Department of Equine and Small Animal Medicine, University of Helsinki, Helsinki, Finland.
Drug Metab Dispos. 2012 Mar;40(3):445-9. doi: 10.1124/dmd.111.042671. Epub 2011 Nov 23.
Growing evidence supports the use of (2R-trans)-N-(2-(1,3,4,7,12b-hexahydro-2'-oxo-spiro(2H-benzofuro(2,3-a)quinolizine-2,4'-imidazolidin)-3'-yl)ethyl) methanesulfonamide (MK-467), a peripherally acting α(2)-adrenoceptor antagonist, in conjunction with the sedative-anesthetic agent dexmedetomidine in animals to avoid hemodynamic compromise. We evaluated the possible effects of different doses of MK-467 on the plasma concentrations of dexmedetomidine in eight beagle dogs. Both drugs were administered intravenously. Each dog received five treatments: dexmedetomidine alone (10 μg/kg), MK-467 alone (250 μg/kg), and dexmedetomidine (10 μg/kg) combined with different doses of MK-467 (250, 500, and 750 μg/kg) in a randomized, crossover fashion. Selected pharmacokinetic parameters were calculated. The area under the time-concentration curve of dexmedetomidine was significantly greater after dexmedetomidine alone (by 101 ± 20%, mean ± 95% confidence interval) compared with that after dexmedetomidine and 250 μg/kg MK-467. Increasing the dose of the antagonist had no further effect on the exposure to dexmedetomidine. The apparent volume of distribution of dexmedetomidine was significantly smaller after dexmedetomidine alone compared with that after all treatments that included MK-467. Dexmedetomidine (10 μg/kg) did not significantly influence the plasma concentrations of MK-467 (250 μg/kg). The results suggest that the peripherally acting α(2)-adrenoceptor antagonist MK-467 markedly influenced the early disposition of dexmedetomidine without obvious effects on the later plasma concentrations of the drug.
越来越多的证据支持使用（2R-trans）-N-（2-（1,3,4,7,12b-六氢-2'-氧代螺[苯并呋喃（2,3-a）喹嗪-2,4'-咪唑烷]-3'-基）乙基）甲磺酰胺（MK-467），一种外周作用的α（2）-肾上腺素受体拮抗剂，与镇静麻醉剂右美托咪定联合使用，以避免血液动力学障碍。我们评估了不同剂量的 MK-467 对 8 只比格犬体内右美托咪定血浆浓度的可能影响。两种药物均静脉给药。每只狗接受 5 种处理：右美托咪定单独（10μg/kg），MK-467 单独（250μg/kg），以及右美托咪定（10μg/kg）与不同剂量的 MK-467（250μg/kg、500μg/kg 和 750μg/kg）以随机交叉方式联合使用。计算了选定的药代动力学参数。与右美托咪定单独（增加 101±20%，平均值±95%置信区间）相比，右美托咪定单独（10μg/kg）后右美托咪定的时间-浓度曲线下面积显著增加与右美托咪定和 250μg/kg MK-467 联合使用时。增加拮抗剂的剂量对右美托咪定的暴露没有进一步的影响。与所有包含 MK-467 的治疗方案相比，右美托咪定单独（10μg/kg）后右美托咪定的表观分布容积显著减小。右美托咪定（10μg/kg）对 MK-467（250μg/kg）的血浆浓度无明显影响。结果表明，外周作用的α（2）-肾上腺素受体拮抗剂 MK-467 明显影响了右美托咪定的早期处置，而对药物的后期血浆浓度没有明显影响。
