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Investigation of utilization of nanosuspension formulation to enhance exposure of 1,3-dicyclohexylurea in rats: Preparation for PK/PD study via subcutaneous route of nanosuspension drug delivery.

Chiang PC, Ran Y, Chou KJ, Cui Y, Wong H - Nanoscale Res Lett (2011)

Bottom Line: Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal.In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling.It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Chiang.pochang@gene.com.

ABSTRACT
1,3-Dicyclohexylurea (DCU), a potent soluble epoxide hydrolase (sEH) inhibitor has been reported to lower systemic blood pressure in spontaneously hypertensive rats. One limitation of continual administration of DCU for in vivo studies is the compound's poor oral bioavailability. This phenomenon is mainly attributed to its poor dissolution rate and low aqueous solubility. Previously, wet-milled DCU nanosuspension has been reported to enhance the bioavailability of DCU. However, the prosperities and limitations of wet-milled nanosuspension have not been fully evaluated. Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal. In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling. It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation. Based on the model and in vivo data, a subcutaneous route of delivery of nanosuspension of DCU was evaluated and demonstrated to be appropriate for future PK/PD studies.

No MeSH data available.


Related in: MedlinePlus

DCU SC PK plasma exposure. Thirty-milligram per kilogram nanosuspension versus regular suspension).
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Figure 5: DCU SC PK plasma exposure. Thirty-milligram per kilogram nanosuspension versus regular suspension).

Mentions: The SC route of delivery of the DCU nanosuspension in rats was investigated as a means to improve the pharmacokinetic properties of DCU. There are two potential benefits to investigate the SC dose for DCU. First, unlike oral absorption where all drug absorbed will first go through the liver then the circulation, the drug absorbed via the SC route will go directly into the circulation and hence avoid the "first pass" effect and potentially improve systemic exposure [30]. Secondly, the SC drug depot should continuously provide a slow release of drug to the bloodstream providing a longer and sometimes steady drug supply. Combined, both effects may result in a drug plasma profile with a more sustained drug coverage and lower P/T ratio. Despite the described advantages, the SC route of dosing is not free of problems. Drug exposure via SC route of delivery can be still limited by absorption, stability, dissolution rate, and solubility of the drug. In order to overcome these limitations, a suitable formulation was needed to maximize the potential of DCU in vivo. Several formulations strategies for SC dose have been assessed. Formulations such as emulsions and cosolvents were quickly found unsuitable since the goal was to target a formulation that can be directly applied to the efficacy model without any interference of excipients (i.e., high organic). After carefully evaluating all available options, nanosuspension was found to be the best option for the purpose. In order to understand the impact of nanosuspensions on the systemic exposure of DCU, both nanosuspension and regular suspension were dosed in vivo to contrast. It was found that when dosed via the SC route, the DCU nanosuspension greatly improved the exposure when compared with regular suspension. Results of this SC investigation are illustrated in Figure 5.


Investigation of utilization of nanosuspension formulation to enhance exposure of 1,3-dicyclohexylurea in rats: Preparation for PK/PD study via subcutaneous route of nanosuspension drug delivery.

Chiang PC, Ran Y, Chou KJ, Cui Y, Wong H - Nanoscale Res Lett (2011)

DCU SC PK plasma exposure. Thirty-milligram per kilogram nanosuspension versus regular suspension).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3211509&req=5

Figure 5: DCU SC PK plasma exposure. Thirty-milligram per kilogram nanosuspension versus regular suspension).
Mentions: The SC route of delivery of the DCU nanosuspension in rats was investigated as a means to improve the pharmacokinetic properties of DCU. There are two potential benefits to investigate the SC dose for DCU. First, unlike oral absorption where all drug absorbed will first go through the liver then the circulation, the drug absorbed via the SC route will go directly into the circulation and hence avoid the "first pass" effect and potentially improve systemic exposure [30]. Secondly, the SC drug depot should continuously provide a slow release of drug to the bloodstream providing a longer and sometimes steady drug supply. Combined, both effects may result in a drug plasma profile with a more sustained drug coverage and lower P/T ratio. Despite the described advantages, the SC route of dosing is not free of problems. Drug exposure via SC route of delivery can be still limited by absorption, stability, dissolution rate, and solubility of the drug. In order to overcome these limitations, a suitable formulation was needed to maximize the potential of DCU in vivo. Several formulations strategies for SC dose have been assessed. Formulations such as emulsions and cosolvents were quickly found unsuitable since the goal was to target a formulation that can be directly applied to the efficacy model without any interference of excipients (i.e., high organic). After carefully evaluating all available options, nanosuspension was found to be the best option for the purpose. In order to understand the impact of nanosuspensions on the systemic exposure of DCU, both nanosuspension and regular suspension were dosed in vivo to contrast. It was found that when dosed via the SC route, the DCU nanosuspension greatly improved the exposure when compared with regular suspension. Results of this SC investigation are illustrated in Figure 5.

Bottom Line: Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal.In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling.It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Small Molecule Research, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Chiang.pochang@gene.com.

ABSTRACT
1,3-Dicyclohexylurea (DCU), a potent soluble epoxide hydrolase (sEH) inhibitor has been reported to lower systemic blood pressure in spontaneously hypertensive rats. One limitation of continual administration of DCU for in vivo studies is the compound's poor oral bioavailability. This phenomenon is mainly attributed to its poor dissolution rate and low aqueous solubility. Previously, wet-milled DCU nanosuspension has been reported to enhance the bioavailability of DCU. However, the prosperities and limitations of wet-milled nanosuspension have not been fully evaluated. Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal. In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling. It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation. Based on the model and in vivo data, a subcutaneous route of delivery of nanosuspension of DCU was evaluated and demonstrated to be appropriate for future PK/PD studies.

No MeSH data available.


Related in: MedlinePlus