Dihydropyridine Calcium Antagonists in Mice: Blood and Brain Pharmacokinetics and Efficacy Against Pentylenetetrazol Seizures

Summary: 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 < 0.021, 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. RESUME Les antagonistes calciques dihydropyridiniques sont des anticonvulsivants potentiels, mais on sait peut de choses sur leur penetration das le cerveau. Les pharmacocinetiques de la nifedipine (NFD) et de la nimodipine (NMD) ont ete comparees dansle sang et dans le cerveau de souris, et leur activite contre lescrises induites par pentylenetetrazol (PTZ) a eteevaluee. Apres injection intraperitoneale (i.p.), les deux dihydropyridines ont presente un pic sanguin et cerebral en moins de cinq minutes. Les demi-vies d'elimination evaluees au niveau du sang et ducerveau etaient de 16.7 et 22.4 minutes respectivement pour la NMD; elles etaient legerement plus longues que celles de la NFD(11.2 et 14.7 rnin). Les concentrations sanguines et cerebrales etaient correlees pour la NFD (r = 0.701, p < 0.001) et pour laNMD (r = 0.572, p < 0.001). L'injection de ces dihydropyridinesen suspension n'a pas modifie la penetration cerebrale; en revanche I'absorption systemique etait plus variable. Les crisesinduites par PTZ ont ete inhibees par administration i.p. de NFD(p < 0.001), de NMD (p < 0.02) et de carbamazepine (CBZ, p