Papers by Malinee Wongnawa
Phyllanthus amarus Schum. & Thonn. has been used for the treatment of various diseases. Previous ... more Phyllanthus amarus Schum. & Thonn. has been used for the treatment of various diseases. Previous in vitro study in human liver microsome demonstrated the inhibitory activity of P. amarus extract on CYP3A4, an enzyme responsible for various drug metabolism. The objective of this study was to evaluate the effect of P. amarus ethanolic extract on the pharmacokinetics of midazolam, a CYP3A4 probe drug, in rabbits. Midazolam plasma concentration time-profiles (0-8 h) after a single oral dose of 10 mg/kg midazolam were examined in rabbits receiving P. amarus extract compared to control. In treatment group, P. amarus extract (500 mg/kg) was orally administered for 7 days and on the experiment day prior to midazolam administration. The results showed that pretreatment with P. amarus significantly increased the mean maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under curve (AUC0-8), and elimination half-life (T1/2) (2.9-, 1.6-, 2.8-, and 1.4-fold, respectivel...
Asia Pacific Journal of Pharmacology, 1998
Andrographis paniculata (Burm.f.) Nees has been widely used for centuries in Asia for the treatme... more Andrographis paniculata (Burm.f.) Nees has been widely used for centuries in Asia for the treatment of common cold and diarrhea. Although it was previously reported to inhibit cytochrome P450 in vitro, the potential to cause herb-drug interaction has been questioned. The purpose of this study was to evaluate the effects of A. paniculata on the pharmacokinetics and pharmacodynamics of midazolam, a CYP3A4 probe drug, in normal healthy volunteers. The study was an open-label, randomized, 2-phase crossover design with a 2-weeks washout period. Twelve healthy male volunteers received 4 capsules of 250 mg A. paniculata 3 times a day orally for 7 days. Midazolam plasma concentration time profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and after A. paniculata medication. Pharmacodynamics of midazolam were also evaluated. The results demonstrated that pretreatment with A. paniculata did not change mean pharmacokinetic parameters (C max , T max , AUC...
Bulletin of the Department of Medical Sciences วารสารกรมวิทยาศาสตร์การแพทย์, Jun 8, 2012
The methanolic extract of Piper sarmentosum Roxb. leaves at doses of 50, 100 and 200 mg/kg was in... more The methanolic extract of Piper sarmentosum Roxb. leaves at doses of 50, 100 and 200 mg/kg was investigated for anti-inflammatory and antipyretic activities on carrageenan-induced rat paw edema and brewer's yeast-induced pyrexia in rats. The results revealed that the extract at test doses produced a significant anti-inflammatory activity at 3 h with an inhibition of paw edema of 8.6% (P<0.05), 18.6% (P<0.01) and 24.7% (P<0.01), respectively, compared to the reference drug aspirin 200 mg/kg p.o. with an inhibition of 33.3% (P<0.01). Only the extract at the dose of 200 mg/kg p.o. showed a significant inhibition ofcarrageenan-induced rat paw edema beginning at 2 h of 11.8% (P<0.01) and at 3, 4 and 5 h of 24.7% (P< 0.01), 14.1% (P<0.01) and 11.9% (P<0.01), respectively, whereas the reference drug aspirin 200 mg/kg p.o. exhibited a significant inhibition of edema beginning at 1 h of 15.6% (P<0.05) and at 2, 3, 4 and 5 h of 31.8% (P<0.01), 33.3% (P<0.0...
Clinical pharmacology and therapeutics, 2002
Praziquantel is extensively metabolized by the hepatic cytochrome P450 (CYP) enzymes. The CYP3A i... more Praziquantel is extensively metabolized by the hepatic cytochrome P450 (CYP) enzymes. The CYP3A isoforms are likely to be major enzymes responsible for praziquantel metabolism. Rifampin (INN, rifampicin), a potent enzyme inducer of CYP-mediated metabolism (especially CYP2C9, CYP2C19, and CYP3A4), is known to markedly decrease plasma concentrations and effects of a number coadministered drugs. The aim of this investigation was to study the possible pharmacokinetic interaction between rifampin and praziquantel. An open, randomized, 2-phase crossover design was used in each study of single or multiple doses. In the single-dose study, 10 healthy Thai male volunteers ingested single doses of 40 mg/kg praziquantel alone (phase 1) or after pretreatment with 600 mg of oral rifampin once daily for 5 days (phase 2). In the multiple-dose study, all participants received multiple doses of 25 mg/kg praziquantel alone (phase 1) or after 5-day pretreatment with 600 mg of oral rifampin once daily (...
Journal of Bioequivalence & Bioavailability, 2011
Quetiapine is an atypical antipsychotic indicated for the treatment of schizophrenia and related ... more Quetiapine is an atypical antipsychotic indicated for the treatment of schizophrenia and related psychoses. Uses of generic drugs are essential due to economic reason. Interchangeability of drugs is determined by bioequivalence studies. We aim to study the bioequivalence of a generic quetiapine (Ketipinor ® , Orion Corporation, Finland) and the innovator product (Seroquel ® , AstraZeneca, UK). The study was a randomized, two-way crossover design with a two-week washout period in 24 healthy Thai male volunteers. After a single 200-mg oral dosing, serial blood samples were collected at appropriate interval up to 48 h. Plasma quetiapine concentrations were determined by using a validated LC-MS/MS method. Pharmacokinetic parameters were estimated using the WinNonlin ® software with noncompartment model analysis. The mean ± SD of maximum plasma concentration (C max), the area under the plasma concentration-time curve from 0 to 48 h (AUC 0-last) and the area under the plasma concentration-time curve from 0 to infinity (AUC 0-∞) of Ketipinor ® v.s.
Journal of Pharmacy and Pharmacology, 2000
Mefloquine is a 4-quinolinemethanol compound structurally related to quinine. Quinine is mainly m... more Mefloquine is a 4-quinolinemethanol compound structurally related to quinine. Quinine is mainly metabolized by the cytochrome P450 3A4 isozyme (CYP3A4), whereas rifampin, a potent inducer of CYP3A4, is known to markedly decrease plasma quinine concentration. Our aim was to study the effect of rifampin on the pharmacokinetics of mefloquine, and explore a possible role of CYP3A4 on mefloquine metabolism. In an open, two-phase crossover study, seven healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone, or 500 mg mefloquine plus a long-term administration of 600 mg rifampin. Blood samples were collected at specific time points over a 56-day period. Plasma mefloquine and its carboxylic acid metabolite were measured by HPLC for pharmacokinetic analysis. The results indicate that rifampin significantly decreased the area under the plasma concentration-time curve (AUC0-∞) of mefloquine by 68% (P<0.01), maximum plasma concentration (Cmax) by 19% (P<0.01),...
Journal of Pharmaceutical and Biomedical Analysis, 2002
A simple high-performance liquid chromatographic (HPLC) method for the determination of praziquan... more A simple high-performance liquid chromatographic (HPLC) method for the determination of praziquantel in human plasma was developed and validated. The present method was described by adding drop-wise 0.2 M Zinc sulfate and acetonitrile to plasma sample for deproteinization. This method used a reversed-phase Spherisorb ODS 2 column (5 mm), 250 ×4.6 mm i.d. as a stationary phase with a mobile phase consisting of acetonitrilemethanol-water (36:10:54, v/v/v), a flow rate of 1.5 ml/min and UV detection wavelength of 217 nm. Diazepam was used as internal standard. The standard calibration curve was linear over the concentration range of 100-2000 ng/ml (r =0.999). The equation of a linear regression line was y= 8.05E-04+7.25E-04x with slope and intercept values of 0.0007 and 0.0008, respectively. The limit of detection was 12.25 ng/ml and the limit of quantification was set at 100 ng/ml. The intra-and inter-day assay coefficients of variation (CV) were 3.0 9 1.7 and 6.3 9 1.9%, respectively. The percentage of recovery was 102.1 95.6. Therefore, the HPLC method described here was simple, rapid and reproducible since it did not require extraction and evaporation processes in sample preparation, which will reduce time-consuming or expensive sample preparation.
Journal of Ethnopharmacology, 2009
The effects and plausible mechanism of action of Curcuma aeruginosa Roxb. (Zingiberaceae) rhizome... more The effects and plausible mechanism of action of Curcuma aeruginosa Roxb. (Zingiberaceae) rhizome chloroform and methanol extracts on the uterine contraction were investigated using isolated uterus strips from estrogen primed rats. The contractile responses were recorded isometrically with a Grass FT03 force transducer connected to a MacLab system. The experiments were carried out on both nonstimulated, agonist-and KCl-stimulated uteri. In the nonstimulated uterus, the two extracts (10-400 g/ml) had no significant effect. In contrast, in the stimulated uterus, the chloroform and methanol extracts exerted concentration-dependent inhibition of the contractions induced by oxytocin (1 mU/ml), prostaglandin F 2␣ (PGF 2␣ , 0.5 g/ml), ACh (3 × 10 −6 M) and KCl (40 mM) with the IC 50 (inhibition of force) of 31.4, 58.59, 56.21 and 29.28 g/ml; and 57.79, 69.3, 223.8 and 69.19 g/ml, respectively. Verapamil, the reference Ltype calcium channel blocker, exhibited a similar pattern of inhibition with the IC 50 of 0.03, 0.25, 0.35 and 0.04 g/ml. The IC 50 of diclofenac against a PGF 2␣-induced contraction was 31.36 g/ml. It is known that the contraction induced by agonists and KCl is mainly due to calcium influx through the voltage-gated L-type calcium channels opened indirectly or directly by agonist-receptor activation and KCl. Thus, it is speculated that the two plant extracts might inhibit uterine contraction by interrupting the influx of Ca 2+ probably through voltage-gated L-type calcium channels. This possibility was further substantiated by the ability of the extracts to shift the CaCl 2-contraction curves to the right. As the methanol extract also reduced the contraction of oxytocin in Ca 2+-free EDTA solution; thus, it is suggested that part of its action may be involved with an intracellular mechanism. The effect of the two extracts did not involve the activation of  2-adrenoceptors since their effects were unaffected by propranolol. Based on the inhibitory effect of the extracts on the oxytocin-induced contraction, it is concluded that the extracts might be useful as tocolytic agents for the prevention of preterm labor. Their effects on the inhibition of PGF 2␣-induced contractions also seem useful for the treatment of dysmenorrhea. There are reports by others that the plant rhizome contains -pinene and sesquiterpenes. In addition, there is evidence that these compounds possess spasmolytic effects in the rat intestine and uterus. Therefore, the uterine relaxant effect of the plant extracts could be due to -pinene and some sesquiterpene lactones contents. The methanol extract is less potent than the chloroform extract, and this might be due to the lower amount of terpene compounds or different compounds may involve in this action.
Journal of Clinical Pharmacy and Therapeutics, 2007
Background: Although cytochrome P450 (CYP) 2D6 is often thought to be the only CYP responsible fo... more Background: Although cytochrome P450 (CYP) 2D6 is often thought to be the only CYP responsible for the metabolism of risperidone, many reports suggest that CYP3A may be involved too. Rifampin, a potent CYP3A inducer, has been known to markedly decrease plasma concentrations of various drugs, which are concomitantly administered during treatment. Objective: To examine the effect of rifampin on plasma concentrations of a single oral dose of risperidone in healthy Thai male volunteers. Methods: In an open, randomized two-phase crossover study, separated by a 2-week period, 10 healthy Thai male volunteers received a single oral dose of 4-mg risperidone alone or with 600 mg rifampin, orally once daily for 5 days. Serial blood samples were collected at specific time points for a 48-h period. Risperidone was measured in plasma using high performance liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were determined by using non-compartmental analysis. Results: Co-administration with 600-mg rifampin once daily for 5 days was associated with a significant decrease in risperidone area under the curve (AUC 0-48) and maximal concentration (C max) by 72% (157AE49 ± 48AE80 vs. 42AE66 ± 7AE81 ng/L/h; P < 0AE01) and 50% (32AE44 ± 6AE05 vs. 16AE16 ± 2AE73 ng/mL; P < 0AE05), respectively when compared with risperidone alone. Conclusions: Rifampin when used concurrently with risperidone significantly decreases the plasma concentration of risperidone. Our results provide in vivo evidence of the involvement of CYP3A in the metabolism of risperidone, in addition to CYP2D6. Thus, co-administration of risperidone with CYP3A inducer(s), including rifampin should be recognized or avoided in clinical practice.
Journal of Clinical Pharmacy and Therapeutics, 2005
Background: Antimalarial mefloquine has a structure related to quinine. The major metabolite of q... more Background: Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine. Objective: To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy Thai male volunteers. Methods: In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day period. Plasma mefloquine and mefloquine carboxylic metabolite concentrations during 56 days were measured by a modified and validated highperformance liquid chromatographic method with UV detection. Results: Co-administration with ketoconazole markedly increased the mean values of mefloquine AUC 0)t , t 1/2 , and C max when compared with mefloquine alone by 79% (P < 0AE001), 39% (P < 0AE05) and 64% (P < 0AE001) respectively. The AUC 0)t , and C max of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0AE05) and 31% (P < 0AE05), respectively when compared with mefloquine alone. Conclusions: Co-administration with ketoconazole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloquine is co-administered with ketoconazole, drugdrug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy.
Journal of Clinical Pharmacy and Therapeutics, 2011
Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mai... more Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mainly metabolized by human cytochrome P450 CYP2D6 and partly by CYP3A4 to 9-hydroxyrisperidone. Ketoconazole is used as a CYP3A4 inhibitor probe for studying drug-drug interactions. We aim to investigate the effect of ketoconazole on the pharmacokinetics of risperidone in healthy male volunteers. An open-label, randomized, two-phase crossover design with a 2-week washout period was performed in 10 healthy male volunteers. The volunteers received a single oral dose of 2mg of risperidone alone or in combination with 200mg of ketoconazole, once daily for 3days. Serial blood samples were collected at specific periods after ingestion of risperidone for a period of 96h. Plasma concentrations of risperidone and 9-hydroxyrisperidone were determined using a validated HPLC-tandem mass spectrometry method. After pretreatment with ketoconazole, the clearance of risperidone decreased significantly by 34·81±5·10% and the T(1/2) of risperidone increased significantly by 28·03±40·60%. The AUC(0-96) and AUC(0-∞) of risperidone increased significantly by 66·61± 43·03% and 66·54±39·76%, respectively. The Vd/f of risperidone increased significantly by 39·79±53·59%. However, the C(max) and T(max) of risperidone were not significantly changed, indicating that ketoconazole had minimal effect on the absorption of risperidone. The C(max) , T(max) and T(1/2) of 9-hydroxyrisperidone did not decrease significantly. However, the Cl/f of 9-hydroxyrisperidone increased significantly by 135·07± 124·68%, and the Vd/f of 9-hydroxyrisperidone decreased significantly by 29·47±54·64%. These changes led to a corresponding significant decrease in the AUC(0-96) and AUC(0-∞) of 9-hydroxyrisperidone by 47·76±22·39% and 48·49± 20·03%, respectively. Ketoconazole significantly inhibited the metabolism of risperidone through the inhibition of hepatic CYP3A4. our results suggest that besides CYP2D6, CYP3A4 contributes significantly to the metabolism of risperidone. The pharmacokinetics of risperidone was affected by the concomitant administration of ketoconazole. If a CYP3A4 inhibitor is used concomitantly with risperidone, it is necessary for the clinicians to monitor their patients for signs of adverse drug reactions.
Int. Journal of Clinical Pharmacology and Therapeutics, 2008
To study the bioequivalence of a generic quetiapine (Quantia 200, manufactured by the Unison Labo... more To study the bioequivalence of a generic quetiapine (Quantia 200, manufactured by the Unison Laboratories Co., Ltd., Bangkok, Thailand) and the innovator product (Seroquel, AstraZeneca, Macclesfield, UK). The study was a randomized, 2-way crossover design with a 2-week washout period in 24 healthy Thai male volunteers. After a single 200 mg oral dosing, serial blood samples were collected at appropriate interval up to 48 h. Plasma quetiapine concentrations were determined by high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were estimated using the WinNonlin software with noncompartment model analysis. Comparative bioequivalence between the two formulations was determined by analysis of variance (ANOVA) for 2-way crossover design. The mean +/- SD of maximum plasma concentration (Cmax), the area under the plasma concentration-time curve from 0 - 48 h (AUC0-48) and the area under the plasma concentration-time curve from 0 to infinity (AUC0-inf) of Quantia 200 vs. Seroquel were 886.60 +/- 356.50 vs. 811.34 +/- 323.37 ng/ml; 3,754.41 +/- 1,453.00 vs. 3,420.00 +/- 1,229.6 ng x h/ml and 4,015.35 +/- 1,528.25 vs. 3,769.45 +/- 1,296.69 ng x h/ml, respectively. Time to reach Cmax (tmax) of Quantia 200 and Seroquel were 1.08 +/- 0.778 and 1.10 +/- 0.79 h, respectively, and thus not significantly different. The 90% confidence interval of the ratios of the logarithmically transformed of Cmax, AUC0-48 and AUC0-inf were 98.21 - 124.37%, 94.43 - 117.03% and 94.77 - 116.61%, respectively, which were within the acceptable range of 80 - 125%. Power of the test for Cmax, AUC0-48 and AUC0-inf was 92.1%, 96.9% and 97.4%, respectively. Quantia 200, used in this study, was bioequivalent to Seroquel in terms of both the rate and extent of absorption.
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Papers by Malinee Wongnawa