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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 profiles of reversible and TDI of CYP2C9 enzyme by Labisia pumila root extract (A) and its alkyl phenolic constituents (B–E). The data are represented as mean ± SD of 3 independent experiments (n = 2 in each experiment).
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Figure 3: Dose response profiles of reversible and TDI of CYP2C9 enzyme by Labisia pumila root extract (A) and its alkyl phenolic constituents (B–E). The data are represented as mean ± SD of 3 independent experiments (n = 2 in each experiment).

Mentions: Based on these results, we further tested the TDI potential of extract and selected constituents toward CYP3A4, 2C9, and 2C19. The test samples were pre-incubated for 30 min with the co-factors, control protein, and specific enzymes before substrates were added. IC50 shift was determined as described in the Materials and Methods. Compounds which showed IC50 shift ratio of greater than 1.5 were considered to have potential to exhibit TDI. Based on these criteria, no time-dependent inhibition was observed with recombinant CYP2C9 and 2C19 enzymes by the test compounds or the methanol extract. The dose curves were identical from co-incubation and pre-incubation experiments (Figures 3 and 4. The IC50 shift fold ratios of the control drugs (tranylcypromine, Table 1) were similar to the published literature values (Naritomi et al., 2004). In contrast, the methanol extract as well as the four alkyl phenols showed a very potent TDI of CYP3A4 with the dose curves shifted significantly to the left, as shown in Figure 2. The IC50 shift fold ratio for 5-[10(Z)-pentadecenyl]-resorcinol, fatimahol, and methanol extract was 13.6, 5.6, and 4.7, respectively, (Table 1 suggesting a very strong potential for TDI of CYP3A4 by these agents. The positive control for TDI, troleandomycin, showed an IC50 shift fold ratio of 3.4 Table 1 which is in accordance to the previous report (Sekiguchi et al., 2009). Further, the dose response curves clearly indicate a significant increase in % inhibition when the extract or the compounds were preincubated with CYP3A4 enzyme (Figure 2).


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 profiles of reversible and TDI of CYP2C9 enzyme by Labisia pumila root extract (A) and its alkyl phenolic constituents (B–E). 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 3: Dose response profiles of reversible and TDI of CYP2C9 enzyme by Labisia pumila root extract (A) and its alkyl phenolic constituents (B–E). The data are represented as mean ± SD of 3 independent experiments (n = 2 in each experiment).
Mentions: Based on these results, we further tested the TDI potential of extract and selected constituents toward CYP3A4, 2C9, and 2C19. The test samples were pre-incubated for 30 min with the co-factors, control protein, and specific enzymes before substrates were added. IC50 shift was determined as described in the Materials and Methods. Compounds which showed IC50 shift ratio of greater than 1.5 were considered to have potential to exhibit TDI. Based on these criteria, no time-dependent inhibition was observed with recombinant CYP2C9 and 2C19 enzymes by the test compounds or the methanol extract. The dose curves were identical from co-incubation and pre-incubation experiments (Figures 3 and 4. The IC50 shift fold ratios of the control drugs (tranylcypromine, Table 1) were similar to the published literature values (Naritomi et al., 2004). In contrast, the methanol extract as well as the four alkyl phenols showed a very potent TDI of CYP3A4 with the dose curves shifted significantly to the left, as shown in Figure 2. The IC50 shift fold ratio for 5-[10(Z)-pentadecenyl]-resorcinol, fatimahol, and methanol extract was 13.6, 5.6, and 4.7, respectively, (Table 1 suggesting a very strong potential for TDI of CYP3A4 by these agents. The positive control for TDI, troleandomycin, showed an IC50 shift fold ratio of 3.4 Table 1 which is in accordance to the previous report (Sekiguchi et al., 2009). Further, the dose response curves clearly indicate a significant increase in % inhibition when the extract or the compounds were preincubated with CYP3A4 enzyme (Figure 2).

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