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Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier.

Diao XX, Zhong K, Li XL, Zhong DF, Chen XY - Acta Pharmacol. Sin. (2015)

Bottom Line: In the rat plasma, 60%±5.2% of 10-OH-NBP was unbound to proteins versus only 22%±2.3% of 3-OH-NBP being unbound, whereas in the rat brain, free fractions of 3-OH-NBP and 10-OH-NBP were 100%±9.7% and 49.9%±14.1%, respectively.Incubation of rat brain homogenate with NBP yielded 3-OH-NBP but not 10-OH-NBP.The abundant 10-OH-NBP is not generated in rat brains.

View Article: PubMed Central - PubMed

Affiliation: Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

ABSTRACT

Aim: To investigate the mechanisms underlying the isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP (3-OH-NBP) and 10-hydroxy-NBP (10-OH-NBP), across the blood brain barrier (BBB).

Methods: After oral administration of NBP (20 mg/kg) to rats, the pharmacokinetics of two major hydroxylated metabolites, 3-OH-NBP and 10-OH-NBP, in plasma and brains were investigated. Plasma and brain protein binding of 3-OH-NBP and 10-OH-NBP was also assessed. To evaluate the influences of major efflux transporters, rats were pretreated with the P-gp inhibitor tariquidar (10 mg/kg, iv) and BCRP inhibitor pantoprazole (40 mg/kg, iv), then received 3-OH-NBP (12 mg/kg, iv) or 10-OH-NBP (3 mg/kg, iv). The metabolic profile of NBP was investigated in rat brain homogenate.

Results: After NBP administration, the plasma exposure of 3-OH-NBP was 4.64 times that of 10-OH-NBP, whereas the brain exposure of 3-OH-NBP was only 11.8% of 10-OH-NBP. In the rat plasma, 60%±5.2% of 10-OH-NBP was unbound to proteins versus only 22%±2.3% of 3-OH-NBP being unbound, whereas in the rat brain, free fractions of 3-OH-NBP and 10-OH-NBP were 100%±9.7% and 49.9%±14.1%, respectively. In the rats pretreated with tariquidar and pantoprazole, the unbound partition coefficient Kp,uu of 3-OH-NBP was significantly increased, while that of 10-OH-NBP showed a slight but not statistically significant increase. Incubation of rat brain homogenate with NBP yielded 3-OH-NBP but not 10-OH-NBP.

Conclusion: The isomer-selective distribution of 10-OH-NBP and 3-OH-NBP across the BBB of rats is mainly attributed to the differences in plasma and brain protein binding and the efflux transport of 3-OH-NBP. The abundant 10-OH-NBP is not generated in rat brains.

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The Kp, Kp,u, and Kp,uu values and ratios for 3-OH-NBP and 10-OH-NBP. Mean±SD, n=3.
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fig4: The Kp, Kp,u, and Kp,uu values and ratios for 3-OH-NBP and 10-OH-NBP. Mean±SD, n=3.

Mentions: To more clearly see the differences between 3-OH-NBP and 10-OH-NBP, we reorganized the data in plasma and brain homogenate in terms of the target molecules. As shown in Figure 3A, the Kp (AUCtot,br,0-24h/AUCtot,pl,0-24h) value for 3-OH-NBP was 0.022, whereas the Kp value for 10-OH-NBP was 0.88 (Figure 3B), which indicates that the concentration of 10-OH-NBP was similar inside and outside the BBB, and the concentration of 3-OH-NBP was much lower inside the BBB than outside. The Kp value of 10-OH-NBP was 39.8 times greater than that of 3-OH-NBP (Figure 4), suggesting that 10-OH-NBP can easily cross the BBB into the brain compared to 3-OH-NBP.


Isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP and 10-hydroxy-NBP, across the rat blood-brain barrier.

Diao XX, Zhong K, Li XL, Zhong DF, Chen XY - Acta Pharmacol. Sin. (2015)

The Kp, Kp,u, and Kp,uu values and ratios for 3-OH-NBP and 10-OH-NBP. Mean±SD, n=3.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4816231&req=5

fig4: The Kp, Kp,u, and Kp,uu values and ratios for 3-OH-NBP and 10-OH-NBP. Mean±SD, n=3.
Mentions: To more clearly see the differences between 3-OH-NBP and 10-OH-NBP, we reorganized the data in plasma and brain homogenate in terms of the target molecules. As shown in Figure 3A, the Kp (AUCtot,br,0-24h/AUCtot,pl,0-24h) value for 3-OH-NBP was 0.022, whereas the Kp value for 10-OH-NBP was 0.88 (Figure 3B), which indicates that the concentration of 10-OH-NBP was similar inside and outside the BBB, and the concentration of 3-OH-NBP was much lower inside the BBB than outside. The Kp value of 10-OH-NBP was 39.8 times greater than that of 3-OH-NBP (Figure 4), suggesting that 10-OH-NBP can easily cross the BBB into the brain compared to 3-OH-NBP.

Bottom Line: In the rat plasma, 60%±5.2% of 10-OH-NBP was unbound to proteins versus only 22%±2.3% of 3-OH-NBP being unbound, whereas in the rat brain, free fractions of 3-OH-NBP and 10-OH-NBP were 100%±9.7% and 49.9%±14.1%, respectively.Incubation of rat brain homogenate with NBP yielded 3-OH-NBP but not 10-OH-NBP.The abundant 10-OH-NBP is not generated in rat brains.

View Article: PubMed Central - PubMed

Affiliation: Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

ABSTRACT

Aim: To investigate the mechanisms underlying the isomer-selective distribution of 3-n-butylphthalide (NBP) hydroxylated metabolites, 3-hydroxy-NBP (3-OH-NBP) and 10-hydroxy-NBP (10-OH-NBP), across the blood brain barrier (BBB).

Methods: After oral administration of NBP (20 mg/kg) to rats, the pharmacokinetics of two major hydroxylated metabolites, 3-OH-NBP and 10-OH-NBP, in plasma and brains were investigated. Plasma and brain protein binding of 3-OH-NBP and 10-OH-NBP was also assessed. To evaluate the influences of major efflux transporters, rats were pretreated with the P-gp inhibitor tariquidar (10 mg/kg, iv) and BCRP inhibitor pantoprazole (40 mg/kg, iv), then received 3-OH-NBP (12 mg/kg, iv) or 10-OH-NBP (3 mg/kg, iv). The metabolic profile of NBP was investigated in rat brain homogenate.

Results: After NBP administration, the plasma exposure of 3-OH-NBP was 4.64 times that of 10-OH-NBP, whereas the brain exposure of 3-OH-NBP was only 11.8% of 10-OH-NBP. In the rat plasma, 60%±5.2% of 10-OH-NBP was unbound to proteins versus only 22%±2.3% of 3-OH-NBP being unbound, whereas in the rat brain, free fractions of 3-OH-NBP and 10-OH-NBP were 100%±9.7% and 49.9%±14.1%, respectively. In the rats pretreated with tariquidar and pantoprazole, the unbound partition coefficient Kp,uu of 3-OH-NBP was significantly increased, while that of 10-OH-NBP showed a slight but not statistically significant increase. Incubation of rat brain homogenate with NBP yielded 3-OH-NBP but not 10-OH-NBP.

Conclusion: The isomer-selective distribution of 10-OH-NBP and 3-OH-NBP across the BBB of rats is mainly attributed to the differences in plasma and brain protein binding and the efflux transport of 3-OH-NBP. The abundant 10-OH-NBP is not generated in rat brains.

Show MeSH
Related in: MedlinePlus