Influence of lysine on cimetidine uptake and on excretion of cimetidine by the rat mammary gland

Cimetidine is actively transported into human and rat milk. However, the transporters involved have not been characterized. It is possible that xenobiotics may be actively transported into milk by an amino acid transport system. The objective of these studies was to determine the influence of lysine on the uptake of cimetidine into rat mammary explants (study 1), and on the excretion of cimetidine into rat milk (study 2). In study 1, excised lactating rat mammary epithelial tissue fragments were exposed to H-3-cimetidine and C-14-lysine in the presence of 10 muM, 1 mM, or 1 M cold lysine, and the uptake of H-3-cimetidine and C-14-lysine were measured by liquid scintillation counting after 5 or 20 minutes of incubation. After 5 minutes of incubation, 1 M lysine inhibited H-3-cimetidine uptake by 47.7% (SD +/- 6.5%), compared with 10 muM lysine (P < 0.05), and C-14-lysine uptake was also inhibited by 54.1% (SD +/- 6.4%) (P < 0.05). Similar results were seen after 20 minutes of incubation. In a randomized crossover study (study 2), 6 lactating female rats were infused to steady state with cimetidine (0.5 mg/h) in the presence or absence of lysine (360 mg/h). Cimetidine concentrations in serum and milk were determined by high-performance liquid chromatography. Cimetidine systemic clearance (28.6 +/- 15.0 mL/kg/min vs. 38.9 +/- 3.9 mL/kg/min, mean +/- SD) and milk to serum cimetidine ratio (M/S) (28.0 +/- 16.1 vs. 28.9 +/- 6.7), respectively, were not significantly altered by the presence or absence of lysine. Although 1 M lysine inhibited uptake of cimetidine in rat mammary explants, the concentrations of lysine used in this study, which approached toxicity in vivo, produced no significant effects on cimetidine transport into milk or the systemic clearance of cimetidine.