In vivo specific binding characteristics and pharmacokinetics of a 1,4-dihydropyridine calcium channel antagonist in the senescent mouse brain.
OBJECTIVE
To characterize the in vivo specific binding and pharmacokinetics of a 1,4-dihydropyridine (DHP) calcium channel antagonist, PN 200-110, in the senescent brain, using senescence-accelerated prone mice (SAMP8) and senescence-resistant mice (SAMR1).


METHODS
Blood, brain, and heart samples were taken periodically from SAMR1 and SAMP8 following intravenous injection of (+)-[3H]PN 200-110, and the concentration of (+)-[3H]PN 200-110 in the plasma and tissues was determined. In addition, the in vivo specific binding of (+)-[3H]PN 200-110 in the brains of SAMRI and SAMP8 was measured periodically after intravenous injection of the radioligand.


RESULTS
There was very little significant difference between SAMR1 and SAMP8 in terms of the half-life (t(1/2)), total body clearance (CL(tot)), steady-state volume of distribution (Vd(ss)). and AUC for the plasma concentration of (+)-[3H]PN 200-110 after intravenous injection of the radioligand. The brain concentration (AUCbrain) for (+)-[3H]PN 200-110 and the brain/plasma AUC ratio (AUCbrain/AUCplasma) were significantly lower in SAMP8 than in SAMR1, and the heart concentration (AUCheart) and the heart/plasma AUC ratio (AUCheart/AUCplasma) were similar in both strains. Also, the brain/plasma unbound AUC ratio (AUCbrain/AUCplasma-free) for (+)-[3H]PN 200-110 was significantly lower in SAMP8 than in SAMRI. The in vivo specific binding (AUCspecific binding, maximal number of binding sites: Bmax) of (+)-[3H]PN 200-110 was significantly lower in brain particulate fractions of SAMP8 than SAMR1.


CONCLUSIONS
The concentration and in vivo specific binding of (+)-[3H]PN 200-110 was significantly reduced in the senescent brain. The simultaneous analysis of the concentrations of centrally acting drugs and the in vivo specific binding in the brain in relation to their pharmacokinetics may be valuable in evaluating their CNS effects.
Uchida
S
S
Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Yamada
S
S
Deguchi
Y
Y
Yamamoto
M
M
Kimura
R
R
D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics*; D004095:Dihydropyridines / Q000097:blood / Q000493:pharmacokinetics; D017275:Isradipine / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C038806:1,4-dihydropyridine; D017275:Isradipine