Association of HLA-B*5701 genotypes and abacavir-induced hypersensitivity reaction: a systematic review and meta-analysis.

OBJECTIVES: This study aimed to systematically review and quantitatively synthesize the association between HLA-B*5701 and abacavir-induced hypersensitivity reaction (ABC-HSR). METHODS: We searched for studies that investigated the association between HLA-B genotype and ABC-HSR and provided information about the frequency of carriers of HLA-B genotypes among cases and controls. We then performed a meta-analysis with a random-effects model to pool the data and to investigate the sources of heterogeneity. RESULTS: From 1,026 articles identified, ten studies were included. Five using clinical manifestation as their diagnostic criteria, 409 and 1,883 subjects were included as cases and controls. Overall OR was 23.6 (95% CI = 15.4 - 36.3). Whereas, the another five studies using confirmed immunologic test as their diagnostic criteria, 110 and 1,968 subjects were included as cases and controls, respectively. The association of ABC-HSR was strong in this populations with HLA-B*5701. Overall OR was 1,056.2 (95% CI = 345.0 - 3,233.3). CONCLUSIONS: Using meta-analysis technique, the association between HLA-B*5701 and ABC-HSR is strong in the studies using immunologic confirmation to identify ABC-HSR. These results support the US FDA recommendations for screening HLA-B*5701 allele before initiating abacavir therapy.

Pharmacokinetics of Psilocybin, a Tryptamine Alkaloid in Magic Mushroom (Psilocybe cubensis): A Systematic Review.

Psilocybin, a major indole alkaloid found in magic mushrooms (Psilocybe cubensis), has recently drawn attention as a breakthrough therapy to treat major depressive disorder. This review aimed to summarize and identify knowledge gaps concerning their pharmacokinetic characteristics of psilocybin and its active metabolite, psilocin. Original studies related to pharmacokinetics of psilocybin conducted in vitro, animals, and humans were systematically collected from PubMed, Scopus, and ScienceDirect, from their inceptions to November 2023. Twenty articles were included in this work and assessed for study quality. A comprehensive review of the pharmacokinetics of psilocybin and psilocin in both animals and humans was performed. Psilocybin is considered a prodrug that is dephosphorylated to psilocin by alkaline phosphatase. Following ingestion, the peak psilocin plasma and brain levels were rapidly achieved in a dose-dependent manner. Psilocin is metabolized primarily through both Phase I and Phase II processes with the half-life of 2-3 hours. This review also identified lack of some pharmacokinetic related information and limitations of available research that may help direct future investigations to better understand the pharmacokinetics and improve study design including dose selection and dosage optimization.

Paraquat exposure and Parkinson's disease: A systematic review and meta-analysis.

To reconcile and unify available results regarding paraquat exposure and Parkinson's disease (PD), we conducted a systematic review and meta-analysis to provide a quantitative estimate of the risk of PD associated with paraquat exposure. Six scientific databases including PubMed, Cochrane libraries, EMBASE, Scopus, ISI Web of Knowledge, and TOXLINE were systematically searched. The overall odds ratios (ORs) with corresponding 95% CIs were calculated using a random-effects model. Of 7,309 articles identified, 13 case control studies with 3,231 patients and 4,901 controls were included into our analysis. Whereas, one prospective cohort studies was included into our systematic review. A subsequent meta-analysis showed an association between PD and paraquat exposure (odds ratio = 1.64 (95% CI: 1.27-2.13; I2 = 24.8%). There is a statistically significant association between paraquat exposure and PD. Thus, future studies regarding paraquat and Parkinson's disease are warranted.

Hepatic sequestration of chlordecone and hexafluoroacetone evaluated by pharmacokinetic modeling.

Chlordecone (CD) and mirex (M) differ by a single carbonyl group in CD in place of two chlorines in M. Although both compounds are lipophilic, their tissue distributions differ markedly: CD concentrations are highest in liver; M concentrations are highest in fat. We used tissue time course data in rats from our laboratory for CD and M and literature data from monkeys to develop PBPK models to study differences in liver and fat partitioning. The PK model for M had partitioning in tissue without specific hepatic binding. The CD model had partitioning similar to M, and also included liver binding: the maximal binding (B(max)) and binding affinity constant (Kd) required to describe the rat data were 370 nmol/g liver and 100 nM, respectively. To see if other ketones with electron withdrawing constituents at the alpha carbon were also preferentially distributed to liver, we developed a PBPK description for tissue distribution of hexafluoroacetone (HFA). Compared to acetone, HFA is known to be preferentially sequestered in liver and more slowly excreted unchanged from the body. Acetone is more equally distributed to tissues. HFA distribution was evaluated with a PBPK model that included hepatic binding. B(max) and Kd were 1.58 micromol/g liver and 301 microM. In summary, liver sequestration of CD and HFA most likely represents relatively high-affinity but reversible binding of activated carbonyls in these compounds (activated by the presence of electron withdrawing substituents on the alpha-carbons) with glutathione and glutathione transferases, that are present at much higher concentrations in liver than in other tissues. Strong, but reversible hemithioketal formation with active sulfhydryls may also be associated with the toxic responses to CD and HFA.

A physiologically-based pharmacokinetic model of methotrexate incorporating hepatic excretion via multidrug-resistance-associated protein 2 (Mrp2) in mice, rats, dogs, and humans.

An updated physiologically-based pharmacokinetic (PBPK) model of methotrexate (MTX) was built based on an earlier model developed by Bischoff et al. (1971). MTX has been known to be a substrate of multidrug-resistance-associated protein 2 (Mrp2). A three-dimensional quantitative structure-activity relationship model (3D-QSAR) of Mrp2 was developed by Hirono et al. (2005). In our updated PBPK model of MTX, using the computational chemistry-derived binding affinity (Km), a Mrp2-mediated biliary excretion process was incorporated as the MTX excretory pathway. Our model simulation results are consistent with numerous datasets obtained from mice, rats, dogs, and humans, at a variety of dose levels. Comparisons were made between our updated PBPK model and the earlier one from Bischoff et al. using a PBPK Index approach. Our new PBPK model was further verified against additional pharmacokinetic datasets from rats under special experimental conditions (cannulated bile duct) and Eisai hyperbirilubinemic rats.

A pharmacokinetic model of drug-drug interaction between clopidogrel and omeprazole at CYP2C19 in humans.

BACKGROUND: Clopidogrel is a thienopryridine antiplatelet agent commonly used in the management of cardiovascular diseases. Clopidogrel is metabolized by hepatic CYP2C19 and CYP2B6, therefore, co-administration of clopidogrel and CYP2C19 inhibitors can alter pharmacokinetics of clopidogrel. Omeprazole is a proton pump inhibitor used for decreasing gastric acid production. Omeprazole is known to be a potent inhibitor of CYP2C19. Thus when the drugs are simultaneously administered, clopidogrel plasma concentration levels can be increased. However, plasma levels of the active metabolite of clopidogrel can be significantly decreased, thereby, its antiplatelet activity is reduced. OBJECTIVES: We aimed to develop a mathematical model describing a drug-drug interaction between clopidogrel and omeprazole in humans. METHODS: Searching for pharmacokinetic interaction studies between clopidogrel and omeprazole in humans was performed in PubMed. Six studies were selected into our modeling purposes to develop 3 mathematical models (i.e. 4 studies for clopidogrel alone, 1 study for omeprazole alone and 1 study for clopidogrel-omeprazole interaction). Subsequently, concentration-time course data from the selected studies were extracted. Computer codes and simulations were performed using the Advanced Continuous Simulating Language Extreme (ACSLX) program. RESULTS: We successfully developed 3 mathematical models which are able to describe all of the datasets. CONCLUSIONS: Our clopidogrel-omeprazole pharmacokinetic interaction model with a description of competitive inhibition at CYP2C19 could successfully describe concentration-time courses from the selected datasets. Our interaction model may be useful in predicting plasma levels of clopidogrel and its active metabolite.

Development of a physiologically based pharmacokinetic model of paraquat.

Paraquat (N, N'-dimethyl-4,4'-bipyridium dichloride) is a potent and widely used herbicide in agricultural countries, including Thailand. The presence of this chemical in the body can lead to toxic effects in the liver, kidney, and lung. Pulmonary toxicity has been identified as the main cause of acute toxicity in animals and humans. Chronic exposure to paraquat is associated with Parkinson's disease in humans. Paraquat is transported into the lungs by neutral amino acid transporter. Therefore, a physiologically based pharmacokinetic (PBPK) model of paraquat was developed with a description of the protein transporter mechanism. To develop a PBPK model of paraquat, a pharmacokinetic study of paraquat in rats was selected from the ThaiLIS and Pubmed database. The selected study contained tissue-specific concentration-time course information such as paraquat concentration levels in liver, kidney and lung. Physiologic parameters were acquired from the literature or determined using a Markov-Chain Monte Carlo (MCMC) technique. The developed PBPK model consisted of 5 organ compartments (i.e. kidney, liver, slowly perfused organs, richly perfuse organs and lung), featuring an incorporation of neutral amino acid transporter in the lung. Our model simulations could explain the data from the literature and adequately describe pharmacokinetics of paraquat in the rats. This developed PBPK model may be able help in understanding of paraquat-induced Parkinson's disease as well as in risk assessment of paraquat.

An updated physiologically based pharmacokinetic model for hexachlorobenzene: incorporation of pathophysiological states following partial hepatectomy and hexachlorobenzene treatment.

Physiologically based pharmacokinetic (PBPK) modeling is generally used for describing xenobiotic disposition in animals and humans with normal physiological conditions. We describe here an updated PBPK model for hexachlorobenzene (HCB) in male F344 rats with the incorporation of pathophysiological conditions. Two more features contribute to the distinctness of this model from the earlier published versions. This model took erythrocyte binding into account, and a particular elimination process of HCB, the plasma-to-gastrointestinal (GI) lumen passive diffusion (i.e., exsorption), was incorporated. Our PBPK model was developed using data mined from multiple pharmacokinetic studies in the literature, and then modified to simulate HCB disposition under the conditions of our integrated pharmacokinetics/liver foci bioassay. This model included plasma, erythrocytes, liver, fat, rapidly and slowly perfused compartments, and GI lumen. To account for the distinct characteristics of HCB absorption, the GI lumen was split into an upper and a lower part. HCB was eliminated through liver metabolism and the exsorption process. The pathophysiological changes after partial hepatectomy, such as alterations in the liver and body weights and fat volume, were incorporated in our model. With adjustment of the transluminal diffusion-related parameters, the model adequately described the data from the literature and our bioassay. Our PBPK model simulation suggests that HCB absorption and exsorption processes depend on exposure conditions; different exposure conditions dictate different absorption and exsorption rates. This model forms a foundation for our further exploration of the quantitative relationship between HCB exposure and development of preneoplastic liver foci.

Additive Synergism between Asbestos and Smoking in Lung Cancer Risk: A Systematic Review and Meta-Analysis.

Smoking and asbestos exposure are important risks for lung cancer. Several epidemiological studies have linked asbestos exposure and smoking to lung cancer. To reconcile and unify these results, we conducted a systematic review and meta-analysis to provide a quantitative estimate of the increased risk of lung cancer associated with asbestos exposure and cigarette smoking and to classify their interaction. Five electronic databases were searched from inception to May, 2015 for observational studies on lung cancer. All case-control (N = 10) and cohort (N = 7) studies were included in the analysis. We calculated pooled odds ratios (ORs), relative risks (RRs) and 95% confidence intervals (CIs) using a random-effects model for the association of asbestos exposure and smoking with lung cancer. Lung cancer patients who were not exposed to asbestos and non-smoking (A-S-) were compared with; (i) asbestos-exposed and non-smoking (A+S-), (ii) non-exposure to asbestos and smoking (A-S+), and (iii) asbestos-exposed and smoking (A+S+). Our meta-analysis showed a significant difference in risk of developing lung cancer among asbestos exposed and/or smoking workers compared to controls (A-S-), odds ratios for the disease (95% CI) were (i) 1.70 (A+S-, 1.31-2.21), (ii) 5.65; (A-S+, 3.38-9.42), (iii) 8.70 (A+S+, 5.8-13.10). The additive interaction index of synergy was 1.44 (95% CI = 1.26-1.77) and the multiplicative index = 0.91 (95% CI = 0.63-1.30). Corresponding values for cohort studies were 1.11 (95% CI = 1.00-1.28) and 0.51 (95% CI = 0.31-0.85). Our results point to an additive synergism for lung cancer with co-exposure of asbestos and cigarette smoking. Assessments of industrial health risks should take smoking and other airborne health risks when setting occupational asbestos exposure limits.

Bioequivalence study of enalapril tablets in healthy Thai male volunteers.

The bioequivalence study of 5-mg enalapril tablets, Enaril (Biolab, Thailand) compared to Renitec (Merck Sharp & Dohme, USA) was conducted in 14 healthy Thai male volunteers following a single dose, two-period, crossover design. Each subject received 4 tablets of 5-mg enalapril tablets of both formulations with a 1-week washout period. Plasma samples collected over a 24-hour period after administration were analyzed by LC/MS/MS. Pharmacokinetic parameters were determined by using non-compartmental analysis. Regarding bioequivalence testing, the 90 per cent confidence intervals of Cmax and AUC(0-infinity) ratios (Enaril/Renitec) of enalapril were 86.3-126.1 per cent and 93.0-118.5 per cent and those of enalaprilat were 86.4-124.1 per cent and 90.3-116.8 per cent. Based on the European bioequivalence guideline, the 90 per cent confidence interval of Cmax and AUC(0-infinity) ratios of both parent and metabolite forms were within acceptable ranges of 70-143 per cent and 80-125 per cent, respectively. It was concluded that Enaril 5 mg tablet was bioequivalent to Renitec 5 mg tablet.

Relative bioavailability study of 20-mg enalapril tablets in healthy male volunteers.

The pharmacokinetic and relative bioavailability studies of 20-mg enalapril tablets, the test product manufactured by Biolab, Thailand compared to the reference product (Merck Sharp & Dohme, USA) was conducted in 14 healthy Thai male volunteers following a single dose, two-period, crossover design. Each subject received 20-mg enalapril tablets of both formulations with a 1-week washout period. Plasma samples collected over a 24-h period after administration were analyzed by LC/MS/MS. Pharmacokinetic parameters were determined by using non-compartmental analysis. Regarding bioequivalence testing, the 90 per cent confidence intervals of Cmax and AUC(0-infinity) ratios (test/reference) of enalapril were 101.8-134.9 per cent and 105.9-121.4 per cent and those of enalaprilat were 104.2-122.3 per cent and 104.5-118.1 per cent. Based on the European bioequivalence guideline, the 90 per cent confidence intervals of Cmax and AUC(0-infinity) ratios of both parent and metabolite forms were within the acceptable ranges of 70-143 per cent and 80-125 per cent, respectively. It was concluded that the test formulation was bioequivalent to the reference formulation and both formulations can be used interchangeably in clinical practice.

Bioequivalence study of ondansetron tablet in healthy Thai male volunteers.

OBJECTIVES: To assess the average bioequivalence of two formulations of 8-mg ondansetron tablets--test product (Unison Laboratories, Thailand) and reference product (Glaxo Wellcome, USA)--in 14 healthy Thai male volunteers. MATERIAL AND METHOD: In a randomized, single dose, fasting, two-period, crossover study design with a 1-week washout period, each subject received an 8-mg ondansetron tablet. Serum samples were collected over a 24-hour period after administration. Subsequently serum concentrations of ondansetron were analyzed by using a validated HPLC-UV method. Pharmacokinetic parameters were determined by using non-compartmental analysis. RESULTS: No significant difference was observed in any of the pharmacokinetic parameters analyzed. The time to reach the maximal concentration (Tmax, hour), the peak concentration (Cmax, ng/ ml) and the area under the concentration-time curve (AUC(0-infinity), ng x h/ml) of ondansetron for reference and test preparations were 2.6 + 1.8 vs 2.2 + 0.6, 49.5 +/- 18.9 vs 48.5 +/- 13.7 and 352.2 +/- 184.7 vs 323.8 +/- 154.5, respectively. The 90 per cent confidence intervals for Test/Reference ratio of Cmax and AUC(0-infinity) were found within the bioequivalence range of 80-125 per cent (90.3-110.0% and 88.4-99.6%, respectively). CONCLUSION: The bioequivalence of these two ondansetron preparations was demonstrated.

A possible role of multidrug resistance-associated protein 2 (Mrp2) in hepatic excretion of PCB126, an environmental contaminant: PBPK/PD modeling.

3,3',4,4',5'-Pentachlorobiphenyl (PCB126) is a carcinogenic environmental pollutant and its toxicity is mediated through binding with aryl hydrocarbon receptor (AhR). Earlier, we found that PCB126 treated F344 rats had 110-400 times higher PCB126 concentration in the liver than in the fat. Protein binding was suspected to be a major factor for the high liver concentration of PCB126 despite its high lipophilicity. In this research, we conducted a combined pharmacokinetic/pharmacodynamic study in male F344 rats. In addition to blood and tissue pharmacokinetics, we use the development of hepatic preneoplastic foci (glutathione-S-transferase placental form [GSTP]) as a pharmacodynamic endpoint. Experimental data were utilized for building a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model. PBPK/PD modeling was consistent with the experimental PK and PD data. Salient features of this model include: (1) bindings between PCB126 and hepatic proteins, particularly the multidrug resistance-associated protein (Mrp2), a protein transporter; (2) Mrp2-mediated excretion; and (3) a relationship between area under the curve of PCB126 in the livers and % volume of GSTP foci. Mrp2 involvement in PCB126 pharmacokinetics is supported by computational chemistry calculation using a three-dimensional quantitative structure-activity relationship model of Mrp2 developed by S. Hirono et al. (2005, Pharm. Res. 22, 260-269). This work, for the first time, provided a plausible role of a versatile hepatic transporter for drugs, Mrp2, in the disposition of an important environmental pollutant, PCB126.

Quantitative analysis of liver GST-P foci promoted by a chemical mixture of hexachlorobenzene and PCB 126: implication of size-dependent cellular growth kinetics.

The objectives of this study were twofold: (1) evaluating the carcinogenic potential of the mixture of two persistent environmental pollutants, hexachlorobenzene (HCB) and 3,3',4,4',5-pentachlorobiphenyl (PCB 126), in an initiation-promotion bioassay involving the development of pi glutathione S-transferase (GST-P) liver foci, and (2) analyzing the GST-P foci data using a biologically-based computer model (i.e., clonal growth model) with an emphasis on the effect of focal size on the growth kinetics of initiated cells. The 8-week bioassay involved a series of treatments of initiator, two-thirds partial hepatectomy, and daily oral gavage of the mixture of two doses in male F344 rats. The mixture treatment significantly increased liver GST-P foci development, indicating carcinogenic potential of this mixture. Our clonal growth model was developed to simulate the appearance and development of initiated GST-P cells in the liver over time. In the model, the initiated cells were partitioned into two subpopulations with the same division rate but different death rates. Each subpopulation was further categorized into single cells, mini- (2-11 cells), medium- (12-399 cells), and large-foci (>399 cells) with different growth kinetics. Our modeling suggested that the growth of GST-P foci is size-dependent; in general, the larger the foci, the higher the rate constants of division and death. In addition, the modeling implied that the two doses promoted foci development in different manners even though the experimental foci data appeared to be similar between the two doses. This study further illustrated how clonal growth modeling may facilitate our understanding in chemical carcinogenic process.

Average bioequivalence of generic clarithromycin tablets in healthy Thai male volunteers.

The objective of this study was to assess bioequivalence of 500-mg clarithromycin tablets in 24 healthy volunteers. In a randomized, single dose, fasting state, two-period, crossover study design with a 1-week washout period, each subject received a 500-mg clarithromycin tablet. Plasma samples were collected over a 24-h period after administration and were analyzed by using a validated method using high performance liquid chromatography (HPLC) with electrochemical detection. The time to reach the maximal concentration (t(max),h), the peak concentration (C(max),ng/ml) and the area under the curve (AUC(0- infinity),ng h/ml) of the Reference and Test formulations were 2.1+/-0.7 vs 2.1+/-0.7, 2474+/-702 vs 2559+/-744 and 15803+/-6120 vs 17683+/-6650, respectively. Relative bioavailability was 1.12. The 90% confidence interval (90% CI) of C(max) and AUC(0- infinity) were 95.6-110.8% and 3.5-122.0%, respectively. Bioequivalence between the test and reference preparation can be concluded.

Bioequivalence study of two formulations of simvastatin tablets in healthy Thai volunteers.

The bioequivalence of two formulations of 10 mg tablets of simvastatin (CAS 79902-63-9), Vascor as test and a commercially available preparation as reference, in 18 healthy Thai male volunteers was assessed. In a randomized, single dose, two-period, crossover study design with a 1-week wash-out period, each subject received 4 tablets of 10-mg simvastatin tablets. Plasma samples were collected over a 24-h period after administration. Subsequently, plasma concentrations of simvastatin and its hydroxy acid metabolite were analyzed by using LC/ MS/MS. Pharmacokinetic parameters were determined by using non-compartmental analysis. The results showed that 90% confidence intervals of the peak concentration (Cmax) and the area under the concentration-time curve (AUC) of simvastatin and its hydroxy acid metabolite of reference and test were within 80 %-125%. Consequently the bioequivalence of these two preparations can be concluded.