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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

Dose-response curves of P-gp inhibition by methanol extract of Labisia pumila roots (A), its two saponin constituents (B–C) and positive control verapamil (D), determined by calculating the percent uptake of calcein AM into hMDR1-MDCKII cells. Equations used in evaluating EC50 and % increase in uptake of calcein-AM were described in “Materials and Methods” section. The data are represented as mean ± SD of 3 independent experiments (n = 2 in each experiment).
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Figure 5: Dose-response curves of P-gp inhibition by methanol extract of Labisia pumila roots (A), its two saponin constituents (B–C) and positive control verapamil (D), determined by calculating the percent uptake of calcein AM into hMDR1-MDCKII cells. Equations used in evaluating EC50 and % increase in uptake of calcein-AM were described in “Materials and Methods” section. The data are represented as mean ± SD of 3 independent experiments (n = 2 in each experiment).

Mentions: Next, we determined the inhibition of P-gp by the extract of L. pumila and the constituents by using the two widely used probes calcein-AM and digoxin (Rautio et al., 2006). Calcein-AM uptake was quantified in MDCK and hMDR1-MDCKII cells. The alkyl phenol compounds showed no increase in the uptake of calcein-AM in hMDR1-MDCKII cells. The methanolic extract and the two saponins, primulanin, and ardisimamilloside H, increased the uptake of calcein-AM dose dependently with EC50 values of 28 ± 1.4 μg/mL and 34 ± 2.3 and 42 ± 3.5 μM, respectively, as shown in Figure 5. The effect is comparable to the effect of positive control, verapamil (EC50 32 ± 1.4 μM) but significantly less potent than the effect of cyclosporin A (EC50 8 ± 1.2 μM). The Papp value of LY was in the range of 1.1 ± 0.8 × 10-6 cm/s, which was similar to our previously published values (Manda et al., 2013). Additionally, the TEER measurements before and after experiments confirmed that the test compounds did not alter the monolayer integrity during the experiment.


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)

Dose-response curves of P-gp inhibition by methanol extract of Labisia pumila roots (A), its two saponin constituents (B–C) and positive control verapamil (D), determined by calculating the percent uptake of calcein AM into hMDR1-MDCKII cells. Equations used in evaluating EC50 and % increase in uptake of calcein-AM were described in “Materials and Methods” section. The data are represented as mean ± SD of 3 independent experiments (n = 2 in each experiment).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Dose-response curves of P-gp inhibition by methanol extract of Labisia pumila roots (A), its two saponin constituents (B–C) and positive control verapamil (D), determined by calculating the percent uptake of calcein AM into hMDR1-MDCKII cells. Equations used in evaluating EC50 and % increase in uptake of calcein-AM were described in “Materials and Methods” section. The data are represented as mean ± SD of 3 independent experiments (n = 2 in each experiment).
Mentions: Next, we determined the inhibition of P-gp by the extract of L. pumila and the constituents by using the two widely used probes calcein-AM and digoxin (Rautio et al., 2006). Calcein-AM uptake was quantified in MDCK and hMDR1-MDCKII cells. The alkyl phenol compounds showed no increase in the uptake of calcein-AM in hMDR1-MDCKII cells. The methanolic extract and the two saponins, primulanin, and ardisimamilloside H, increased the uptake of calcein-AM dose dependently with EC50 values of 28 ± 1.4 μg/mL and 34 ± 2.3 and 42 ± 3.5 μM, respectively, as shown in Figure 5. The effect is comparable to the effect of positive control, verapamil (EC50 32 ± 1.4 μM) but significantly less potent than the effect of cyclosporin A (EC50 8 ± 1.2 μM). The Papp value of LY was in the range of 1.1 ± 0.8 × 10-6 cm/s, which was similar to our previously published values (Manda et al., 2013). Additionally, the TEER measurements before and after experiments confirmed that the test compounds did not alter the monolayer integrity during the experiment.

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