Papers by Wichittra Tassaneeyakul
Clinical Pharmacology & Therapeutics, Oct 17, 2012
nature publishing group Allopurinol is the most commonly used drug for the treatment of hyperuric... more nature publishing group Allopurinol is the most commonly used drug for the treatment of hyperuricemia and gout. However, allopurinol is also one of the most common causes of severe cutaneous adverse reactions (SCARs), which include drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A variant allele of the human leukocyte antigen (HLA)-B, HLA-B*58:01, associates strongly with allopurinolinduced SCAR. We have summarized the evidence from the published literature and developed peer-reviewed guidelines for allopurinol use based on HLA-B genotype.
JAMA Dermatology, 2017
Importance: Toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS) are rare, acute, ... more Importance: Toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS) are rare, acute, life-threatening dermatologic disorders involving the skin and mucous membranes. Research into these conditions is hampered by a lack of standardization of case reporting and data collection. Objective: To establish a standardized case report form to facilitate comparisons and maintain data quality based on an international panel of SJS/TEN experts who performed a Delphi consensus-building exercise. Evidence Review: The elements presented for committee scrutiny were adapted from previous case report forms and from PubMed literature searches of highly cited manuscripts pertaining to SJS/TEN. The expert opinions and experience of the members of the consensus group were included in the discussion. Findings: Overall, 21 out of 29 experts who were invited to participate in the online Delphi exercise agreed to participate. Surveys at each stage were administered via an online survery software tool. For the first 2 Delphi rounds, results were analyzed using the Interpercentile Range Adjusted for Symmetry method and statements that passed consensus formulated a new case report form. For the third Delphi round, the case report form was presented to the committee, who agreed that it was "appropriate and useful" for documenting cases of SJS/TEN, making it more reliable and valuable for future research endeavors. Conclusions and Relevance: With the consensus of international experts, a case report form for SJS/TEN has been created to help standardize the collection of patient information in future studies and the documentation of individual cases.
Singapore Medical Journal, Apr 1, 2014
Clinical Pharmacology & Therapeutics, Jul 16, 2015
The use of Moringa oleifera Lam as a healthcare product in Thailand becomes very popular during a... more The use of Moringa oleifera Lam as a healthcare product in Thailand becomes very popular during a past few years. Since medicinal plants constituents may interact with drug metabolizing enzymes, particular cytochromes P450 (CYP) raises the potential of herb-drug interactions. The aim of the present study was to determine the inhibitory effects of M. oleifera extractions on human CYP activities including CYP1A2, CYP2D6, CYP2E1 and CYP3A4 using selective substrate of these enzymes. The results revealed that both ethanolic and aqueous extracts of M. oleifera inhibited CYP1A2, CYP2D6, CYP2E1 and CYP3A4 activities in a dose-dependent manner. Moreover ethanolic extract of M. oleifera exhibited selective inhibition of CYP1A2 with IC50 values of 13.8 + 9.8 μg/mL incubation. The results obtained from the present study suggested the possibility of potential herb and drug interactions of M. oleifera. Therefore, healthcare professionals and patients should be aware when using this medicinal pla...
Drug Metabolism and Pharmacokinetics, 2017
วารสารเภสัชวิทยา (Thai Journal of Pharmacology), 2010
It has been reported that addition of bovine serum albumin (BSA) to in vitro incubations improves... more It has been reported that addition of bovine serum albumin (BSA) to in vitro incubations improves estimation of kinetic parameters, intrinsic clearance (CLint = Vmax/Km), by decreasing the Km for drugs metabolised by cytochrome P450 2C9 (CYP2C9). However, the effect of BSA on other CYP isozymes was unclear. The aims of this study were to characterize effect of BSA on kinetics of specific pathways for CYP2C8, 2C19, and 3A4 whether the addition of BSA could improve the prediction of in vivo clearance by using human hepatic microsomal 6α-hydroxypaclitaxel, 5-hydroxyomeprazole, and omeprazole sulfone formations as markers for CYP2C8, 2C19, and 3A4 pathways, respectively. The metabolite formations were determined by HPLC. In the presence of 2% BSA, rate of CYP2C8-mediated 6α-hydroxypaclitaxel formation was well described by single enzyme Michaelis-Menten kinetic. Mean CLint was significantly increased about 4 fold. Thus the extrapolation of in vitro CLint to in vivo clearance for paclitaxel 6α-hydroxylation was more accurate in the presence of BSA in the incubation. 5-Hydroxyomeprazole formation in the presence of 2% BSA followed two enzyme Michaelis-Menten kinetics. In the presence of 2% BSA, the mean Km1 and Vmax1 for omeprazole 5-hydroxylation were decreased 4 and 2 fold, respectively which resulted in 2-fold increases in the mean CLint1. Moreover, the mean Km and Vmax for CYP3A4-mediated omeprazole sulfoxidation were increased (15-19 fold) in the presence of 2% BSA therefore the mean CLint was not significantly changed. BSA converted omeprazole sulfoxidation from two enzyme to single enzyme Michaelis-Menten kinetic. In conclusion, the addition of 2% BSA is likely to improve in vitro clearance prediction for CYP2C8-mediated paclitaxel 6α-hydroxylation. Moreover, BSA showed minor effect on the CYP2C19-mediated omeprazole 5-hydroxylation whereas had no effect on CYP3A4- mediated omeprazole sulfoxidation. The effect of albumin on individual CYP isoforms was variable; the use of BSA to improve prediction of in vivo intrinsic clearance seems to be possible with only CYP2C8.
ABSTRACT Omeprazole (OMP) is metabolised by CYP2C19 and CYP3A4 to 5-hydroxyomeprazole and omepraz... more ABSTRACT Omeprazole (OMP) is metabolised by CYP2C19 and CYP3A4 to 5-hydroxyomeprazole and omeprazole sulfone, respectively. It has been demonstrated that polyunsaturated fatty acids (PUFAs) are substrates and potent inhibitors of CYP2C19. We hypothesise that the addition of bovine serum albumin (BSA) to incubations of human liver microsomes (HLM) will sequester PUFAs that are released from the membranes of HLM during the course of incubation, therefore providing true estimates of kinetic parameters. This study investigated the effect of BSA on the kinetics of OMP 5-hydroxylation and sulfoxidation by microsomes from 5 human livers. In the absence of BSA, 5-hydroxyomeprazole and omeprazole sulfone formation followed two enzyme Michaelis-Menten kinetics. The mean apparent ( S.D.) kinetic parameters for OMP 5-hydroxylation were: Km1= 8.63 6.83 M, Vmax1 = 97.3 46.7 pmol/min.mg and CLint1 = 13.8 8.39 L/min.mg; Km2 = 156 123 M, Vmax2 = 239 77.4 pmol/min.mg and CLint2 = 2.34 1.47 L/min.mg. The mean apparent ( S.D.) kinetic parameters for OMP sulfoxidation were: Km1= 16.5 11.5 M, Vmax1 = 63.0 60.2 pmol/min.mg and CLint1 = 3.16 1.50 L/min.mg; Km2 = 195 105 M, Vmax2 = 240 116 pmol/min.mg and CLint2 = 1.38 0.54 L/min.mg. In the presence of 2% BSA, 5-hydroxyomeprazole formation also followed two enzyme Michaelis-Menten kinetics whereas omeprazole sulfone formation followed a single enzyme Michaelis-Menten model. In the presence of 2% BSA, the Km1 and Vmax1 for OMP 5-hydroxylation were significantly reduced (2 to 4 fold) consequently CLint1 was increased (2 fold). Hence, the addition of BSA to the reaction incubations had minor effect on the CYP2C19 catalysed high affinity component (Km1 and Vmax1) of OMP 5-hydroxylation, whereas the effect of BSA on OMP sulfoxidation was less clear. Further investigations of the effect of BSA on OMP 5-hydroxylation and sulfoxidation by recombinant CYP2C19 and CYP3A4 are required to clarify the role of BSA on in vitro OMP kinetics.
British Journal of Clinical Pharmacology, Dec 1, 1993
Alfentanil, sufentanil, and fentanyl are synthetic opioids that are metabolized by oxidative N-de... more Alfentanil, sufentanil, and fentanyl are synthetic opioids that are metabolized by oxidative N-dealkylation in the liver. We have previously shown that cytochrome P-450 3A4 (CYP3A4) contributes significantly to human liver microsomal alfentanil oxidation. Since identification of specific drug-metabolizing enzymes allows prediction of the variables affecting drug metabolism, the purpose of the present study was to identify the P-450 enzymes responsible for sufentanil and fentanyl metabolism in human liver microsomes. Microsomal preparations fortified with a reduced nicotinamide-adenine dinucleotide phosphate-generating system were incubated with 0.25 PM 3H-fentanyl or 3H-sufentanil. Rates of N-dealkylated metabolite formation significantly correlated with nifedipine oxidation activity (a marker of CYP3A4 activity) for fentanyl and sufentanil (Y = 0.93 and 0.87, rz = 18, respectively), but not with the oxidation activity for ethoxyresorufin (CYPlA2), S-mephenytoin (CYP2C19), bufuralol (CYP2D6), or chlorzoxazone (CYP2El). Gestodene and troleandomycin (chemical inhibitors of CYP3A4) and antibody to CYP3A4 inhibited N-dealkylation of fentanyl and sufentanil. Chemical inhibitors of CYP2C, 2E1, and 2D6 did not inhibit N-dealkylation of fentanyl and sufentanil. Recombinant CYP3A4 expressed in Esckerickiu coli showed N-dealkylation activity of fentanyl and sufentanil, while expressed CYPlA2,2ClO, and 2El enzymes did not. We conclude that CYP3A4 is responsible for fentanyl and sufentanil N-dealkylation in vitro.
Value in Health, Jun 1, 2023
Long chain unsaturated fatty acids inhibit several cytochrome P450 and UDPglucuronosyltransferase... more Long chain unsaturated fatty acids inhibit several cytochrome P450 and UDPglucuronosyltransferase (UGT) enzymes involved in drug metabolism, including CYP2C8, CYP2C9, UGT1A9, UGT2B4 and UGT2B7. Bovine serum albumin (BSA) enhances these P450 and UGT activities by sequestering fatty acids that are released from membranes, especially with human liver microsomes (HLM) as the enzyme source. Here we report the effects of BSA on CYP1A2-catalyzed phenacetin (PHEN) O-deethylation and lidocaine (LID) N-deethylation using HLM and E.coli-expressed CYP1A2 (rCYP1A2) as the enzyme sources. BSA (2% w/v) reduced (p < 0.05) the K m values of the high affinity components of human liver microsomal PHEN and LID deethylation by approximately 70%, without affecting V max. The K m (or S 50) values for PHEN and LID deethylation by rCYP1A2 were reduced to a similar extent. A fatty acid mixture, comprising 3 µM each of oleic acid and linoleic acid plus 1.5 µM arachidonic acid, doubled the K m value for PHEN O-deethylation by rCYP1A2. Inhibition was reversed by the addition of BSA. K i values for the individual fatty acids ranged from 4.7 µM to 16.7 µM. Single point in vitro-in vivo extrapolation (IV-IVE) based on the human liver microsomal kinetic parameters obtained in the presence, but not absence, of BSA predicted in vivo hepatic clearances of PHEN Odeethylation and LID N-deethylation that were comparable to values reported in humans, although in vivo intrinsic clearances were underpredicted. Prediction of the in vivo clearances of the CYP1A2 substrates observed here represents an improvement on other experimental systems employed for IV-IVE.
วารสารเภสัชวิทยา (Thai Journal of Pharmacology), 2000
Cytochrome P450 2C19 (CYP2C19) is a polymorphically expressed enzyme responsible for the metaboli... more Cytochrome P450 2C19 (CYP2C19) is a polymorphically expressed enzyme responsible for the metabolism of several drugs including barbiturates, carisoprodal, diazepam, mephenytoin, omeprazole, lansoprazole, proguanil and propranolol. Genetic polymorphism of this enzyme shows marked interracial differences with the poor metabolizer (PM) phenotype representing 2-5 % of Caucasian and 13-23 % of Oriental populations. More than 99 % of the PM in Asian populations are defined by two defective alleles, CYP2C19*2 and CYP2C19*3. In the present study, the phenotype and genotype of CYP2C19 was investigated in 55 Northeastern Thai subjects using omeprazole hydroxylation index and polymerase chain reactionrestriction fragment length polymorphism technique, respectively. The distribution of omeprazole hydroxylation index in these subjects was biomodal. Four of these subjects (7.3 %) were identified as PM with omeprazole hydroxylation index higher than 7 (8.31-29.59). Analysis of CYP2C19 genotype in these 55 subjects revealed that the allele frequencies of CYP2C19*1, CYP2C19*2 and CYP2C19*3 were 72.72, 22.72 and 2.72 %, respectively. The frequencies of the defective CYP2CJ9*2 and CYP2CJ 9*3 alleles in the Northeastern Thai PMs were 50 % and 25 %, respectively. It is noteworthy that one of our four PMs appeared to be an outlier whose phenotype could not be explained by the two major defective alleles. Whether this PM representing a novel defective allele need to be further investigated.
Journal of pediatric genetics, Sep 8, 2020
Genetic polymorphisms of thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked ... more Genetic polymorphisms of thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 ( NUDT15 ) genes have been proposed as key determinants of 6-mercaptopurine (6-MP)-induced myelosuppression in pediatric acute lymphoblastic leukemia (ALL). In the present study, genotypes of TPMT and NUDT15 were investigated in 178 Thai pediatric patients with ALL by the TaqMan SNP genotyping assay and DNA sequencing. The frequency of TPMT*3C was 0.034. Among NUDT15 variants, NUDT15*3 is the most common variant with the allele frequency of 0.073, whereas those of NUDT15*2 , NUDT15*5 , and NUDT15*6 variants were 0.022, 0.011, and 0.039. These data suggest that a high proportion of Thai pediatric ALL patients may be at risk of thiopurine-induced myelosuppression.
วารสารเภสัชวิทยา (Thai Journal of Pharmacology), Dec 30, 2015
The addition of bovine serum albumin (BSA) to incubations of HLM or recombinant enzymes enhances ... more The addition of bovine serum albumin (BSA) to incubations of HLM or recombinant enzymes enhances the activities of several human cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes, including CYP1A2, CYP2C8, CYP2C9, UGT1A8, UGT1A9, UGT1A10, UGT2A1, UGT2B4, UGT2B7, and UGT2B15. Available evidence suggests that BSA increases the activities of these drug metabolizing enzymes by sequestering polyunsaturated fatty acids that are released from membranes, especially when using human liver microsomes (HLM) as the enzyme source. Despite the importance of the ‘albumin effect’ for the accurate determination of kinetic parameters, the effects of BSA on CYP enzymes other than CYP1A2, CYP2C8, and CYP2C9 are yet to be investigated. This study aimed to investigate the effects of BSA on kinetic characterization of human liver microsomal omeprazole (OMP) 5¢-hydroxylation and chlorzoxazone (CZX) 6-hydroxlation pathways which are catalyzed by CYP2C19 and CYP2E1, respectively. When BSA (2% w/v) was added to incubations, the K m and V max valuesfor CYP2C19-catalyzed OMP 5¢-hydroxylation were decreased by approximately 75% and 50%, resulting in a 2-fold increase in CL int . By contrast, BSA had a minimal effect on the K m , V max , and CL int values for human liver microsomal CYP2E1-catalyzed CZX 6-hydroxylation. These data confirm that BSA selectively affects human liver microsomal CYP activities.
European Heart Journal, Aug 2, 2013
maker implantation due to total AV block. Main ECG findings: RBBB morphology (55.5%), LBBB (27.7%... more maker implantation due to total AV block. Main ECG findings: RBBB morphology (55.5%), LBBB (27.7%), atrial fibrillation (AF) (33.3%), atrial flutter (AFL) (16.7%), atrial tachycardia (11.1%), non-sustained VT (5.5%) and SVT in 12 (67%). ECHO showed generalized and diffuse LVH with septal thickness ≥15 mm and good contractility. Mitral valve insufficiency (50%) and diastolic dysfunction (61.1%). SCD occurred in 4=22% PT. Two PT had SCD at age 37 (f) and 27 (m). Three episodes of aborted SCD were documented in two PT with WPW in association with HC due to AF and AFL with anterograde conduction through the accessory pathway Direct sequencing of PRKAG2 revealed a missense mutation in exon 7 of PRKAG2, A869T (K290I).This mutation has not been previously described Conclusion: SCD had a high incidence in this cohort and the documented mechanism was AF and AFL with anterograde conduction through the accessory pathway. A new mutation in PRKAG2 was found in an initial study of subgroup. P2309 | BEDSIDE Relationship between polymorphism of SCN5A gene and primary cardiac conduction disorders A. Chernova, S.Y.U. Nikulina on behalf of Research center of the cardiogenetics.
British Journal of Clinical Pharmacology, 2021
AimsCarbamazepine (CBZ) is one of the most common causative drugs of severe cutaneous adverse dru... more AimsCarbamazepine (CBZ) is one of the most common causative drugs of severe cutaneous adverse drug reactions (SCARs) including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reactions with eosinophilia and systemic symptoms. Although genetic polymorphisms of the human leucocyte antigens (HLA) are well recognized key elements for the susceptibility to CBZ‐induced SCARs, some evidence suggest that polymorphisms of microsomal epoxide hydrolase 1 (EPHX1) may also contribute to the risk of these SCARs. This study investigated the association between the HLA and EPHX1 polymorphisms on CBZ‐induced SCARs in large sample sizes and well‐defined SCARs patients.MethodsNinety‐one CBZ‐induced SCARs Thai patients and 144 CBZ‐tolerant patients were enrolled in the study. The genotypes of HLA‐A, HLA‐B and EPHX1 were determined.ResultsOnly 2 HLA alleles including HLA‐B*15:02 and HLA‐A*24:07 were statistically significant association with CBZ‐induced SJS/TEN. The highest ris...
Moxifloxacin-HCl, a fluoroquinolone, is a broad spectrum antibacterial agent against respiratory ... more Moxifloxacin-HCl, a fluoroquinolone, is a broad spectrum antibacterial agent against respiratory tract pathogens, including Gram-positive and Gram-negative bacteria, anaerobic bacteria and atypical respiratory tract pathogens. In order to ensure the efficacy and safety of generic moxifloxacin formulations, the bioequivalence study of these products need to be evaluated. Thus the aim of this study was to compare the rate and extent of absorption of a new generic moxifloxacin formulation (Rapiflox®, Atlantic Laboratories Corporation Ltd., Bangkok, Thailand) with that of a Reference formulation (Avelox®, Bayer HealthCare AG, Leverkusen, Germany) when given at a dose of 400 mg. A single dose randomized two treatments, crossover with 2 weeks washout period was performed in twenty health Thai volunteers. The subjects received either 400 mg of the Reference or Test formulation. Blood samples were collected at predose (0 hr) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 34 hr post dose. ...
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Papers by Wichittra Tassaneeyakul