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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 CYP3A probe drug and its metabolite.(A) Time profile plasma concentration of CBZ and (B) CBZ-E 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 CBZ (50 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. Superscript a and b indicates significant difference in BM pretreated rats compared to vehicle treated rats with p<0.05 and p<0.01, respectively.
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pone-0072517-g005: Plasma concentration time profile of CYP3A probe drug and its metabolite.(A) Time profile plasma concentration of CBZ and (B) CBZ-E 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 CBZ (50 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. Superscript a and b indicates significant difference in BM pretreated rats compared to vehicle treated rats with p<0.05 and p<0.01, respectively.

Mentions: We observed the decrease in CYP3A-mediated testosterone hydroxylation activity in BM pretreated rats; therefore there might be the chance of alteration in the pharmacokinetics of carbamazepine with BM administration. Therefore, we assess the effect of BM pretreatment on the oral pharmacokinetics of carbamazepine in BM pretreated rats and compared to pharmacokinetics of carbamazepine in control rats. The plasma concentration CBZ-E and CBZ were investigated in vehicle pretreated rats and BM pretreated rats. Plasma concentration-time profile of CBZ and CBZ-E is shown in Figure 5A and 5B, respectively. The pharmacokinetics parameters of both CBZ and CBZ-E are summarized in Table 4. Concentration time profile of CBZ revealed increase in plasma concentration at each time point studied. The mean AUC and Cmax of CBZ were significantly increased by 4 and 1.8 times respectively in BM pretreated rats, compared to vehicle pretreated rats. However, CL/F was decreased significantly by 3.8 times in BM pretreated rats compared to vehicle pretreated rats. Moreover, AUC ratio (CBZ-E/CBZ) was significantly decreased by 4 times.


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 CYP3A probe drug and its metabolite.(A) Time profile plasma concentration of CBZ and (B) CBZ-E 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 CBZ (50 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. Superscript a and b indicates significant difference in BM pretreated rats compared to vehicle treated rats with p<0.05 and p<0.01, respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756011&req=5

pone-0072517-g005: Plasma concentration time profile of CYP3A probe drug and its metabolite.(A) Time profile plasma concentration of CBZ and (B) CBZ-E 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 CBZ (50 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. Superscript a and b indicates significant difference in BM pretreated rats compared to vehicle treated rats with p<0.05 and p<0.01, respectively.
Mentions: We observed the decrease in CYP3A-mediated testosterone hydroxylation activity in BM pretreated rats; therefore there might be the chance of alteration in the pharmacokinetics of carbamazepine with BM administration. Therefore, we assess the effect of BM pretreatment on the oral pharmacokinetics of carbamazepine in BM pretreated rats and compared to pharmacokinetics of carbamazepine in control rats. The plasma concentration CBZ-E and CBZ were investigated in vehicle pretreated rats and BM pretreated rats. Plasma concentration-time profile of CBZ and CBZ-E is shown in Figure 5A and 5B, respectively. The pharmacokinetics parameters of both CBZ and CBZ-E are summarized in Table 4. Concentration time profile of CBZ revealed increase in plasma concentration at each time point studied. The mean AUC and Cmax of CBZ were significantly increased by 4 and 1.8 times respectively in BM pretreated rats, compared to vehicle pretreated rats. However, CL/F was decreased significantly by 3.8 times in BM pretreated rats compared to vehicle pretreated rats. Moreover, AUC ratio (CBZ-E/CBZ) was significantly decreased by 4 times.

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