Dependency of salivary excretion of mexiletine on the plasma concentration in rats.

The effect of steady-state plasma concentrations on the salivary excretion of mexiletine was investigated following simultaneous bolus intravenous injection of the loading dose (2.7 or 16.1 mg kg-1) and constant-rate intravenous infusion of the maintenance dose (15 or 102 micrograms min-1 kg-1) in male Wistar rats. Parotid and mandibular saliva was collected separately by stimulating salivation with a constant-rate infusion of pilocarpine (50 micrograms kg-1 min-1) in each rat. The low and high steady-state levels of mexiletine in blood plasma were attained at 0.259 +/- 0.123 and 1.616 +/- 0.475 micrograms mL-1, respectively, within the first 1-2 h after drug administration. Similarly, the two different steady-states in both parotid and mandibular saliva were attained. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva at any steady-state (P < 0.001 or 0.01). In parotid saliva, the high steady-state produced greater saliva to plasma drug concentration ratios (S/P ratio, 0.475 +/- 0.160) than that (0.386 +/- 0.131) at the low steady-state (P < 0.05). The S/P ratio for mandibular saliva at the high (0.204 +/- 0.060) steady-state was also greater than that at the low (0.158 +/- 0.050) steady-state (P < 0.01). These changes in the S/P ratio could not be explained by the pH for either parotid or mandibular saliva, but partially by the change in the unbound fraction of the drug which tended to be consistent with that in the ratio for both salivary glands. These findings suggest that the salivary excretion of mexiletine may be dependent on the plasma unbound concentration in rats.