Nirogi Ramakrishna, Bhyrapuneni Gopinadh, Kandikere Vishwottam, Benade Vijay, Muddana Nageswararao, Saralaya Ramanatha, Irappanavar Shantaveer, Ponnamaneni Ranjithkumar, Mukkanti K
Pharmacokinetics and Drug Metabolism, Discovery Research, Suven Life Sciences Ltd, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad, 500034, India,
Eur J Drug Metab Pharmacokinet. 2012 Feb 3. doi: 10.1007/s13318-012-0081-1.
Psychotic and behavioral symptoms are common in patients with dementia. Thus, it is rational to assume that patients with dementia would gain benefit from combination therapy of an antipsychotic agent and a cognitive enhancer. Antipsychotics are not approved by the US FDA in elderly patients with dementia but their use is still prevalent in other population. In the current study, we investigate the effect of atypical antipsychotics on acetylcholine modulation by donepezil. In addition, the plasma pharmacokinetics on concurrent administration of these drugs was studied. Acetylcholine modulation was carried out in the ventral hippocampus of Sprague-Dawley rats using brain microdialysis technique. In a parallel group of animals, pharmacokinetic parameters were evaluated on administration of donepezil (5.0 mg kg(-1), ip) alone and in combination with olanzapine, clozapine, or quetiapine. Donepezil produced 348% increase in hippocampal acetylcholine levels. Coadministration of olanzapine and donepezil produced 393% increase in extracellular acetylcholine, and the effect was supported by a significantly (p < 0.05) decreased clearance of donepezil in plasma. Whereas, other plasma pharmacokinetic parameters of donepezil "AUC(0-24h), T (1/2) and T (max)" were moderately altered after this combination treatment. Concurrent administrations of clozapine or quetiapine with donepezil produced a non-significant change in acetylcholine levels in comparison to donepezil alone. The plasma pharmacokinetics of donepezil was unaltered. Results from this preclinical investigation indicate that extrapyramidal side effects may precipitate upon coadministration of donepezil with olanzapine. Care must be exercised by physicians and caregivers while administering these two drugs together.
精神病性和行为症状在痴呆患者中很常见。因此，有理由认为痴呆患者将从抗精神病药物和认知增强剂的联合治疗中获益。抗精神病药物未被美国食品药品监督管理局批准用于老年痴呆患者，但在其他人群中其使用仍然普遍。在当前的研究中，我们研究了非典型抗精神病药物对多奈哌齐调节乙酰胆碱的影响。此外，还研究了这些药物同时给药时的血浆药代动力学。使用脑微透析技术在Sprague-Dawley大鼠的腹侧海马中进行乙酰胆碱调节。在一组平行的动物中，评估了单独给予多奈哌齐（5.0mg kg(-1)，腹腔注射）以及与奥氮平、氯氮平或喹硫平联合给药时的药代动力学参数。多奈哌齐使海马乙酰胆碱水平增加了348%。奥氮平和多奈哌齐联合给药使细胞外乙酰胆碱增加了393%，并且血浆中多奈哌齐清除率显著降低（p<0.05）支持了这一效果。而在这种联合治疗后，多奈哌齐的其他血浆药代动力学参数“AUC(0-24h)、T(1/2)和T(max)”有适度改变。与单独使用多奈哌齐相比，氯氮平或喹硫平与多奈哌齐同时给药时乙酰胆碱水平无显著变化。多奈哌齐的血浆药代动力学未改变。这项临床前研究的结果表明，多奈哌齐与奥氮平联合给药可能会引发锥体外系副作用。医生和护理人员在同时使用这两种药物时必须谨慎。
