting an ad sorption component was occurring also.