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Evaluation of drug interaction potential of Labisia pumila (Kacip Fatimah) and its constituents.

Manda VK, Dale OR, Awortwe C, Ali Z, Khan IA, Walker LA, Khan SI - Front Pharmacol (2014)

Bottom Line: The extract of L. pumila showed a significant time dependent inhibition (TDI) of CYP3A4, reversible inhibition of CYP2C9 and 2C19 and a weak inhibition of 1A2 and 2D6 as well as an inhibition of P-gp and rifampicin-induced PXR activation.The alkyl phenols inhibited CYP3A4 (TDI), CYP2C9, and 2C19 (reversible) while saponins inhibited P-gp and PXR.In conclusion, L. pumila and its constituents showed significant modulation of all three regulatory proteins (CYPs, P-gp, and PXR) suggesting a potential to alter the pharmacokinetic and pharmacodynamic properties of conventional drugs if used concomitantly.

View Article: PubMed Central - PubMed

Affiliation: National Center for Natural Products Research, School of Pharmacy, The University of Mississippi Oxford, MS, USA.

ABSTRACT
Labisia pumila (Kacip Fatimah) is a popular herb in Malaysia that has been traditionally used in a number of women's health applications such as to improve libido, relieve postmenopausal symptoms, and to facilitate or hasten delivery in childbirth. In addition, the constituents of this plant have been reported to possess anticancer, antioxidant, and anti-inflammatory properties. Clinical studies have indicated that cytochrome P450s (CYPs), P-glycoprotein (P-gp), and Pregnane X receptor (PXR) are the three main modulators of drug-drug interactions which alter the absorption, distribution, and metabolism of drugs. Given the widespread use of Kacip Fatimah in dietary supplements, the current study focuses on determining the potential of its constituents to affect the activities of CYPs, P-gp, or PXR using in vitro assays which may provide useful information toward the risk of herb-drug interaction with concomitantly used drugs. Six compounds isolated from the roots of L. pumila (2 saponins and 4 alkyl phenols) were tested, in addition to the methanolic extract. The extract of L. pumila showed a significant time dependent inhibition (TDI) of CYP3A4, reversible inhibition of CYP2C9 and 2C19 and a weak inhibition of 1A2 and 2D6 as well as an inhibition of P-gp and rifampicin-induced PXR activation. The alkyl phenols inhibited CYP3A4 (TDI), CYP2C9, and 2C19 (reversible) while saponins inhibited P-gp and PXR. In conclusion, L. pumila and its constituents showed significant modulation of all three regulatory proteins (CYPs, P-gp, and PXR) suggesting a potential to alter the pharmacokinetic and pharmacodynamic properties of conventional drugs if used concomitantly.

No MeSH data available.


Related in: MedlinePlus

Induction of PXR by fatimahol and rifampicin (A) and inhibition of rifampicin mediated induction of PXR by Labisia pumila methanol extract and its constituents (B) at indicated concentrations. Ketoconazole (KTZ) was used as a positive control in the inhibition assay. *P < 0.05, **P < 0.01, and ***P < 0.001, determined by One way ANOVA, followed by Dunnett’s multiple comparison tests. The data are represented as mean ± SD of triplicate measurements in three independent experiments.
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Figure 7: Induction of PXR by fatimahol and rifampicin (A) and inhibition of rifampicin mediated induction of PXR by Labisia pumila methanol extract and its constituents (B) at indicated concentrations. Ketoconazole (KTZ) was used as a positive control in the inhibition assay. *P < 0.05, **P < 0.01, and ***P < 0.001, determined by One way ANOVA, followed by Dunnett’s multiple comparison tests. The data are represented as mean ± SD of triplicate measurements in three independent experiments.

Mentions: Finally, we looked at the modulation of PXR activity by the extract and the constituents using a reporter gene assay in HepG2 cells. One of the alky phenols, fatimahol, significantly induced PXR activity (1.8-fold) at the highest tested concentration of 30 μM, while at lower concentration the effect was not significant Figure 7A. These results suggest that there is no effect on the PXR activation by KF extract or its constituents. The positive control, rifampicin (10 μM) caused a fourfold induction in PXR activity which is in agreement with previous reports (Li and Chiang, 2006; Figure 7A). On the other hand, the methanolic extract (3–30 μg/mL) and the two saponins (primulanin and ardisimamilloside H; 3–30 μM) dose dependently decreased rifampicin-induced PXR activity (Figure 7B). These results indicate that L. pumila and its constituents significantly modulate the activity of PXR and thereby could affect the downstream genes involved in PXR signaling. Additionally, no cytotoxicity was observed toward HepG2 cells with either KF methanolic extract or its constituents up to the highest tested concentration of 30 μg/mL or 30 μM (data not shown) confirming that the inhibition of PXR as seen with methanolic extract and the two saponins is not due to the toxicity toward HepG2 cells.


Evaluation of drug interaction potential of Labisia pumila (Kacip Fatimah) and its constituents.

Manda VK, Dale OR, Awortwe C, Ali Z, Khan IA, Walker LA, Khan SI - Front Pharmacol (2014)

Induction of PXR by fatimahol and rifampicin (A) and inhibition of rifampicin mediated induction of PXR by Labisia pumila methanol extract and its constituents (B) at indicated concentrations. Ketoconazole (KTZ) was used as a positive control in the inhibition assay. *P < 0.05, **P < 0.01, and ***P < 0.001, determined by One way ANOVA, followed by Dunnett’s multiple comparison tests. The data are represented as mean ± SD of triplicate measurements in three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126480&req=5

Figure 7: Induction of PXR by fatimahol and rifampicin (A) and inhibition of rifampicin mediated induction of PXR by Labisia pumila methanol extract and its constituents (B) at indicated concentrations. Ketoconazole (KTZ) was used as a positive control in the inhibition assay. *P < 0.05, **P < 0.01, and ***P < 0.001, determined by One way ANOVA, followed by Dunnett’s multiple comparison tests. The data are represented as mean ± SD of triplicate measurements in three independent experiments.
Mentions: Finally, we looked at the modulation of PXR activity by the extract and the constituents using a reporter gene assay in HepG2 cells. One of the alky phenols, fatimahol, significantly induced PXR activity (1.8-fold) at the highest tested concentration of 30 μM, while at lower concentration the effect was not significant Figure 7A. These results suggest that there is no effect on the PXR activation by KF extract or its constituents. The positive control, rifampicin (10 μM) caused a fourfold induction in PXR activity which is in agreement with previous reports (Li and Chiang, 2006; Figure 7A). On the other hand, the methanolic extract (3–30 μg/mL) and the two saponins (primulanin and ardisimamilloside H; 3–30 μM) dose dependently decreased rifampicin-induced PXR activity (Figure 7B). These results indicate that L. pumila and its constituents significantly modulate the activity of PXR and thereby could affect the downstream genes involved in PXR signaling. Additionally, no cytotoxicity was observed toward HepG2 cells with either KF methanolic extract or its constituents up to the highest tested concentration of 30 μg/mL or 30 μM (data not shown) confirming that the inhibition of PXR as seen with methanolic extract and the two saponins is not due to the toxicity toward HepG2 cells.

Bottom Line: The extract of L. pumila showed a significant time dependent inhibition (TDI) of CYP3A4, reversible inhibition of CYP2C9 and 2C19 and a weak inhibition of 1A2 and 2D6 as well as an inhibition of P-gp and rifampicin-induced PXR activation.The alkyl phenols inhibited CYP3A4 (TDI), CYP2C9, and 2C19 (reversible) while saponins inhibited P-gp and PXR.In conclusion, L. pumila and its constituents showed significant modulation of all three regulatory proteins (CYPs, P-gp, and PXR) suggesting a potential to alter the pharmacokinetic and pharmacodynamic properties of conventional drugs if used concomitantly.

View Article: PubMed Central - PubMed

Affiliation: National Center for Natural Products Research, School of Pharmacy, The University of Mississippi Oxford, MS, USA.

ABSTRACT
Labisia pumila (Kacip Fatimah) is a popular herb in Malaysia that has been traditionally used in a number of women's health applications such as to improve libido, relieve postmenopausal symptoms, and to facilitate or hasten delivery in childbirth. In addition, the constituents of this plant have been reported to possess anticancer, antioxidant, and anti-inflammatory properties. Clinical studies have indicated that cytochrome P450s (CYPs), P-glycoprotein (P-gp), and Pregnane X receptor (PXR) are the three main modulators of drug-drug interactions which alter the absorption, distribution, and metabolism of drugs. Given the widespread use of Kacip Fatimah in dietary supplements, the current study focuses on determining the potential of its constituents to affect the activities of CYPs, P-gp, or PXR using in vitro assays which may provide useful information toward the risk of herb-drug interaction with concomitantly used drugs. Six compounds isolated from the roots of L. pumila (2 saponins and 4 alkyl phenols) were tested, in addition to the methanolic extract. The extract of L. pumila showed a significant time dependent inhibition (TDI) of CYP3A4, reversible inhibition of CYP2C9 and 2C19 and a weak inhibition of 1A2 and 2D6 as well as an inhibition of P-gp and rifampicin-induced PXR activation. The alkyl phenols inhibited CYP3A4 (TDI), CYP2C9, and 2C19 (reversible) while saponins inhibited P-gp and PXR. In conclusion, L. pumila and its constituents showed significant modulation of all three regulatory proteins (CYPs, P-gp, and PXR) suggesting a potential to alter the pharmacokinetic and pharmacodynamic properties of conventional drugs if used concomitantly.

No MeSH data available.


Related in: MedlinePlus