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Ocular Pharmacokinetic/Pharmacodynamic Modeling for Bunazosin After Instillation into Rabbits

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Abstract

Purpose. To develop a pharmacokinetic/pharmacodynamic (PK/PD) model for an α1-blocker (bunazosin) after instillation. The PK/PD model can predict both the drug concentrations in various ocular tissues and the hypotensive effect.

Methods. Bunazosin concentrations were determined with High Performance Liquid Chromatography (HPLC) in tear fluid, the aqueous humor, cornea, and iris-ciliary body after instillation or ocular injection into the anterior chamber in rabbits. After instillation of bunazosin in rabbits, intraocular pressure (IOP) was also determined with a pneumatic tonometer. The PK/PD parameters were estimated by fitting the concentration-time profiles and the hypotensive effect-time profiles to the developed PK/PD models using the MULTI (RUNGE) program.

Results. On the basis of the concentration-time profiles of bunazosin, a PK model, including seven compartments, was developed for examining the behavior of bunazosin after instillation. Then, two PK/PD models for hypotensive effect of bunazosin were developed using an indirect response (model A) and the relationship between IOP and aqueous humor flow (model B). These models well described the concentration-time profiles and hypotensive effect-time profiles of bunazosin after instillation.

Conclusions. This study is the first trial to develop a PK/PD model for an antiglaucoma agent using an indirect response and the relationship between IOP and aqueous humor flow.

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Authors and Affiliations

  1. Department of Hospital Pharmacy, Nagasaki University School of Medicine, Nagasaki, 852-8501, Japan

    Koji Sakanaka, Masahide Tomonari, Takashi Kitahara, Mikiro Nakashima & Hitoshi Sasaki

  2. Santen Pharmaceutical Co., Ltd., Nara Research and Development Center, Ikoma-shi, 630-0101, Japan

    Koji Sakanaka & Kouichi Kawazu

  3. Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, 852-8521, Japan

    Shigeru Kawakami, Koyo Nishida & Junzo Nakamura

Authors
  1. Koji Sakanaka
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  2. Kouichi Kawazu
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  3. Masahide Tomonari
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  4. Takashi Kitahara
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  5. Mikiro Nakashima
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  6. Shigeru Kawakami
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  7. Koyo Nishida
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  8. Junzo Nakamura
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  9. Hitoshi Sasaki
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Correspondence to Hitoshi Sasaki.

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Sakanaka, K., Kawazu, K., Tomonari, M. et al. Ocular Pharmacokinetic/Pharmacodynamic Modeling for Bunazosin After Instillation into Rabbits. Pharm Res 21, 770–776 (2004). https://doi.org/10.1023/B:PHAM.0000026426.20012.36

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  • DOI: https://doi.org/10.1023/B:PHAM.0000026426.20012.36

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