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Evaluation of memory enhancing clinically available standardized extract of Bacopa monniera on P-glycoprotein and cytochrome P450 3A in Sprague-Dawley rats.

Singh R, Panduri J, Kumar D, Kumar D, Chandsana H, Ramakrishna R, Bhatta RS - PLoS ONE (2013)

Bottom Line: The BM treatment decreased the cytochrome P450 3A (CYP3A) mediated testosterone 6β-hydroxylation activity of the liver and intestine by 2 and 1.5 fold, respectively compared to vehicle treated control.Similarly pretreatment with BM extract decreased the expression of intestinal P-glycoprotein (Pgp) as confirmed by Western blot analysis but did not alter the expression of hepatic Pgp.Significant increase in AUC and Cmax of carbamazepine (4 and 1.8 fold) and digoxin (1.3 and 1.2 fold), respectively following the BM pre-treatment confirmed the down regulation of CYP3A and Pgp.

View Article: PubMed Central - PubMed

Affiliation: Pharmacokinetics and Metabolism Division. CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.

ABSTRACT
Bacopa monniera is a traditional Ayurvedic herbal medicine used to treat various mental ailments from ancient times. Recently, chemically standardized alcoholic extract of Bacopa monniera (BM) has been developed and currently available as over the counter herbal remedy for memory enhancement in children and adults. However, the consumption of herbal drugs has been reported to alter the expression of drug metabolizing enzymes and membrane transporters. Present study in male Sprague-Dawley rat was performed to evaluate the effect of memory enhancing standardized extract of BM on hepatic and intestinal cytochrome P450 3A and P-glycoprotein expression and activity. The BM (31 mg/kg/day) was orally administered for one week in BM pre-treated group while the control group received the same amount of vehicle for the same time period. The BM treatment decreased the cytochrome P450 3A (CYP3A) mediated testosterone 6β-hydroxylation activity of the liver and intestine by 2 and 1.5 fold, respectively compared to vehicle treated control. Similarly pretreatment with BM extract decreased the expression of intestinal P-glycoprotein (Pgp) as confirmed by Western blot analysis but did not alter the expression of hepatic Pgp. To investigate whether this BM pretreatment mediated decrease in activity of CYP3A and Pgp would account for the alteration of respective substrate or not, pharmacokinetic study with carbamazepine and digoxin was performed in BM pre-treated rats and vehicle treated rats. Carbamazepine and digoxin were used as CYP3A and Pgp probe drugs, respectively. Significant increase in AUC and Cmax of carbamazepine (4 and 1.8 fold) and digoxin (1.3 and 1.2 fold), respectively following the BM pre-treatment confirmed the down regulation of CYP3A and Pgp.

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Plasma concentration time profile of P-gp probe drug.(A) Time profile of plasma concentration of digoxin in BM pretreated and control (vehicle pretreated) rats. Rats (n = 3) were orally administered with BM (31 mg/kg/day) for seven days in BM pretreated rats while control group received the same amount of vehicle. On the 8th day digoxin (0.2 mg/kg) was given orally in both groups of rat. PK study in BM pretreated rats was performed only after 24 hours of last BM dose. Data point represents mean ± SD. (B) Tissue digoxin concentration in BM pretreated and control (vehicle pretreated) rats. Rats (n = 3) were orally administered with BM (31 mg/kg/day) for seven days in BM pretreated rats while control group received the same amount of vehicle. On the 8th day digoxin (0.2 mg/kg) was given orally in both groups of rat. Digoxin concentration in tissue was observed after 2 hour of digoxin oral gavage. Values are expressed as mean ± S.D. Asterisks * and ** indicates significant difference in BM pretreated rats compared to vehicle treated rats with p<0.05 and p<0.001, respectively.
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pone-0072517-g006: Plasma concentration time profile of P-gp probe drug.(A) Time profile of plasma concentration of digoxin in BM pretreated and control (vehicle pretreated) rats. Rats (n = 3) were orally administered with BM (31 mg/kg/day) for seven days in BM pretreated rats while control group received the same amount of vehicle. On the 8th day digoxin (0.2 mg/kg) was given orally in both groups of rat. PK study in BM pretreated rats was performed only after 24 hours of last BM dose. Data point represents mean ± SD. (B) Tissue digoxin concentration in BM pretreated and control (vehicle pretreated) rats. Rats (n = 3) were orally administered with BM (31 mg/kg/day) for seven days in BM pretreated rats while control group received the same amount of vehicle. On the 8th day digoxin (0.2 mg/kg) was given orally in both groups of rat. Digoxin concentration in tissue was observed after 2 hour of digoxin oral gavage. Values are expressed as mean ± S.D. Asterisks * and ** indicates significant difference in BM pretreated rats compared to vehicle treated rats with p<0.05 and p<0.001, respectively.

Mentions: Similar to CBZ pharmacokinetics the plasma level of digoxin was also increased at every time point in rats pre-treated with BM compared to vehicle pre-treated group (Figure 6A). Digoxin Cmax was significantly increased by 9% in rats with BM pre-treatment compared to vehicle treated rats. Digoxin AUC was increased by 37% in BM pre-treated rats compared to vehicle treated rats. MRT and T1/2 was increased by 17 and 48% respectively in BM pre-treated rats compared to vehicle treated rats. CL/F was decreased by 27% in BM pre-treated rats compared to vehicle treated rats (Table 5). Tissue digoxin concentration significantly increased by 1.3 fold in kidney and intestine. No significant difference in digoxin concentration was observed in liver and brain (Figure 6B).


Evaluation of memory enhancing clinically available standardized extract of Bacopa monniera on P-glycoprotein and cytochrome P450 3A in Sprague-Dawley rats.

Singh R, Panduri J, Kumar D, Kumar D, Chandsana H, Ramakrishna R, Bhatta RS - PLoS ONE (2013)

Plasma concentration time profile of P-gp probe drug.(A) Time profile of plasma concentration of digoxin in BM pretreated and control (vehicle pretreated) rats. Rats (n = 3) were orally administered with BM (31 mg/kg/day) for seven days in BM pretreated rats while control group received the same amount of vehicle. On the 8th day digoxin (0.2 mg/kg) was given orally in both groups of rat. PK study in BM pretreated rats was performed only after 24 hours of last BM dose. Data point represents mean ± SD. (B) Tissue digoxin concentration in BM pretreated and control (vehicle pretreated) rats. Rats (n = 3) were orally administered with BM (31 mg/kg/day) for seven days in BM pretreated rats while control group received the same amount of vehicle. On the 8th day digoxin (0.2 mg/kg) was given orally in both groups of rat. Digoxin concentration in tissue was observed after 2 hour of digoxin oral gavage. Values are expressed as mean ± S.D. Asterisks * and ** indicates significant difference in BM pretreated rats compared to vehicle treated rats with p<0.05 and p<0.001, respectively.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3756011&req=5

pone-0072517-g006: Plasma concentration time profile of P-gp probe drug.(A) Time profile of plasma concentration of digoxin in BM pretreated and control (vehicle pretreated) rats. Rats (n = 3) were orally administered with BM (31 mg/kg/day) for seven days in BM pretreated rats while control group received the same amount of vehicle. On the 8th day digoxin (0.2 mg/kg) was given orally in both groups of rat. PK study in BM pretreated rats was performed only after 24 hours of last BM dose. Data point represents mean ± SD. (B) Tissue digoxin concentration in BM pretreated and control (vehicle pretreated) rats. Rats (n = 3) were orally administered with BM (31 mg/kg/day) for seven days in BM pretreated rats while control group received the same amount of vehicle. On the 8th day digoxin (0.2 mg/kg) was given orally in both groups of rat. Digoxin concentration in tissue was observed after 2 hour of digoxin oral gavage. Values are expressed as mean ± S.D. Asterisks * and ** indicates significant difference in BM pretreated rats compared to vehicle treated rats with p<0.05 and p<0.001, respectively.
Mentions: Similar to CBZ pharmacokinetics the plasma level of digoxin was also increased at every time point in rats pre-treated with BM compared to vehicle pre-treated group (Figure 6A). Digoxin Cmax was significantly increased by 9% in rats with BM pre-treatment compared to vehicle treated rats. Digoxin AUC was increased by 37% in BM pre-treated rats compared to vehicle treated rats. MRT and T1/2 was increased by 17 and 48% respectively in BM pre-treated rats compared to vehicle treated rats. CL/F was decreased by 27% in BM pre-treated rats compared to vehicle treated rats (Table 5). Tissue digoxin concentration significantly increased by 1.3 fold in kidney and intestine. No significant difference in digoxin concentration was observed in liver and brain (Figure 6B).

Bottom Line: The BM treatment decreased the cytochrome P450 3A (CYP3A) mediated testosterone 6β-hydroxylation activity of the liver and intestine by 2 and 1.5 fold, respectively compared to vehicle treated control.Similarly pretreatment with BM extract decreased the expression of intestinal P-glycoprotein (Pgp) as confirmed by Western blot analysis but did not alter the expression of hepatic Pgp.Significant increase in AUC and Cmax of carbamazepine (4 and 1.8 fold) and digoxin (1.3 and 1.2 fold), respectively following the BM pre-treatment confirmed the down regulation of CYP3A and Pgp.

View Article: PubMed Central - PubMed

Affiliation: Pharmacokinetics and Metabolism Division. CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.

ABSTRACT
Bacopa monniera is a traditional Ayurvedic herbal medicine used to treat various mental ailments from ancient times. Recently, chemically standardized alcoholic extract of Bacopa monniera (BM) has been developed and currently available as over the counter herbal remedy for memory enhancement in children and adults. However, the consumption of herbal drugs has been reported to alter the expression of drug metabolizing enzymes and membrane transporters. Present study in male Sprague-Dawley rat was performed to evaluate the effect of memory enhancing standardized extract of BM on hepatic and intestinal cytochrome P450 3A and P-glycoprotein expression and activity. The BM (31 mg/kg/day) was orally administered for one week in BM pre-treated group while the control group received the same amount of vehicle for the same time period. The BM treatment decreased the cytochrome P450 3A (CYP3A) mediated testosterone 6β-hydroxylation activity of the liver and intestine by 2 and 1.5 fold, respectively compared to vehicle treated control. Similarly pretreatment with BM extract decreased the expression of intestinal P-glycoprotein (Pgp) as confirmed by Western blot analysis but did not alter the expression of hepatic Pgp. To investigate whether this BM pretreatment mediated decrease in activity of CYP3A and Pgp would account for the alteration of respective substrate or not, pharmacokinetic study with carbamazepine and digoxin was performed in BM pre-treated rats and vehicle treated rats. Carbamazepine and digoxin were used as CYP3A and Pgp probe drugs, respectively. Significant increase in AUC and Cmax of carbamazepine (4 and 1.8 fold) and digoxin (1.3 and 1.2 fold), respectively following the BM pre-treatment confirmed the down regulation of CYP3A and Pgp.

Show MeSH
Related in: MedlinePlus