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In Vivo Specific Binding Characteristics and Pharmacokinetics of a 1,4-Dihydropyridine Calcium Channel Antagonist in the Senescent Mouse Brain

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Abstract

Purpose. To characterize the in vivo specific binding andpharmacokinetics of a 1,4-dihydropyridine (DHP) calcium channel antagonist, PN200-110, in the senescent brain, using senescence-accelerated pronemice (SAMP8) and senescence-resistant mice (SAMR1).

Methods. Blood, brain, and heart samples were taken periodically fromSAMR1 and SAMP8 following intravenous injection of (+)-[3H]PN200-110, and the concentration of (+)-[3H]PN 200-110 in the plasmaand tissues was determined. In addition, the in vivo specific bindingof (+)-[3H]PN 200-110 in the brains of SAMR1 and SAMP8 wasmeasured periodically after intravenous injection of the radioligand.

Results. There was very little significant difference between SAMR1and SAMP8 in terms of the half-life (t1/2), total body clearance (CLtot),steady-state volume of distribution (Vdss), and AUC for the plasmaconcentration of (+)-[3H]PN 200-110 after intravenous injection ofthe radioligand. The brain concentration (AUCbrain) for (+)-[3H]PN200-110 and the brain/plasma AUC ratio (AUCbrain/AUCplasma) weresignificantly lower in SAMP8 than in SAMR1, and the heartconcentration (AUCheart) and the heart/plasma AUC ratio (AUCheart/AUCplasma)were similar in both strains. Also, the brain/plasma unbound AUCratio (AUCbrain/AUCplasma-free) for (+)-[3H]PN 200-110 wassignificantly lower in SAMP8 than in SAMR1. The in vivo specific binding(AUCspecific binding, maximal number of binding sites: Bmax) of(+)-[3H]PN 200-110 was significantly lower in brain particulate fractionsof SAMP8 than SAMR1.

Conclusions. The concentration and in vivo specific binding of(+)-[3H]PN 200-110 was significantly reduced in the senescent brain. Thesimultaneous analysis of the concentrations of centrally acting drugsand the in vivo specific binding in the brain in relation to theirpharmacokinetics may be valuable in evaluating their CNS effects.

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Authors and Affiliations

  1. Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan

    Shinya Uchida, Yoshiharu Deguchi & Ryohei Kimura

  2. Department of Hospital Pharmacy, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu, 431-3192, Japan

    Shinya Uchida

  3. Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan

    Shizuo Yamada

  4. Clinical Pharmacology Research Lab, Yamanouchi Pharmaceutical Co., Ltd., Tokyo, 174-8511, Japan

    Minoru Yamamoto

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  1. Shinya Uchida
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  4. Minoru Yamamoto
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  5. Ryohei Kimura
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Uchida, S., Yamada, S., Deguchi, Y. et al. In Vivo Specific Binding Characteristics and Pharmacokinetics of a 1,4-Dihydropyridine Calcium Channel Antagonist in the Senescent Mouse Brain. Pharm Res 17, 844–850 (2000). https://doi.org/10.1023/A:1007512426420

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