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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 in vivo exposure model fit (SD rat PK).
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Figure 3: DCU in vivo exposure model fit (SD rat PK).

Mentions: All of the above parameters were obtained by using the 3-mg/kg rat oral PK data with regular suspension [14] as the base case and predictions were performed for higher doses (10 and 30 mg/kg) with nanosuspension formation. Results for 3, 10, and 30 mg/kg are listed in Table 1. According to theory, this model should hold within the linear range where absorption efficacy AE should be very close (amount of drug absorbed is affected by dissolution hence surface area) if oral absorption is dissolution rate-limited and should show deviations when absorption becomes solubility rate-limited. Within the linear range, an increased surface area (i.e., due to the nanolized drug) will result in a linear increase of oral absorption. This model was found to be sufficient to predict the exposure for dissolution rate-limited absorption at a 10-mg/kg dose. A much bigger deviation was observed at a 30-mg/kg dose when the predicted verse observed was compared with the absorbed amount (Figure 3). According to the model, at Cmax, a total of 3.0 mg of DCU should be absorbed where only 1.1 mg was observed in vivo (Table 1). A reduction in absorption efficiency (AE) was observed particularly between the 10- and 30-mg/kg doses (Table 1). These changes suggested that at a 30-mg/kg dose, the absorption is no longer dissolution rate-limited and most likely solubility rate-limited. The simulations suggest that doses of DCU that are higher than 30 mg/kg delivered using nanosuspension will not provide significantly higher exposure in vivo. Based on the modeling, doses higher than 30 mg/kg PO were not tested in vivo. Simulations for oral dosing were performed using the 30-mg/kg oral dose in order to assess the dose frequency required to hit a range of target concentrations.


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 in vivo exposure model fit (SD rat PK).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: DCU in vivo exposure model fit (SD rat PK).
Mentions: All of the above parameters were obtained by using the 3-mg/kg rat oral PK data with regular suspension [14] as the base case and predictions were performed for higher doses (10 and 30 mg/kg) with nanosuspension formation. Results for 3, 10, and 30 mg/kg are listed in Table 1. According to theory, this model should hold within the linear range where absorption efficacy AE should be very close (amount of drug absorbed is affected by dissolution hence surface area) if oral absorption is dissolution rate-limited and should show deviations when absorption becomes solubility rate-limited. Within the linear range, an increased surface area (i.e., due to the nanolized drug) will result in a linear increase of oral absorption. This model was found to be sufficient to predict the exposure for dissolution rate-limited absorption at a 10-mg/kg dose. A much bigger deviation was observed at a 30-mg/kg dose when the predicted verse observed was compared with the absorbed amount (Figure 3). According to the model, at Cmax, a total of 3.0 mg of DCU should be absorbed where only 1.1 mg was observed in vivo (Table 1). A reduction in absorption efficiency (AE) was observed particularly between the 10- and 30-mg/kg doses (Table 1). These changes suggested that at a 30-mg/kg dose, the absorption is no longer dissolution rate-limited and most likely solubility rate-limited. The simulations suggest that doses of DCU that are higher than 30 mg/kg delivered using nanosuspension will not provide significantly higher exposure in vivo. Based on the modeling, doses higher than 30 mg/kg PO were not tested in vivo. Simulations for oral dosing were performed using the 30-mg/kg oral dose in order to assess the dose frequency required to hit a range of target concentrations.

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