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Dive into the research topics where Verawan Uchaipichat is active.

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Featured researches published by Verawan Uchaipichat.


Drug Metabolism and Disposition | 2005

Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) "probes" for human udp-glucuronosyltransferases.

Verawan Uchaipichat; Peter I. Mackenzie; David J. Elliot; John O. Miners

Relatively few selective substrate and inhibitor probes have been identified for human UDP-glucuronosyltransferases (UGTs). This work investigated the selectivity of trifluoperazine (TFP), as a substrate, and amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone, as inhibitors, for human UGTs. Selectivity was assessed using UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15 expressed in HEK293 cells. TFP was confirmed as a highly selective substrate for UGT1A4. However, TFP bound extensively to both HEK293 lysate and human liver microsomes in a concentration-dependent manner (fuinc 0.20–0.59). When corrected for nonspecific binding, Km values for TFP glucuronidation were similar for both UGT1A4 (4.1 μM) and human liver microsomes (6.1 ± 1.2 μM) as the enzyme sources. Of the compounds screened as inhibitors, hecogenin, alone, was selective; significant inhibition was observed only for UGT1A4 (IC50 1.5 μM). Using phenylbutazone and quinine as “models,” inhibition kinetics were variously described by competitive and noncompetitive mechanisms. Inhibition of UGT2B7 by quinidine was also investigated further, because the effects of this compound on morphine pharmacokinetics (a known UGT2B7 substrate) have been ascribed to inhibition of P-glycoprotein. Quinidine inhibited human liver microsomal and recombinant UGT2B7, with respective Ki values of 335 ± 128 μM and 186 μM. In conclusion, TFP and hecogenin represent selective substrate and inhibitor probes for UGT1A4, although the extensive nonselective binding of the former should be taken into account in kinetic studies. Amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone are nonselective UGT inhibitors.


Journal of Pharmacology and Experimental Therapeutics | 2010

In Vitro–In Vivo Extrapolation Predicts Drug–Drug Interactions Arising from Inhibition of Codeine Glucuronidation by Dextropropoxyphene, Fluconazole, Ketoconazole, and Methadone in Humans

Pritsana Raungrut; Verawan Uchaipichat; David J. Elliot; Benjamas Janchawee; Andrew A. Somogyi; John O. Miners

Because codeine (COD) is eliminated primarily via glucuronidation, factors that alter COD glucuronide formation potentially affect the proportion of the dose converted to the pharmacologically active metabolite morphine. Thus, in vitro–in vivo extrapolation approaches were used to identify potential drug–drug interactions arising from inhibition of COD glucuronidation in humans. Initial studies characterized the kinetics of COD-6-glucuronide (C6G) formation by human liver microsomes (HLM) and demonstrated an 88% reduction in the Michaelis constant (Km) (0.29 versus 2.32 mM) for incubations performed in the presence of 2% bovine serum albumin (BSA). Of 13 recombinant UDP-glucuronosyltransferase (UGT) enzymes screened for COD glucuronidation activity, only UGT2B4 and UGT2B7 exhibited activity. The respective S50 values (0.32 and 0.27 mM) generated in the presence of BSA were comparable with the mean Km observed in HLM. Known inhibitors of UGT2B7 activity in vitro or in vivo and drugs marketed as compound formulations with COD were investigated for inhibition of C6G formation by HLM. Inhibition screening identified potential interactions with dextropropoxyphene, fluconazole, ketoconazole, and methadone. Inhibitor constant values generated for dextropropoxyphene (3.5 μM), fluconazole (202 μM), ketoconazole (0.66 μM), and methadone (0.32 μM) predicted 1.60- to 3.66-fold increases in the area under the drug plasma concentration–time curve ratio for COD in vivo. Whereas fluconazole and ketoconazole inhibited UGT2B4- and UGT2B7-catalyzed COD glucuronidation to a similar extent, inhibition by dextropropoxyphene and methadone resulted largely from an effect on UGT2B4. Interactions with dextropropoxyphene, fluconazole, ketoconazole, and methadone potentially affect the intensity and duration of COD analgesia.


Molecular Pharmacology | 2008

Kinetic Modeling of the Interactions between 4-Methylumbelliferone, 1-Naphthol, and Zidovudine Glucuronidation by UDP-Glucuronosyltransferase 2B7 (UGT2B7) Provides Evidence for Multiple Substrate Binding and Effector Sites

Verawan Uchaipichat; Aleksandra Galetin; J. Brian Houston; Peter I. Mackenzie; J. Andrew Williams; John O. Miners

Interactions between the UGT2B7-catalyzed glucuronidation of zidovudine (AZT), 4-methylumbelliferone (4MU), and 1-naphthol (1NP) were analyzed using multisite and empirical kinetic models to explore the existence of multiple substrate and effector binding sites within this important drug metabolizing enzyme. 4MU and 1NP glucuronidation by UGT2B7 exhibit sigmoidal kinetics characteristic of homotropic cooperativity (autoactivation), which may be modeled assuming the existence of two equivalent, interacting substrate binding sites. In contrast, UGT2B7-catalyzed AZT glucuronidation follows hyperbolic (Michaelis-Menten) kinetics. Although 4MU and 1NP decreased the binding affinity of AZT, the kinetics of AZT glucuronidation changed from hyperbolic to sigmoidal in the presence of both modifiers. Data were well described by a generic two-substrate binding site model in which there is no interaction between the sites in the absence of 4MU or 1NP, but heterotropic cooperativity results from the binding of modifier. Inhibition of 4MU and 1NP glucuronidation by AZT and interactions between 4MU and 1NP required more complex three-site models, where the modifier acts via a distinct effector site to alter either substrate binding affinity or Vmax without affecting the homotropic cooperativity characteristic of 4MU and 1NP glucuronidation. It is noteworthy that 1NP inhibited 4MU glucuronidation, whereas 4MU activated 1NP glucuronidation. The results are consistent with the existence of two “catalytic” sites for each substrate within the UGT2B7 active site, along with multiple effector sites. The multiplicity of binding and effector sites results in complex kinetic interactions between UGT2B7 substrates, which potentially complicates inhibition screening studies.


Drug Metabolism and Disposition | 2013

The Glucuronidation of R- and S-Lorazepam: Human Liver Microsomal Kinetics, UDP-Glucuronosyltransferase Enzyme Selectivity, and Inhibition by Drugs

Verawan Uchaipichat; Chuthamanee Suthisisang; John O. Miners

The widely used hypnosedative-anxiolytic agent R,S-lorazepam is cleared predominantly by conjugation with glucuronic acid in humans, but the enantioselective glucuronidation of lorazepam has received little attention. The present study characterized the kinetics of the separate R and S enantiomers of lorazepam by human liver microsomes (HLMs) and by a panel of recombinant human UDP-glucuronosyltransferase (UGT) enzymes. Respective mean Km and Vmax values for R- and S-lorazepam glucuronidation by HLM were 29 ± 8.9 and 36 ± 10 µM, and 7.4 ± 1.9 and 10 ± 3.8 pmol/min ⋅ mg. Microsomal intrinsic clearances were not significantly different, suggesting the in vivo clearances of R- and S-lorazepam are likely to be similar. Both R- and S-lorazepam were glucuronidated by UGT2B4, 2B7, and 2B15, whereas R-lorazepam was additionally metabolized by the extrahepatic enzymes UGT1A7 and 1A10. Based on in vitro clearances and consideration of available in vivo and in vitro data, UGT2B15 is likely to play an important role in the glucuronidation of R- and S-lorazepam. However, the possible contribution of other enzymes and the low activities observed in vitro indicate that the lorazepam enantiomers are of limited use as substrate probes for UGT2B15. To identify potential drug-drug interactions, codeine, fluconazole, ketamine, ketoconazole, methadone, morphine, valproic acid, and zidovudine were screened as inhibitors of R- and S-lorazepam glucuronidation by HLM. In vitro–in vivo extrapolation suggested that, of these drugs, only ketoconazole had the potential to inhibit lorazepam clearance to a clinically significant extent.


Drug Metabolism and Disposition | 2011

Effects of Ketamine on Human UDP-Glucuronosyltransferases In Vitro Predict Potential Drug-Drug Interactions Arising from Ketamine Inhibition of Codeine and Morphine Glucuronidation

Verawan Uchaipichat; Pritsana Raungrut; Nuy Chau; Benjamas Janchawee; Allan M. Evans; John O. Miners

In this study, the selectivity of UDP-glucuronosyltransferase (UGT) enzyme inhibition by ketamine (KTM) and the kinetics of KTM inhibition of human liver microsomal morphine (MOR) and codeine (COD) glucuronidation were characterized to explore a pharmacokinetic basis for the KTM-opioid interaction. With the exception of UGT1A4, KTM inhibited the activities of recombinant human UGT enzymes in a concentration-dependent manner. However, IC50 values were <100 μM only for UGT2B4, UGT2B7, and UGT2B15. UGT2B7 catalyzes MOR 3- and 6-glucuronidation and the 6-glucuronidation of COD, with an additional substantial contribution of UGT2B4 to the latter reaction. Consistent with the effects of KTM on the activities of recombinant UGT2B enzyme activities, KTM competitively inhibited human liver microsomal MOR and COD glucuronidation. Ki values for KTM inhibition of MOR 3- and 6-glucuronidation and COD 6-glucuronidation by human liver microsomes supplemented with 2% bovine serum albumin were 5.8 ± 0.1, 4.6 ± 0.2, and 3.5 ± 0.1 μM, respectively. Based on the derived inhibitor constants, in vitro-in vivo extrapolation was used to predict the effects of anesthetic and analgesic doses of KTM on MOR and COD clearances. Potentially clinically significant interactions (>50% increases in the in vivo area under the curve ratios) with MOR and COD were predicted for anesthetic doses of KTM and for a subanesthetic dose of KTM on COD glucuronidation.


Molecules | 2010

Effects of Andrographis paniculata and Orthosiphon stamineus extracts on the glucuronidation of 4-methylumbelliferone in human UGT isoforms.

Sabariah Ismail; Nur Aziah Hanapi; Mohd Rohaimi Ab Halim; Verawan Uchaipichat; Peter I. Mackenzie

The effects of Andrographis paniculata and Orthosiphon stamineus extracts on the in vitro glucuronidation of 4-methylumbelliferone (4MU) by recombinant human UGTs, UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A10, UGT2B7 and UGT2B15 were determined. The potential inhibitory effects of both of the extracts on the activity of each of the UGT isoforms were investigated using 4MU as the substrate. Incubations contained UDP-glucuronic acid (UDPGA) as the cofactor, MgCl2, cell lysate of respective isoform, and 4MU at the approximate apparent Km or S50 value of each isoform. Final concentrations of Andrographis paniculata and Orthosiphon stamineus extracts used were 0.025, 0.25, 2.5, 25 and 50 μg/mL and 0.01, 0.10, 1.0, 10 and 50 μg/mL respectively. Both extracts variably inhibited the activity of most of the isoforms in a concentration dependent manner. Andrographis paniculata extract was the better inhibitor of all the isoforms studied (IC50 1.70 μg/mL for UGT1A3, 2.57 μg/mL for UGT1A8, 2.82 μg/mL for UGT2B7, 5.00 μg/mL for UGT1A1, 5.66 μg/mL for UGT1A6, 9.88 μg/mL for UGT1A7 and 15.66 μg/mL for UGT1A10). Both extracts showed less than 70% inhibition of UGT2B15, so the IC50 values were >50μg/mL. The inhibition of human UGTs by Andrographis paniculata and Orthosiphon stamineus extracts in vitro suggests a potential for drug-herbal extract interactions in the therapeutic setting.


Journal of The Saudi Pharmaceutical Society | 2017

Prevalence of potential drug interactions in Thai patients receiving simvastatin: The causality assessment of musculoskeletal adverse events induced by statin interaction

Methira Siriangkhawut; Patthana Tansakul; Verawan Uchaipichat

Drug-drug interactions are one of the major risk factors associated with statin-induced myopathy. Although simvastatin is widely used in Thailand, studies investigating the prevalence of potential simvastatin-drug interactions (SDIs) and its clinical relevance in Thai population are still limited. We aimed to investigate the prevalence of potential SDIs (phase 1 study) and musculoskeletal adverse effects (AEs) associated with those interactions (phase 2 study). A phase 1 study was retrospectively conducted with outpatients at a 60-bed hospital who received simvastatin between July 1, 2012 and June 30, 2013. In phase 2, study was cross-sectionally conducted in outpatients whose prescriptions contain potential SDIs. Musculoskeletal AEs were evaluated by using symptom checklist questionnaires and measuring plasma creatinine kinase (CK). The causal relationship between the AEs and the potential SDIs was assessed using a Drug Interaction Probability Scale. Out of 3447 simvastatin users, potential SDIs were found in 314 patients (9.1%). The prevalence of prescriptions containing potential SDIs was in the range of 4.7–6.0%. Two-thirds of the potential SDIs were rated to be highly significant while more than 70% were in contraindication list. The most common precipitant drugs were gemfibrozil (382 prescriptions), colchicine (171 prescriptions) and amlodipine (152 prescriptions). Of 49 patients recruited into phase 2 study, we found that 31 patients (63.3%) had myopathy. Myalgia was the most frequently identified AEs (n = 18, 58.1%), followed by asymptomatic rising CK (n = 8, 25.8%), and myositis (n = 5, 16.1%). Musculoskeletal AEs associated with SDIs were found in 16 patients (51.6%). Of these, we found 50.0%, 31.3% and 18.8% had asymptomatic rising CK, myalgia, and myositis, respectively. Precipitant drugs associated with myopathy were amlodipine (2 possible cases), colchicine (3 possible cases), gemfibrozil (8 possible and 1 probable cases), nevirapine (1 possible case), and nicotinic acid (1 possible case). Potential SDIs have been found in the Thai population with a prevalence that is consistent with previous reports. Half of the musculoskeletal AEs identified were associated with SDIs. Systematic screening and management with interdisciplinary co-operation are needed to increase awareness of potential SDIs.


Pharmacoepidemiology and Drug Safety | 2016

Initial development and testing of an instrument for patient self‐assessment of adverse drug reactions

Narumol Jarernsiripornkul; Nataporn Chaipichit; Thongchai Pratipanawatr; Verawan Uchaipichat; Janet Krska

To develop and conduct preliminary testing of a causality assessment tool for patients, for potential use in encouraging both discussions with clinicians about suspected adverse drug reactions (ADRs) and reporting to authorities.


Drug Metabolism and Disposition | 2004

Human udp-glucuronosyltransferases: isoform selectivity and kinetics of 4-methylumbelliferone and 1-naphthol glucuronidation, effects of organic solvents, and inhibition by diclofenac and probenecid.

Verawan Uchaipichat; Peter I. Mackenzie; Xiao-Hui Guo; Dione Gardner-Stephen; Aleksandra Galetin; J. Brian Houston; John O. Miners


British Journal of Clinical Pharmacology | 2006

Quantitative prediction of in vivo inhibitory interactions involving glucuronidated drugs from in vitro data: the effect of fluconazole on zidovudine glucuronidation.

Verawan Uchaipichat; Leanne Winner; Peter I. Mackenzie; David J. Elliot; J. Andrew Williams; John O. Miners

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Poj Kulvanich

Chulalongkorn University

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