Ocular Pharmacokinetic/Pharmacodynamic Modeling for Bunazosin After Instillation into Rabbits

Sakanaka, Koji; Kawazu, Kouichi; Tomonari, Masahide; Kitahara, Takashi; Nakashima, Makoto; Kawakami, Shigeru; Nishida, Koyo; Nakamura, Junzo; Sasaki, Hidetada

doi:10.1023/b:pham.0000026426.20012.36

Cited by 8 publications

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References 13 publications

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“…6,7) Briefly, 25 ml of drug solution (mixture containing 0.01% bunazosin and 0.5% timolol in PBS) was carefully instilled in the middle of the lower conjunctival sac of unanaesthetized normal rabbits placed in restraint boxes. The rabbits were sacrificed with an overdose of sodium pentobarbital at the designated time after drug instillation.…”

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

“…6,7) Briefly, for bunazosin determination a 50 ml aliquot of the aqueous humor was added to 1 ml acetonitrile containing prazosin hydrochloride (20 nM) as an internal standard. After mixing, each mixture was centrifuged at 8000ϫg for 5 min, and the supernatant (100 ml) was diluted with 200 ml of water.…”

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

“…Based on these relationships, IOP was expressed by the aqueous humor flow as follows: (2) In rabbits, bunazosin reduces IOP by promoting aqueous humor outflow through the uveoscleral route alone, 3) and timolol reduces IOP by suppressing aqueous humor formation alone. 10) Therefore, the differential equation of IOP after instillation of timolol can be expressed as follows: (3) According to our previous reports on the PK/PD model for bunazosin, 6) the differential equation of F us was expressed as…”

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

“…(5) (6) where K in BZ is the zero-order rate constant for the production of F us , K out BZ is the first-order rate constant for the loss of F us , I max BZ is the maximum inhibitory effect attributed to bunazosin, and IC 50 BZ is the bunazosin concentration that exhibits 50% of the maximum inhibitory effect. K in TM is the zero-order rate constant for the production of F in , and K out TM is the first-order rate constant for the loss of F in .…”

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

“…In the previous reports, we have succeeded in developing two ocular PK/PD models for anti-glaucoma drugs after instillation into rabbits. One is the model for an a 1 -adrenergic antagonist, bunazosin, 6) and the other is for a b-adrenergic antagonist, timolol, 7) but no ocular PK/PD model for multidrug therapy for the eye has been devised. The models for bunazosin and timolol each include aqueous humor dynamics based on each action mechanism, which are different from one another; therefore, a combined ocular PK/PD model after instillation of a combination of multiple drugs must be able to be constructed by including each action mechanism.…”

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Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

Sakanaka

Kawazu

Tomonari

et al. 2008

Biological & Pharmaceutical Bulletin

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The current mainstay of glaucoma treatment is topical medications of ocular hypotensive effect drugs in controlling intraocular pressure (IOP) and preserving visual field. IOP is mainly determined by the aqueous humor dynamics, which is the coupling of aqueous humor formation in the ciliary body and its drainage through the uveoscleral route and the trabecular meshwork route.1) The action mechanisms of anti-glaucoma drugs are well known and classified into several action mechanisms 2,3) : b-adrenergic antagonists (e.g., timolol, betaxolol), carbonic anhydrase inhibitors (e.g., dorzolamide), and a 2 -adrenergic agonists (e.g., apraclonidine, brimonidine) that suppress aqueous humor formation; prostaglandin FP receptor agonists (e.g., latanoprost, travoprost), prostamides (e.g., bimatoprost), and a 1 -adrenergic antagonists (bunazosin), which promote aqueous humor outflow through the uveoscleral route; and cholinomimetics (e.g., pilocarpine) responsible for promoting aqueous humor outflow through the trabecular meshwork route as a result of contraction of the ciliary muscle.It is also a common practice to use multiple anti-glaucoma drugs in combination to achieve target IOP lowering when a favorable response is not obtained by monotherapy. 4) In order to comprehend the result of multidrug treatment, some comparative studies on the combined effects of drugs were reported. 4,5) However, in multidrug therapy, without experiments it has been impossible to determine the strength and duration of the ocular hypotensive effect quantitatively.Pharmacokinetic/pharmacodynamic (PK/PD) models allow us to predict quantitatively both the drug concentration and pharmacological effect after administration of drugs. In the previous reports, we have succeeded in developing two ocular PK/PD models for anti-glaucoma drugs after instillation into rabbits. One is the model for an a 1 -adrenergic antagonist, bunazosin, 6) and the other is for a b-adrenergic antagonist, timolol, 7) but no ocular PK/PD model for multidrug therapy for the eye has been devised. The models for bunazosin and timolol each include aqueous humor dynamics based on each action mechanism, which are different from one another; therefore, a combined ocular PK/PD model after instillation of a combination of multiple drugs must be able to be constructed by including each action mechanism.In the present study, we constructed a new combined ocular PK/PD model by including both the action mechanisms of bunazosin and timolol, and simulated the theoretical drug concentrations and ocular hypotensive effects after instillation of a combination of bunazosin and timolol into rabbits using the combined model and PK/PD parameters for each drug. In addition, to verify the reliability of the combined model, we confirmed the drug concentrations and ocular hypotensive effects measured by a telemetry system after instillation of the drug combination. The PD parameters for bunazosin were recalculated from the ocular hypotensive effects measured by the telemetry system in order to obtain...

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Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

mentioning

confidence: 99%

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Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

Sakanaka

Kawazu

Tomonari

et al. 2008

Biological & Pharmaceutical Bulletin

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Recent advances in pharmacokinetic modeling

Ahmad

2007

Biopharm & Drug Disp

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A major part of the science of pharmacokinetics is the modeling of the underlying processes that contribute to drug disposition. The purpose of pharmacokinetic models is to summarize the knowledge gained in preclinical and clinical studies at various stages in drug development and to rationally guide future studies with the use of adequately predictive models. This review highlights a variety of recent advances in mechanistic pharmacokinetic modeling. It is aimed at a broad audience, and hence, an attempt was made to maintain a balance between technical information and practical applications of pharmacokinetic modeling. It is hoped that drug researchers from all disciplines would be able to get a flavor of the function and capacity of pharmacokinetic modelers and their contribution to drug development. While this review is not intended to be a technical reference on modeling approaches, the roles of statistical applications and population methodologies are discussed where appropriate.

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Pharmacokinetics and Pharmacodynamics of Ocular Drugs

Dave

Bhansali

2016

Nano-Biomaterials for Ophthalmic Drug Delivery

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This chapter aims to provide the readers a systematic overview of the pharmacokinetics and pharmacodynamics of the drugs intended for ophthalmic use. The concepts of ocular pharmacokinetics and pharmacodynamics are briefly discussed in the introduction. The chapter begins with a discussion on the common anatomical and physiological factors such as blood–ocular and tear fluid–corneal barriers, as well as anterior segment drug loss; and the challenges these factor pose in describing ocular pharmacokinetics and pharmacodynamics. The biopharmaceutics of the ocular drugs describes common pathways of ocular drug absorption. Further, commonly employed routes of administration for ocular drugs are discussed with respect to the choice of the route, properties of the drug, the nature of the ocular disease, the targeted ocular tissue, and the pharmacokinetic behavior of the drugs administered through the route. The pharmacokinetic–pharmacodynamic models that describe the fate of ocular drugs are further reviewed. Finally, recent advances and current trends in understanding of the pharmacokinetics/pharmacodynamics of ocular drugs are discussed based on the reported findings of the scientific and medical community

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Ocular Pharmacokinetic/Pharmacodynamic Modeling for Bunazosin After Instillation into Rabbits

Abstract: 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.

Cited by 8 publications

References 13 publications

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

Recent advances in pharmacokinetic modeling

Pharmacokinetics and Pharmacodynamics of Ocular Drugs

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