Ishizaki J, Yokogawa K, Nakashima E, Takayasu T, Ohshima T, Ichimura F
Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Kanazawa University, Japan.
J Pharm Pharmacol. 1998 Feb;50(2):189-96. doi: 10.1111/j.2042-7158.1998.tb06175.x.
In rats the pharmacokinetic interactions between the anticholinergic drug biperiden and [3H]quinuclidinyl benzylate ([3H]QNB) or [3H]N-methylscopolamine ([3H]NMS) is affected by the sequence in which the drugs are administered. Drug concentrations in various tissues were determined after intravenous administration of [3H]QNB or [3H]NMS (325 ng kg(-1)). Biperiden (6.4 mg kg(-1)) was administered either 5 min before, concomitantly with or 20 min after injection of [3H]QNB or [3H]NMS. When biperiden was administered concomitantly with or before [3H]QNB, distribution of [3H]QNB among the regions of the brain and other tissues was reduced; at 4 h the ratio of the distribution of [3H]QNB for experimental animals to that for control animals ranged from 0.15 to 0.9. When biperiden was administered after [3H]QNB, the distribution of [3H]QNB in the brain and other tissues was significantly higher than for the other two treatments (P < 0.01). However, for [3H]NMS the sequence of administration had no effect on the distribution of the drug in the brain and other tissues except for the kidney. In-vitro, in crude synaptosomal membranes, the amount of [3H]QNB at 2 h relative to the control concentration at equilibrium was 87% when biperiden was added before [3H]QNB and 56% when biperiden was added after [3H]QNB. In both instances the concentration of [3H]NMS reached equilibrium within 30 min. These findings suggest that the difference between the rate constant of association and dissociation at the possible site of action gives rise to the effect of the sequence of administration on the pharmacokinetic interaction.
在大鼠中，抗胆碱能药物比哌立登与[3H]喹核醇基苯甲酸酯（[3H]QNB）或[3H]N-甲基东莨菪碱（[3H]NMS）之间的药代动力学相互作用受给药顺序的影响。静脉注射[3H]QNB或[3H]NMS（325 ng kg(-1)）后，测定各种组织中的药物浓度。比哌立登（6.4 mg kg(-1)）在注射[3H]QNB或[3H]NMS前5分钟、同时或注射后20分钟给药。当比哌立登与[3H]QNB同时或在其之前给药时，[3H]QNB在脑区和其他组织中的分布减少；在4小时时，实验动物与对照动物的[3H]QNB分布比率在0.15至0.9之间。当比哌立登在[3H]QNB之后给药时，[3H]QNB在脑和其他组织中的分布显著高于其他两种处理（P < 0.01）。然而，对于[3H]NMS，给药顺序除了对肾脏外，对药物在脑和其他组织中的分布没有影响。在体外，在粗制突触体膜中，当在[3H]QNB之前加入比哌立登时，2小时时相对于平衡时对照浓度的[3H]QNB量为87%，当在[3H]QNB之后加入比哌立登时为56%。在这两种情况下，[3H]NMS的浓度在30分钟内达到平衡。这些发现表明，在可能的作用位点上结合和解离速率常数的差异导致给药顺序对药代动力学相互作用产生影响。
