Nagasako S, Iwamoto K, Hayashibara M, Katagiri Y
Department of Pharmacy, Shimane Medical University Hospital, Izumo, Japan.
J Pharm Pharmacol. 1993 Feb;45(2):154-6. doi: 10.1111/j.2042-7158.1993.tb03705.x.
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.
在雄性Wistar大鼠中，静脉注射负荷剂量（2.7或16.1mg/kg）并同时持续静脉输注维持剂量（15或102μg/min/kg）后，研究了稳态血浆浓度对美西律唾液排泄的影响。通过以50μg/kg/min的恒定速率输注毛果芸香碱刺激每只大鼠流涎，分别收集腮腺和下颌下唾液。给药后1-2小时内，血浆中美西律的低稳态水平和高稳态水平分别达到0.259±0.123和1.616±0.475μg/mL。同样，腮腺和下颌下唾液也达到了两种不同的稳态。尽管两种唾液中美西律水平均低于血浆中的水平，但在任何稳态下，腮腺唾液中的药物水平始终高于下颌下唾液中的药物水平（P<0.001或0.01）。在腮腺唾液中，高稳态时的唾液与血浆药物浓度比（S/P比，0.475±0.160）高于低稳态时的比值（0.386±0.131）（P<0.05）。下颌下唾液在高稳态（0.204±0.060）时的S/P比也高于低稳态（0.158±0.050）时的比值（P<0.01）。腮腺或下颌下唾液的pH值无法解释S/P比的这些变化，但部分可由药物游离分数的变化来解释，该变化趋势与两个唾液腺比值的变化一致。这些发现表明，大鼠中美西律的唾液排泄可能取决于血浆游离浓度。
