Publications by authors named "Wiriyaporn Sumsakul"

5 Publications

  • Page 1 of 1

Pharmacokinetics, toxicity, and cytochrome P450 modulatory activity of plumbagin.

BMC Pharmacol Toxicol 2016 11 14;17(1):50. Epub 2016 Nov 14.

Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand.

Background: The antimalarial activity of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), a naturally occurring naphthoquinone widely distributed in the Plumbaginaceae family has previously been demonstrated in vitro (good activity) and in vivo (weak activity). The aim of the study was to investigate the pharmacokinetic profile following a single oral dosing to explain inconsistency of results of the in vitro and in vivo antimalarial activities. In addition, toxicity profiles and potential of modulation of cytochrome P450 enzymes (CYP1A2 and CYP3A11) were also investigated.

Methods: The pharmacokinetics and toxicity of plumbagin were investigated in rats. The propensity of plumbagin to modulate the mRNA expression and activities of the two inducible forms of hepatic drug metabolizing enzyme cytochrome P450 (CYP450), i.e., CYP1A2 and CYP3A11, was investigated using microsomes prepared from mouse livers.

Results: Acute and subacute toxicity tests indicate low toxicity of plumbagin with maximum tolerated doses of 150 (single oral dose) and 25 (daily doses for 28 days) mg/kg body weight, respectively. The pharmacokinetic profile of plumbagin following a single oral dose of 100 mg/kg body weight suggests that delayed absorption and short residence time (median values of time to maximal concentration and elimination half-life = 9.63 and 5.0 h, respectively) in plasma. Plumbagin did not modulate mRNA expression and activities of CYP1A2 and CYP3A11.

Conclusions: Plumbagin was well tolerated following oral dose administration in rats. Pharmacokinetic property of this compound may be a limiting factor that explains the weak antimalarial activity of plumbagin observed in animal models. Potential metabolic interaction with co-administered drugs that are metabolized by CYP1A2 or CYP3A11 are unlikely.
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http://dx.doi.org/10.1186/s40360-016-0094-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108082PMC
November 2016

Permeability of plumbagin across human intestinal cell in vitro.

Arch Pharm Res 2016 Mar 30;39(3):380-9. Epub 2015 Nov 30.

Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, 12121, Thailand.

Plumbagin is the active compound isolated from plants used in traditional medicine for treatment of various diseases such as activities malaria, leishmaniasis, viral infections and cancers. The aim of the study was to investigate the permeability of plumbagin across Caco-2 (human epithelial colorectal adenocarcinoma) cell monolayer and its effects on the expression and function of P-glycoprotein. The integrity of Caco-2 cell monolayer was evaluated by measuring trans-epithelial electrical resistance and permeation (Papp) of Lucifer yellow across the cell monolayer. The effect of plumbagin on P-glycoprotein was detected by measuring its interference with the transport of the P-glycoprotein substrate (R123) and the effect on MDR-1 mRNA expression was detected by RT-PCR. The Papp of plumbagin (2-8 µM) for the apical to basolateral and basolateral to apical directions were 10.29-15.96 × 10(-6) and 7.40-9.02 × 10(-6) cm/s, respectively, with the efflux ratios of 0.57-0.73. Plumbagin is not either a substrate or inhibitor of P-glycoprotein. It did not interfere with the P-glycoprotein-mediated R123 transport across Caco-2 cell monolayer, as well as the function of P-glycoprotein and the expression of MDR-1 mRNA. Results suggest moderate permeability of plumbagin across the Caco-2 cell monolayer in both directions. The transport mechanism is likely to be a passive transport.
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http://dx.doi.org/10.1007/s12272-015-0690-8DOI Listing
March 2016

In vitro inhibitory effects of plumbagin, the promising antimalarial candidate, on human cytochrome P450 enzymes.

Asian Pac J Trop Med 2015 Nov 9;8(11):914-918. Epub 2015 Oct 9.

Center of Excellence in Pharmacology and Molecular Biology, Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12121, Thailand. Electronic address:

Objective: To investigate the propensity of plumbagin to inhibit the three isoforms of human cytochrome P450 (CYP), i.e., CYP1A2, CYP2C19, and CYP3A4 using human liver microsomes in vitro.

Methods: Inhibitory effects of plumbagin on the three human CYP isoforms were investigated using pooled human liver microsomes. Phenacetin O-deethylation, omeprazole hydroxylation and nifedipine oxidation were used as selective substrates for CYP1A2, CYP2C19 and CYP3A4 activities, respectively. Concentrations of paracetamol, 5-hydroxyomeprazole, and oxidized nifedipine were determined in microsomal incubation mixture using high-performance liquid chromatography.

Results: Plumbagin showed significant inhibitory effects on all CYP isoforms, but with the most potent activity on CYP2C19-mediated omeprazole hydroxylation. The IC50 (concentration that inhibits enzyme activity by 50%) values of plumbagin and nootkatone (selective inhibitor) for CYP2C19 were (0.78 ± 0.01) and (27.31 ± 0.66) μM, respectively. The inhibitory activities on CYP1A2-mediated phenacetin O-deethylation and CYP3A4-mediated nifedipine oxidation were moderate. The IC50 values of plumbagin and α-naphthoflavone (selective inhibitor) for CYP1A2 were (1.39 ± 0.01) and (0.02 ± 0.36) μM, respectively. The corresponding IC50 values of plumbagin and ketoconazole (selective inhibitor) for CYP3A4 were (2.37 ± 0.10) and (0.18 ± 0.06) μM, respectively.

Conclusions: Clinical relevance of the interference of human drug metabolizing enzymes should be aware of for further development scheme of plumbagin as antimalarial drug when used in combination with other antimalarial drugs which are metabolized by these CYP isoforms.
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http://dx.doi.org/10.1016/j.apjtm.2015.10.016DOI Listing
November 2015

Inhibitory Activities of Thai Medicinal Plants with Promising Activities Against Malaria and Cholangiocarcinoma on Human Cytochrome P450.

Phytother Res 2015 Dec 22;29(12):1926-33. Epub 2015 Oct 22.

Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, 12121, Thailand.

Malaria and cholangiocarcinoma remain important public health problems in tropical countries including Southeast Asian nations. Newly developed chemotherapeutic and plant-derived drugs are urgently required for the control of both diseases. The aim of the present study was to investigate the propensity to inhibit cytochrome P450-mediated hepatic metabolism (CYP1A2, CYP2C19, CYP2D6 and CYP3A4) of the crude ethanolic extract of eight Thai medicinal plants with promising activities against malaria and cholangiocarcinoma, using human liver microsomes in vitro. Piper chaba Linn. (PC) and Atractylodes lancea (thung.) DC. (AL) exhibited the most potent inhibitory activities on CYP1A2-mediated phenacetin O-deethylation with mean IC50 of 0.04 and 0.36 µg/mL, respectively. Plumbago indica Linn. (PI) and Dioscorea membranacea Pierre. (DM) potently inhibited CYP2C19-mediated omeprazole 5-hydroxylation (mean IC50 4.71 and 6.92 µg/mL, respectively). DM, Dracaena loureiri Gagnep. (DL) and PI showed the highest inhibitory activities on dextromethorphan O-demethylation (mean IC50 2.93-9.57 µg/mL). PC, DM, DL and PI exhibited the most potent inhibitory activities on CYP3A4-mediated nifedipine oxidation (mean IC50 1.54-6.43 µg/mL). Clinical relevance of the inhibitory potential of DM, PC and PI is of concern for the further development of these plants for the treatment of malaria and/or cholangiocarcinoma.
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http://dx.doi.org/10.1002/ptr.5485DOI Listing
December 2015

Antimalarial activity of plumbagin in vitro and in animal models.

BMC Complement Altern Med 2014 Jan 12;14:15. Epub 2014 Jan 12.

Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathumtani 12121, Thailand.

Background: Plumbagin is the major active constituent in several plants including Plumbago indica Linn. (root). This compound has been shown to exhibit a wide spectrum of biological and pharmacological activities. The present study aimed to evaluate the in vitro and in vivo antimalarial activity of plumbagin including its acute and subacute toxicity in mice.

Methods: In vitro antimalarial activity of plumbagin against K1 and 3D7 Plasmodium falciparum clones were assessed using SYBR Green I based assay. In vivo antimalarial activity was investigated in Plasmodium berghei-infected mouse model (a 4-day suppressive test).

Results: Plumbagin exhibited promising antimalarial activity with in vitro IC50 (concentration that inhibits parasite growth to 50%) against 3D7 chloroquine-sensitive P. falciparum and K1 chloroquine-resistant P. falciparum clones of 580 (270-640) and 370 (270-490) nM, respectively. Toxicity testing indicated relatively low toxicity at the dose levels up to 100 (single oral dose) and 25 (daily doses for 14 days) mg/kg body weight for acute and subacute toxicity, respectively. Chloroquine exhibited the most potent antimalarial activity in mice infected with P. berghei ANKA strain with respect to its activity on the reduction of parasitaemia on day 4 and the prolongation of survival time.

Conclusions: Plumbagin at the dose of 25 mg/kg body weight given for 4 days was safe and produced weak antimalarial activity. Chemical derivatization of the parent compound or preparation of modified formulation is required to improve its systemic bioavailability.
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http://dx.doi.org/10.1186/1472-6882-14-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897931PMC
January 2014