DIHYDROPYRIDINE CALCIUM-ANTAGONISTS IN MICE - BLOOD AND BRAIN PHARMACOKINETICS AND EFFICACY AGAINST PENTYLENETETRAZOL SEIZURES

被引:47
作者
LARKIN, JG [1 ]
THOMPSON, GG [1 ]
SCOBIE, G [1 ]
FORREST, G [1 ]
DRENNAN, JE [1 ]
BRODIE, MJ [1 ]
机构
[1] UNIV GLASGOW,WESTERN INFIRM,DEPT MED & THERAPEUT,EPILEPSY RES UNIT,GLASGOW G11 6NT,SCOTLAND
关键词
ANTICONVULSANTS; NIFEDIPINE; NIMODIPINE; CARBAMAZEPINE; BLOOD-BRAIN BARRIER; EPILEPSY; PHARMACOKINETICS; PENTYLENETETRAZOL; NEUROLOGIC MODELS;
D O I
10.1111/j.1528-1157.1992.tb02358.x
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Dihydropyridine calcium antagonists are candidate anticonvulsants, but little is known of their penetration into brain. Nifedipine (NFD) and nimodipine (NMD) pharmacokinetics were compared in mouse blood and brain, and their activity against pentylenetetrazol (PTZ) was assessed. After intraperitoneal (i.p.) injection, both dihydropyridines achieved peak blood and brain concentrations in 5 min. Estimated blood and brain elimination half-lives (t1/2) of NMD (16.7 and 22.4 min) were slightly longer than those of NFD (11.2 and 14.7 min). Brain and blood concentrations correlated with both NFD (r = 0.701, p < 0.001) and NMD (r = 0.572, p < 0.001). Injection of the dihydropyridines as a suspension (Tween 80) did not alter brain penetration, although systemic absorption was more erratic. NFD (p < 0.001), NMD (p < 0.02), and carbamazepine (CBZ, p < 0.001) i.p. inhibited PTZ-induced seizures. Brain concentrations of PTZ were not altered by NFD pretreatment. Combining NFD and CBZ was less effective than giving NFD alone (p < 0.005). NFD (p < 0.002) and NMD (p < 0.001) inhibited PTZ seizures after 2-week oral dosing, but low dosing was more effective than high dosing (p < 0.002). NFD and NMD cross the blood-brain barrier (BBB) in mice and inhibit PTZ seizures. A possible therapeutic window was identified, and NFD and CBZ were less effective in combination than singly. A pharmacodynamic interaction may exist, inhibiting effective use of dihydropyridines as adjunctive therapy in epileptic patients.
引用
收藏
页码:760 / 769
页数:10
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