ON THE MECHANISMS OF ¹⁴C-NICOTINE DISTRIBUTION IN RAT SUBMAXILLARY GLAND IN VITRO

¹ Department of Pharmacology, Medical College of Virginia, Health Sciences Center, Virginia Commonwealth University, Richmond, Virginia

The uptake and efflux of nicotine (N methyl-¹⁴C) were studied under various incubation and washout conditions. The 60-minute ¹⁴C-nicotine space at an extracellular pH of 7.40 was 4.037 ± 0.255 (S.E.) ml/g. Elevation or depression of extracellular pH brought about a significant increase or decrease, respectively, in the ¹⁴C-nicotine space. In all cases, the intracellular/extracellular ratios were greater than those calculated from the intracellulax pH determined by 5,5-dimethyloxazolidine-2,4-dione-2-¹⁴C distribution. CN^-, 10^-5 M, or an increase (x 100) in the extracellular concentration of nicotine did not affect the 60-minute spaces. Temperature dependence of the 60-minute spaces was observed but could be explained solely by the effect of temperature on the pK₆ of the drug. Increasing or decreasing pH during efflux significantly decreased and increased the observed rate constants. It is conduded that the uptake of ¹⁴C-nicotine by submaxillary glands occurs by passive diffusion of the un-ionized species across the cell membrane and is followed by binding to intracellular sites and/or partitioning of the un-ionized drug into lipid compartments. The rate-limiting step in efflux is the dissociation of the drug from the cell membrane. The dissociation is greatly facilitated by the collision of a proton from the extracellular hydrogen ion pool.