Dihydropyridine calcium antagonists in mice: blood and brain pharmacokinetics and efficacy against pentylenetetrazol seizures.
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 less than 0.001) and NMD (r = 0.572, p less than 0.001). Injection of the dihydropyridines as a suspension (Tween 80) did not alter brain penetration, although systemic absorption was more erratic. NFD (p less than 0.001), NMD (p less than 0.02), and carbamazepine (CBZ, p less than 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 less than 0.005). NFD (p less than 0.002) and NMD (p less than 0.001) inhibited PTZ seizures after 2-week oral dosing, but low dosing was more effective than high dosing (p less than 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.
Larkin
J G
JG
University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland.
Thompson
G G
GG
Scobie
G
G
Forrest
G
G
Drennan
J E
JE
Brodie
M J
MJ
D000818:Animals; D001812:Blood-Brain Barrier; D001923:Brain Chemistry; D002220:Carbamazepine / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009543:Nifedipine / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D009553:Nimodipine / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics*; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control
D002220:Carbamazepine; D009553:Nimodipine; D009543:Nifedipine; D010433:Pentylenetetrazole