Diffusion determines the extent of accumulation into milk for most xenobiotics. However, cimetidine (CM) and ranitidine (RN) have been reported to accumulate to an extent greater than expected in rat and human milk, suggesting an active transport mechanism. In the present study, lactating Sprague Dawley rats were used in a random crossover design to characterize CM and RN active transport. Rat milk-to-serum ratios (M/S) (29.3 +/- 3.2 vs. 13.0 +/- 6.0; P < .05) and systemic clearance, Cls (12.9 +/- 1.2 vs. 4.6 +/- 1.0 ml/min, P < .05), were significantly reduced when exposed to a higher steady state infusion regimen of CM (0.4 and 30 mg/hr, respectively). By contrast, a infusion regimen of RN (0.4 and 30 mg/hr, respectively) produced modest, but not statistically significant, reductions in M/S (12.7 +/- 3.8 vs. 9.0 +/- 2.6; P > .05) and Cls (12.2 +/- 1.5 vs. 9.9 +/- 2.7 ml/min; P > .05). In a third set of rats, CM M/S (30.4 +/- 2.7 vs. 27.5 +/- 4.6; P > .05) and Cls (12.5 +/- 2.8 vs. 10.7 +/- 4.8 ml/min; P > .05), were marginally reduced by a concomitant RN infusion regimen (30 mg/hr) when compared with CM steady state infusions alone (0.4 mg/hr). By contrast, RN M/S (16.1 +/- 2.0 vs. 10.5 +/- 2.0; P < .05) and Cls (11.0 +/- 1.3 vs. 7.1 +/- 0.9 ml/min, P < .05), were significantly reduced by a concomitant CM infusion regimen (30 mg/hr) when compared with RN steady state infusions alone (0.4 mg/hr). Models for M/S and Cls as a function of CM steady state serum concentration were proposed and fitted to the data. Values for the maximum transport velocity of the transport system (Tmax') and the apparent dissociation constant (Km) for the M/S relationship were 326 and 55 micrograms/ml, respectively. For the Cls relationship, estimates of the nonsaturable clearance component (Clns), the maximum velocity of the saturable elimination process (Vmax), and Km were 3.6 ml/min, 135 micrograms/min, and 16 micrograms/ml, respectively. These observations provide evidence that CM and RN milk transfer can be saturated and inhibited, which would be consistent with the hypothesis that these compounds are actively transported across mammary epithelial cells into rat milk.