Search

Background While it is essential to understand how long is sufficient for return-to-work when designing paid sick-leave systems, little attempt has been done to collect cause-specific information on when and how many of sickness absentees returned to work, became unemployed, or passed away. Methods We studied the first sick-leave episode of ≥30 consecutive days in those ≤55 years of age during 2012-2013 among 11 Japanese private companies (n = 1209), which were followed until 2017. Overall and disease-specific cumulative incidences of return-to-work, resignations, and deaths were estimated using competing risk analysis. Results During the 3.5-year period (follow-up rate: 99.9%), 1014 returned to work, 167 became unemployed, and 27 died. Overall, return-to-work occurred within 1 year in 74.9% of all absentees and in 89.3% of those who successfully returned to work. Resignation occurred within 1 year in 8.7% of all absentees and in 62.9% of all subjects who resigned. According to ICD-10 chapters, the cumulative incidence of return-to-work ranged from 82.1% for mental disorders (F00-F99) to 95.3% for circulatory diseases (I00-I99). The cumulative incidence of return-to-work due to mental disorders ranged from 66.7% in schizophrenia (F20) to 95.8% in bipolar affective disorders (F31). Death was rarely observed except for cases of neoplasms (C00-D48), of which the cumulative incidence of death reached 14.2% by 1.5 years. Conclusions Return-to-work and resignations occurred commonly within 1 year of sick leave among long-term sickness absentees in the Japanese private companies. Our findings may assist occupational physicians and employers in developing effective social protection schemes.

Background While much effort has focused on quantifying disease burden in occupational health, no study has simultaneously assessed disease burden in terms of mortality and morbidity. We aimed to propose a new comprehensive method of quantifying the disease burden in the workplace. Methods The data were obtained from the Japan Epidemiology Collaboration on Occupational Health (J-ECOH) Study, a large-scale prospective study of approximately 80,000 workers. We defined disease burden in the workplace as the number of working years lost among the working population during a 6-year period (April 2012 to March 2018). We calculated the disease burden according to consequences of health problems (ie, mortality, sickness absence [SA], and ill-health retirement) and disease category. We also calculated the age-group- (20-39 and 40-59 years old) and sex-specific disease burden. Results The largest contributors to disease burden in the workplace were mental and behavioural disorders (47.0 person-years lost per 10,000 person-years of working years; ie, per myriad [proportion]), followed by neoplasms (10.8 per myriad) and diseases of the circulatory system (7.1 per myriad). While mental and behavioural disorders made a greater contribution to SA and ill-health retirement compared to mortality, the latter two disorders were the largest contributors to the disease burden in the workplace due to mortality. The number of working years lost was greater among younger versus older female participants, whereas the opposite trend was observed in males. Conclusions Our approach is in contrast to those in previous studies that focused exclusively on mortality or morbidity.

Increased visit-to-visit variability (VVV) of blood pressure, which is calculated based on several readings, has been suggested to be a significant predictor of cardiovascular events and mortality, independent of mean blood pressure. This study examined associations between the VVV of systolic blood pressure (SBP) measured annually and cardiovascular disease (CVD) events among 72,617 Japanese subjects. Data were obtained from the Japan Epidemiology Collaboration on Occupational Health Study, which is an ongoing epidemiological survey of workers in Japan. VVV was calculated as the coefficient of variation of SBP readings from 2008 to 2011; information on fatal and nonfatal CVD events was collected from registries of specific outcomes between April 2012 and March 2019. A Cox proportional hazards model was applied to investigate associations after adjusting for mean SBP between 2008 and 2011 and covariates. During the 7-year follow-up period, there were 63 CVD fatalities and 314 CVD events (combining fatal and nonfatal events). The results showed that a one-standard deviation increase in VVV was associated with a significant increase in the risk of CVD mortality (hazard ratio [HR] = 1.42; 95% confidence interval [CI] = 1.32–1.54); those in the highest tertile had a 3.20 times (95% CI = 1.26–8.17) higher risk of CVD mortality than those in the lowest tertile. We found less pronounced associations regarding CVD events (HR = 1.08, 95% CI = 1.02–1.15). In conclusion, VVV was significantly associated with CVD mortality in our Japanese working population.

p-Toluic acid, a metabolite of organic solvent xylene, has a high reported no‐observed‐effect level (NOEL, 1000 mg/kg) in rats, possibly because of direct glycine conjugation to methylhippuric acid...

OBJECTIVE Prediabetes has been suggested to increase risk for death; however, the definitions of prediabetes that can predict death remain elusive. We prospectively investigated the association of multiple definitions of prediabetes with the risk of death from all causes, cardiovascular disease (CVD), and cancer in Japanese workers. RESEARCH DESIGN AND METHODS The study included 62,785 workers who underwent a health checkup in 2010 or 2011 and were followed up for death from 2012 to March 2019. Prediabetes was defined according to fasting plasma glucose (FPG) or glycated hemoglobin (HbA1c) values or a combination of both using the American Diabetes Association (ADA) or World Health Organization (WHO)/International Expert Committee (IEC) criteria. The Cox proportional hazards regression model was used to investigate the associations. RESULTS Over a 7-year follow-up, 229 deaths were documented. Compared with normoglycemia, prediabetes defined according to ADA criteria was associated with a higher risk of all-cause mortality (hazard ratio [HR] 1.53; 95% CI 1.12–2.09) and death due to cancer (HR 2.37; 95% CI 1.45–3.89) but not with death due to CVD. The results were materially unchanged when prediabetes was defined according to ADA FPG, ADA HbA1c, WHO FPG, or combined WHO/IEC criteria. Diabetes was associated with the risk of all-cause, CVD, and cancer deaths. CONCLUSIONS In a cohort of Japanese workers, FPG- and HbA1c-defined prediabetes, according to ADA or WHO/IEC, were associated with a significantly increased risk of death from all causes and cancer but not CVD.

Recently developed computational models can estimate plasma, hepatic, and renal concentrations of industrial chemicals in rats. Typically, the input parameter values (i.e., the absorption rate constant, volume of systemic circulation, and hepatic intrinsic clearance) for simplified physiologically based pharmacokinetic (PBPK) model systems are calculated to give the best fit to measured or reported in vivo blood substance concentration values in animals. The purpose of the present study was to estimate in silico these three input pharmacokinetic parameters using a machine learning algorithm applied to a broad range of chemical properties obtained from several cheminformatics software tools. These in silico estimated parameters were then incorporated into PBPK models for predicting internal exposures in rats. Following this approach, simplified PBPK models were set up for 246 drugs, food components, and industrial chemicals with a broad range of chemical structures. We had previously generated PBPK models for 158 of these substances, whereas 88 for which concentration series data were available in the literature were newly modeled. The values for the absorption rate constant, volume of systemic circulation, and hepatic intrinsic clearance could be generated in silico by equations containing between 14 and 26 physicochemical properties. After virtual oral dosing, the output concentration values of the 246 compounds in plasma, liver, and kidney from rat PBPK models using traditionally determined and in silico estimated input parameters were well correlated (r ≥ 0.83). In summary, by using PBPK models consisting of chemical receptor (gut), metabolizing (liver), excreting (kidney), and central (main) compartments with in silico-derived input parameters, the forward dosimetry of new chemicals could provide the plasma/tissue concentrations of drugs and chemicals after oral dosing, thereby facilitating estimates of hematotoxic, hepatotoxic, or nephrotoxic potential as a part of risk assessment.

Bromobenzene is an industrial solvent that elicits toxicity predominantly in the liver. In this study, the hepatic concentrations of bromobenzene and its related compounds 1,2-dibromobenzene and 1,4-dibromobenzene in humanized-liver mice were predicted after single oral administrations by simplified physiologically based pharmacokinetic (PBPK) models that had been set up on experimental plasma concentrations after single oral doses of 100 mg/kg to rats and 100-250 mg/kg to control mice and humanized-liver mice. The output values by simplified PBPK models were consistent with measured blood substrate concentrations in rats, control mice, and humanized-liver mice with suitable input parameter values derived from in silico prediction and the literature or estimated by fitting the measured plasma substrate concentrations. The predicted time-dependent hepatic concentrations after virtual administrations in humanized-liver mice were partly confirmed with single measured hepatic concentrations of bromobenzene and 1,4-dibromobenzene 2 h after oral doses of 150-250 mg/kg to humanized-liver mice. Moreover, leaked human albumin mRNA, a marker of the extent of human hepatic injuries, in humanized-liver mouse plasma was detected after oral administration of bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene. These results suggest that dosimetry approaches for determining tissue and/or blood exposures of hepatic toxicants bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene in humanized-liver mice were useful after virtual oral doses using simplified PBPK models. Using simplified PBPK models and plasma data from humanized-liver mice has potential to predict and evaluate the hepatic toxicity of bromobenzenes and related compounds in humanized-liver mice and in humans.

Background The anticoagulant edoxaban is used clinically at doses of 30–60 mg/day; however, we experienced a patient who had taken an overdose of edoxaban of 750 mg. We investigated the pharmacokinetics of edoxaban in this patient by using liquid chromatography–tandem spectrometry to estimate the follow-up period in emergency clinical practice with this medicine. Case presentation The patient was a 57-year-old woman (body weight, 69 kg) who had taken a single oral dose of 750 mg of edoxaban in a suicide attempt. She was emergently admitted to Kyoto Medical Center. The patient’s edoxaban plasma concentrations during ambulance transport (8 h after oral administration) were ~ 4900 ng/ml, and the concentration gradually decreased to ~ 10 ng/mL and to detectable but unmeasurable levels of ~ 1.0 ng/mL at 60 h and 100 h, respectively. The linear range of the relationship between the dose and plasma concentration was assumed to have been exceeded during the first 8 h; however, the measured elimination rate of edoxaban was similar to that visualized curves predicted by a simplified physiologically based pharmacokinetic model previously established. Conclusion Simplified physiologically based pharmacokinetic models for creating visualized curves have proven to be useful not only during drug discovery or chemical risk assessment but also in cases of medical poisoning. We used a physiologically based pharmacokinetic model previously established for edoxaban to predict the pharmacokinetics in the current case. It is hoped that the results of this study, which encompass drug monitoring data in the patient and visualized pharmacokinetic prediction, will serve as an index when setting the treatment and follow-up period in cases of drug overdose for medicines such as edoxaban in emergency clinical practice.

Oral antidyslipidaemic drug pemafibrate is cleared from human plasma via hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 and oxidation by cytochromes P450 (P450) 2C8, 2C9 and 3A4. The pharmacokinetic profiles of pemafibrate with virtual administrations of P450 inhibitors and/or disease interactions were generated using a physiologically based pharmacokinetic (PBPK) model previously established for co-administration of pemafibrate with OATP1B1 inhibitors. This PBPK model was validated in the current study using reported maximum pemafibrate plasma concentrations and areas under the curve from interaction studies in healthy subjects co-administered with clopidogrel (P450 2C8 inhibitor), fluconazole (P450 2C9/3A4 inhibitor) or clarithromycin (P450 3A4 inhibitor). Virtual co-administrations of pemafibrate with clopidogrel, fluconazole or clarithromycin increased the predicted plasma exposures of pemafibrate 1.4-1.7-fold, 1.2-1.4-fold and 2.9-11-fold, respectively, in subjects with or without moderate or severe renal impairment or Child-Pugh A or B liver cirrhosis. Some of the exposure-enhancing effects of clarithromycin may originate from its inhibitory potential toward OATP1B1, because the estimated effects of itraconazole (a P450 3A4 inhibitor) were only minor. Simulations using the current PBPK model in groups of virtual subjects with or without renal or hepatic impairment revealed modified pharmacokinetic profiles for pemafibrate following co-administration of typical P450 inhibitors.

Recently developed high-throughput in vitro assays in combination with computational models could provide alternatives to animal testing. The purpose of the present study was to model the plasma, hepatic, and renal pharmacokinetics of approximately 150 structurally varied types of drugs, food components, and industrial chemicals after virtual external oral dosing in rats and to determine the relationship between the simulated internal concentrations in tissue/plasma and their lowest-observed-effect levels. The model parameters were based on rat plasma data from the literature and empirically determined pharmacokinetics measured after oral administrations to rats carried out to evaluate hepatotoxic or nephrotic potentials. To ensure that the analyzed substances exhibited a broad diversity of chemical structures, their structure-based location in the chemical space underwent projection onto a two-dimensional plane, as reported previously, using generative topographic mapping. A high-throughput in silico one-compartment model and a physiologically based pharmacokinetic (PBPK) model consisting of chemical receptor (gut), metabolizing (liver), central (main), and excreting (kidney) compartments were developed in parallel. For 159 disparate chemicals, the maximum plasma concentrations and the areas under the concentration-time curves obtained by one-compartment models and modified simple PBPK models were closely correlated. However, there were differences between the PBPK modeled and empirically obtained hepatic/renal concentrations and plasma maximal concentrations/areas under the concentration-time curves of the 159 chemicals. For a few compounds, the lowest-observed-effect levels were available for hepatotoxicity and nephrotoxicity in the Hazard Evaluation Support System Integrated Platform in Japan. The areas under the renal or hepatic concentration-time curves estimated using PBPK modeling were inversely associated with these lowest-observed-effect levels. Using PBPK forward dosimetry could provide the plasma/tissue concentrations of drugs and chemicals after oral dosing, thereby facilitating estimates of nephrotoxic or hepatotoxic potential as a part of the risk assessment.

Objective In contrast to the association between excess weight and sickness absence (SA), the association in relation to underweight has been under‐researched. This study aimed to examine the effects of BMI at both extremes of its distribution on SA. Methods Data came from the Japan Epidemiology Collaboration on Occupational Health study of 77,760 workers aged 20 to 59 years (66,166 males, 11,594 females). Information was collected on medically certified long‐term SA (LTSA) (i.e., SA lasting ≥ 30 consecutive days) from April 2012 to March 2017. A sex‐specific Cox proportional hazards model was used to investigate the associations. Results Among males, both obesity (hazard ratio [HR] = 1.81, 95% CI: 1.50‐2.17) and underweight (HR = 1.56, 95% CI: 1.23‐1.96) were significantly associated with LTSA compared with normal weight. This U‐shaped association between BMI categories and LTSA was observed both for mental and physical disorders. Among females, an elevated risk was observed among those with overweight (HR = 1.54, 95% CI: 1.16‐2.05). Conclusions In a cohort of the Japanese working‐age population, both obesity and underweight were associated with a greater risk of LTSA in males. Future research should not overlook the excess risk of LTSA associated with underweight.

Graphical abstract, Highlights • Permeability values of 90 industry chemicals were measured by a Caco-2 system. • A multivariate prediction equation for permeability of chemicals was proposed. • Chemical permeability coefficients were inversely associated with hepatic NOELs., Apparent permeability coefficients (Papp) across a human intestinal epithelial Caco-2 cell monolayer were measured for a range of industrial/drug chemicals. A predictive equation for determining in vitro Papp values of fifty-six substances was set up using multivariate regression analysis based on in silico-estimated physicochemical properties (molecular weights and water distribution coefficients for apical and basal pH environments) (r = 0.77, p

Polymorphic human and cynomolgus macaque flavin-containing monooxygenases (FMO) 3 are important oxygenation enzymes for nitrogen-containing drugs. Inter-animal variability of FMO3-dependent drug oxygenations in vivo is suspected in cynomolgus macaques because such variability is evident in humans. Therefore, this follow-up study was performed to investigate the pharmacokinetics of orally administered deuterium-labeled trimethylamine in three cynomolgus macaques genotyped for FMO3. Trimethylamine-d9 was rapidly absorbed and attained plasma concentrations greater than the background levels of non-labeled trimethylamine. Trimethylamine-d9 was then converted to trimethylamine-d9 N-oxide. The half-lives, maximum plasma concentrations, and areas under the curve for trimethylamine-d9 and its N-oxygenated metabolite and the total clearance for orally administered trimethylamine-d9 were not different among the heterozygote for Q506K FMO3, the heterozygote for V325I FMO3, and the heterozygote for both S99N and F510S FMO3. Trimethylamine N-oxygenation activities mediated by liver microsomes prepared from the same three animals were not substantially different. However, recombinant proteins of the corresponding cynomolgus FMO3 variants showed apparent reduced trimethylamine N-oxygenation activities compared with the wild-type proteins. This study suggests only limited polymorphic effects on the in vivo catalytic function of cynomolgus FMO3. These findings yield important insights in terms of both quantitative and qualitative variations of polymorphic FMO3 in cynomolgus liver.

Background A chemopreventive effect of low-dose aspirin against colorectal tumors was previously found in participants of two Japanese multicenter, double-blind, randomized, placebo-controlled clinical trials investigating the effects of daily aspirin (100 mg/day) for 0.7–2 years on tumor recurrence in colorectal cancer patients whose tumors were excised endoscopically. Methods In the current study, chemopreventive data from single-center subsets having daily aspirin (100 mg/day) were reanalyzed with respect to variations in polymorphic cytochrome P450 2A6 (CYP2A6). From the J-CAPP study, 56 of 311 participants (47 men, 9 women; excluding patients with familial adenomatous polyposis) were genotyped for CYP2A6*1, *4 (whole-gene deletion), *7 (amino acid substitution), and *9 (upstream mutation), and from the J-FAPP IV study, 81 of 102 participants (43 men, 38 women; including patients with familial adenomatous polyposis) were also genotyped. Results The chemopreventive effects of daily aspirin were found to be inversely dependent on the predicted enzyme activity of the CYP2A6 phenotype [based on normal genotypes (CYP2A6*1/*1,*7,*9) and impaired genotypes (CYP2A6*4,*7,*9/*4,*7,*9 and CYP2A6*1/*4)] among a nonsmoker Japanese cohort without familial adenomatous polyposis. Conclusions The CYP2A6 wild-type allele could be a candidate biomarker for reduced chemopreventive effects of daily aspirin in a population with wide-ranging CYP2A6 phenotypes with a high frequency of impaired activities resulting from variations and whole-gene deletions. The CYP2A6 genotypes could be applicable to future personalized treatments for colorectal tumor chemoprevention with daily aspirin.

Background Few studies have investigated the association between tobacco smoking and sick leave (SL) in Japan. Methods We followed 70 896 workers aged 20–59 years (60 133 males, 10 763 females) between April 2012 and March 2017. A Cox proportional hazards model was used to investigate the associations between smoking (smoking status and intensity) and long-term SL (ie, SL lasting ≥30 consecutive days). Cause-specific analyses were also conducted. Results A total of 1777 people took long-term SL during a follow-up of 307 749 person years. Compared with never-smokers, current smokers were at a higher risk of long-term SL (hazard ratio [HR] = 1.32; 95% confidence interval [CI] = 1.19 to 1.48). Cause-specific analyses revealed that current smoking was associated with a higher risk of SL due to all physical disorders (HR = 1.44, 95% CI = 1.22 to 1.69), cancer (HR = 1.49, 95% CI = 1.10 to 2.01), cardiovascular disease (CVD; HR = 2.16, 95% CI = 1.31 to 3.55), and injuries/external causes (HR = 1.83, 95% CI = 1.31 to 2.58). Former smokers were at a higher risk of SL due to cancer at a borderline significance level (HR = 1.38, 95% CI = 0.99 to 1.92). Low-intensity smoking (ie, 1–10 cigarettes smoked per day) was associated with all-cause SL, SL due to CVD, and SL due to injuries/external causes compared with never-smokers. Conclusion In a large cohort of working-age Japanese, smoking was associated with a greater risk of long-term SL. Greater effort is needed to mitigate disease burden associated with smoking at workplace in Japan. Implications Our study contributes to the literature on the association between smoking and SL in several ways. First, the study was conducted among a Japanese working population. While the association has been extensively studied in Western setting, few attempts have been made elsewhere. Second, cause-specific analyses were undertaken in our study. Third, we paid attention to the effect of low-intensity smoking on SL given that there is growing evidence of an elevated health risk associated with low-intensity smoking.

Introduction The effect of weight gain following smoking cessation on cardiovascular risks is unclear. We aimed to prospectively investigate the association of weight gain following smoking cessation with the trajectory of estimated risks of coronary heart disease (CHD). Methods In a cohort of 18 562 Japanese male employees aged 30–64 years and initially free of cardiovascular diseases, participants were exclusively grouped into sustained smokers, quitters with weight gain (body weight increase ≥5%), quitters without weight gain (body weight increase Results During a maximum of 8-year follow-up, both quitters with and without weight gain had a substantially decreased level of estimated 10-year CHD risk after quitting smoking, compared with sustained smokers (all ps for mean differences < .001). The estimated 10-year CHD risk within the first year after cessation decreased more rapidly in quitters without weight gain than in quitters with weight gain (change rate [95% confidence interval, CI] −0.90 [−1.04 to −0.75] vs. −0.40 [−0.60 to −0.19] % per year, p < .0001). Thereafter, the estimated 10-year CHD risk in both groups increased at similar rates (change rate [95% CI] −0.07 [−0.21 to 0.07] vs. 0.11 [−0.09 to 0.30] % per year, p = .16, from year 1 to year 2; and 0.10 [0.05 to 0.15] vs. 0.11 [0.04 to 0.18] % per year, p = .80, from year 2 to year 8). Conclusions In this population of middle-aged, Japanese male workers, smoking cessation greatly reduces the estimated 10-year risk of CHD. However, weight gain weakens the beneficial effect of quitting smoking in a temporary and limited fashion. Implications To the best of our knowledge, this study is the first to examine the effect of weight gain following smoking cessation on the trajectory of the absolute risk of CHD. Our data imply that the benefits of cessation for reducing the absolute risk of CHD outweigh the potential risk increase due to weight gain, and suggest that in order to maximize the beneficial effects of quitting smoking, interventions to control post-cessation weight gain might be warranted.

Objective:To investigate the association between suicide death and serum cholesterol levels as measured at times close to suicide death.Methods:We conducted a nested case-control study of 41 cases of suicide deaths and 205 matched controls with serum total cholesterol (TC) levels till 3 years before suicide death in a large cohort of Japanese workers.Results:Individuals in the lowest versus highest tertile/predefined category of TC in a Japanese working population had a three- to four-fold greater risk of suicide death. Each 10 mg/dl decrement of average TC was associated with an 18% increased chance of suicide death (95% confidence interval, 2–35%). Similar results were found for TC levels at each year.Conclusion:These results suggest that a low serum TC level in recent past is associated with an increased risk of suicide death.

Aims/Introduction We examined a prospective association between serum creatinine levels and diabetes. Materials and Methods The present study included 31,343 male workers without diabetes, and aged between 20 and 64 years at baseline. We calculated the cumulative average of their serum creatinine over the study period. We defined diabetes as either glycated hemoglobin levels ≥6.5%, random glucose levels ≥200 mg/dL, fasting glucose levels ≥126 mg/dL or receiving antidiabetic treatment. Cox proportional hazards regression analysis was carried out to estimate the hazard ratio (HR) and 95% confidence interval (CI). Results With a median observation of 7.7 years, 2,509 participants developed diabetes. After adjusting for age, smoking, body mass index, hypertension and dyslipidemia, lower cumulative average serum creatinine levels were related to a greater diabetes risk: HRs were 1.56 (95% CI 1.35–1.82), 1.22 (1.09–1.35) and 1.06 (0.96–1.17) for the participants with serum creatinine

Steady-state plasma concentrations of anticoagulants and the time since the previous administration in mainly outpatients with atrial fibrillation administered standard or reduced doses were analyzed for 110 elderly Japanese subjects (mean age, 76 years) treated with apixaban (2.5 or 5.0 mg twice daily), dabigatran etexilate (110 or 150 mg twice daily), edoxaban (30 or 60 mg once daily) or rivaroxaban (10 or 15 mg once daily) at one general hospital. The pharmacokinetics in patients treated with standard and reduced doses of the four anticoagulants using liquid chromatography-tandem mass spectrometry was compared with the concentration ranges estimated using physiologically based pharmacokinetic modeling. Reduced doses of anticoagulants resulted in relatively small pharmacokinetic variations compared with the standard dose. Statistical analyses revealed that renal impairment is likely not the sole determinant factor for high plasma concentrations of apixaban, dabigatran, edoxaban and rivaroxaban. Patients with atrial fibrillation should be treated with the correct doses of oral anticoagulants as specified in the package inserts (e.g. reduced doses for elderly patients, patients with low body weights and in combination with P-glycoprotein inhibitor drugs) to avoid excessive or insufficient doses of direct oral anticoagulants.

Background Although the over-the-counter H1 receptor antagonist diphenhydramine is not a common drug of abuse, it was recently recognized as one of the substances causing acute poisoning in patients attempting suicide that led to admissions to our hospital emergency room. Case presentation Two patients [women aged 21 and 27 years (cases 1 and 2)] were emergently admitted after intentionally taking overdoses of 900 and 1200 mg diphenhydramine, respectively. The plasma diphenhydramine concentrations in case 1 were 977 and 425 ng/mL at 2.5 and 11.5 h after single oral overdose, and those in case 2 were 1320 and 475 ng/mL at 3 and 18 h after administration, respectively. We set up a simplified physiologically based pharmacokinetic (PBPK) model that was established using the reported pharmacokinetic data for a microdose of diphenhydramine. The two virtual plasma concentrations and the area under the curve (AUC) values extrapolated using the PBPK model were consistent with the observed overdose data. This finding implied linearity of pharmacokinetics over a wide dosage range for diphenhydramine. Conclusions The determined plasma concentrations of diphenhydramine of around 1000 ng/mL at ~ 3 h after orally administered overdoses in cases 1 and 2 may not have been high enough to cause hepatic impairment because levels of aspartate aminotransferase and alanine aminotransferase were normal; however, there was an increase in total bilirubin in case 1. Nonetheless, high virtual liver exposures of diphenhydramine were estimated by the current PBPK model. The present results based on drug monitoring data and pharmacokinetic predictions could serve as a useful guide when setting the duration of treatment in cases of diphenhydramine overdose.

The accidental ingestion of drugs is a common concern, especially in the case of young children. A physiologically based pharmacokinetic (PBPK) model that implements the age-dependent size growth and ontogeny of organ functions can be used to predict the concentration-time profiles of drugs in the pediatric population. In this study, the feasibility of using a PBPK model for predicting the amount of drug accidentally swallowed by a child was assessed based on a case study in an infant. Alprazolam was the drug involved in the current case. The developed PBPK model of alprazolam was first evaluated using pharmacokinetic data obtained in healthy adult male volunteers. Then, it was adapted for application to virtual Japanese pediatric subjects having the same demographic information as the infant of interest. The pharmacokinetic data observed in the infant fell within the range of the 5th and 95th percentiles of the pharmacokinetic simulations after administration of 0.4 mg alprazolam (equivalent to one tablet) in the panel of virtual infants. PBPK simulations could provide estimates of the amount accidentally ingested by a child and also give mechanistic insights into the observed drug concentrations. The current study demonstrates the potential clinical utility of PBPK modeling.

The oxygenation of food-derived trimethylamine to its N-oxide is a representative reaction mediated by human flavin-containing monooxygenase 3 (FMO3). Impaired FMO3 enzymatic activity is associated with trimethylaminuria (accumulation of substrate), whereas trimethylamine N-oxide (metabolite) is associated with arteriosclerosis. We previously reported FMO3 single-nucleotide and/or haplotype variants with low FMO3 metabolic capacity using urinary phenotyping and the whole-genome sequencing of Japanese populations. Here, we further analyze Japanese volunteers with self-reported malodor and interrogate an updated Japanese database for novel FMO3 single-nucleotide and/or haplotype variants. After 3 years of follow up, seven probands were found to harbor the known impaired FMO3 variant p.(Gly191Cys) identified in the database or novel variants/haplotypes including p.(Met66Val), p.(Arg223Gln), p.(Glu158Lys;Glu308Gly;Arg492Trp), and p.(Glu158Lys;Glu308Gly;Pro496Ser). The known severe mutation p.(Cys197Ter) (a TG deletion) and four variants including p.(Tyr269His) and p.(Pro496Ser) were first detected in the updated genome panel. Among previously unanalyzed FMO3 variants, the trimethylamine/benzydamine N-oxygenation activities of recombinant p.(Met66Val), p.(Arg223Gln), p.(Tyr269His), p.(Glu158Lys;Glu308Gly;Arg492Trp), and p.(Glu158Lys;Glu308Gly;Pro496Ser) FMO3 variant proteins were severely decreased (Vmax/Km

Background Combinations of antidepressant duloxetine (at doses of 40–60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt. Case presentation The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient’s plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model. Conclusion Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.

Tetrabromobisphenol A, a brominated flame retardant, is increasingly prevalent worldwide and presents a potential health risk. Adjusted animal biomonitoring equivalents of tetrabromobisphenol A after orally administered doses in humanized-liver mice were scaled up to humans using known species allometric scaling factors to set up simplified physiologically based pharmacokinetic (PBPK) models. Absorbed tetrabromobisphenol A was slightly, moderately, and extensively metabolized in vivo to its glucuronide in rats, control mice, and humanized-liver mice tested, respectively. In silico estimated hepatic exposures of tetrabromobisphenol A and its glucuronide generated using the rat PBPK model-generated plasma concentration profiles were consistent with the reported values. The extent of hepatic injury in humanized-liver mice caused by tetrabromobisphenol A was evaluated by detecting human albumin mRNA in mouse plasma after oral administration of a high dose of tetrabromobisphenol A (1000 mg/kg). Reverse dosimetry analyses were carried out using two human PBPK models (set up based on the humanized-liver-mouse model and by optimizing the input parameters for reported human plasma concentrations of tetrabromobisphenol A glucuronide) to estimate the tetrabromobisphenol A daily intake based on reported human serum concentrations of total tetrabromobisphenol A from biomonitoring data. Within the predictability of the forward and reverse dosimetry estimations, the calculated daily intake was found to be far below established health benchmark levels (i.e., the suggested daily reported reference dose) with a wide (4 orders of magnitude) safety margin. These results suggest that the simplified PBPK models can be successfully applied to forward and reverse dosimetry estimations of tissue and/or blood exposures of tetrabromobisphenol A in humans after oral doses.

Plasma concentrations of acetaminophen, its glucuronide and sulfate conjugates, and cysteinyl acetaminophen were experimentally determined after oral administrations of 10 mg/kg in humanised-liver mice, control mice, rats, common marmosets, cynomolgus monkeys, and minipigs; the results were compared with reported human pharmacokinetic data. Among the animals tested, only rats predominantly converted acetaminophen to sulfate conjugates, rather than glucuronide conjugates. In contrast, the values of area under the plasma concentration curves of acetaminophen, its glucuronide and sulfate conjugates, and cysteinyl acetaminophen after oral administration of acetaminophen in marmosets and minipigs were consistent with those reported in humans under the present conditions. Physiologically based pharmacokinetic (PBPK) models (consisting of the gut, liver, and central compartments) for acetaminophen and its primary metabolite could reproduce and estimate, respectively, the plasma and hepatic concentrations of acetaminophen in experimental animals and humans after single virtual oral doses. The values of area under the curves of hepatic concentrations of acetaminophen estimated using PBPK models were correlated with the measured levels of cysteinyl acetaminophen (a deactivated metabolite) in plasma fractions in these species. Consequently, using simple PBPK models and plasma data to predict hepatic chemical concentrations after oral doses could be helpful as an indicator of

Coumarin is a dietary-derived substance that is extensively metabolized by human liver to excretable 7-hydroxycoumarin. Although coumarin under daily dietary consumption is generally regarded as nontoxic, the substance is of toxicological and clinical interest because of its potential association with hepatotoxicity, which is especially evident in rats. In this study, the pharmacokinetics of coumarin were modeled after virtual oral administration in humans. The adjusted monitoring equivalents of coumarin, along with the biotransformation of coumarin to o-hydroxyphenylacetic acid (via 3,4-epoxidation) based on reported plasma concentrations from rat studies, were scaled to human coumarin equivalents using known species allometric scaling factors. Using rat and human liver preparations, data on the rapid in vitro metabolic clearance for humans (~50-fold faster than in rats) were obtained for in vitro-in vivo extrapolation. For human physiologically based pharmacokinetic (PBPK) modeling, the metabolic ratios to o-hydroxyphenylacetic acid and 7-hydroxycoumarin were set at minor (0.1) and major (0.9) levels for the total disappearance of coumarin. The resulting modeled plasma concentration curves in humans generated by simple PBPK models were consistent with reported simulated coumarin maximum concentrations. These results provide basic information to simulate plasma levels of coumarin and its primary metabolite 7-hydroxycoumarin or its secondary activated metabolite o-hydroxyphenylacetic acid (via 3,4-epoxidation) resulting from dietary foodstuff consumption. Under the current assumptions, little toxicological impact of coumarin was evident in humans, thereby indicating the usefulness of forward dosimetry using PBPK modeling for human risk assessment.

Flavin-containing monooxygenase (FMO) catalyzes the oxygenation of a wide variety of medicines and dietary-derived compounds. However, little information is available regarding drug interactions mediated by FMO3 in vivo. Consequently, we investigated interactions between FMO substrates in humanized-liver mice. Trimethylamine-d9 and itopride were, respectively, intravenously and orally administered to humanized-liver mice (n = 5–7). The pharmacokinetic profiles of itopride (the victim drug) in the presence of trimethylamine (the perpetrator drug) were determined for 24 h after co-administration using liquid chromatography/tandem mass spectrometry. Itopride (10 mg/kg) was extensively oxygenated in humanized-liver mice to its N-oxide. The plasma concentrations of itopride N-oxide after co-administration of itopride and trimethylamine (10 and 100 mg/kg) were significantly suppressed in a dose-dependent manner, but only during the early phase, i.e., up to 2 h after co-administration. With the higher dose of trimethylamine, the areas under the concentration–time curves of itopride and its N-oxide significantly increased (1.6-fold) and decreased (to 60%), respectively; modeling suggested that these modified pharmacokinetics resulted from suppression of the in vivo hepatic intrinsic clearance (to 67%). These results suggest that food-derived trimethylamine may result in interactions with FMO drug substrates immediately after administration; however, the potential for this to occur in vivo may be limited.

Purpose To analyze the usefulness of intravaginal insemination (IVI) for the infertility treatment in couples with sexual dysfunction before applying assisted reproductive technology (ART). Methods Among 208 couples who presented sexual dysfunction, 144 couples underwent IVI procedures. The profiles of pregnant and non‐pregnant patients were compared. Results Of 144 patients, 58 women conceived successfully (40.3% pregnancy rate). Between the pregnant and non‐pregnant cases, the husband's age and infertility period were significantly higher (P = .0104) and longer (P = .0027) in the unsuccessful cases than the successful ones. The husbands who could not impregnate had a significantly higher ratio of sperm abnormalities (P = .0048). Among the 57 successful cases who underwent IVI treatment, 38 (66.7%) patients became pregnant within 3 times of the procedure, while 48 (84.2%) patients conceived within 6 times. Conclusion The authors can propose the following inclusion IVI criteria for couples with sexual dysfunction: (a) younger husband (36 years old or less) which may be most important, (b) infertility duration of 3 years or less, (c) normal sperm condition, and (d) IVI trial for 3 times (maximum of 6 times). Since IVI appears to be a simple, noninvasive, and inexpensive way for couples with sexual dysfunction, it can be attempted before ART application., Intravaginal insemination (IVI) is a useful method for the infertility treatment in couples with sexual dysfunction before ART application. The following inclusion criteria can be proposed; (a) younger husband (36 years old or less), (b) infertility duration of 3 years or less, (c) normal sperm condition, and (d) IVI trial up to 3 times (maximum of 6 times).

Flavin-containing monooxygenase 3 (FMO3) is a polymorphic drug metabolizing enzyme associated with the genetic disorder trimethylaminuria. We phenotyped a white Argentinian 11-year-old girl by medical sensory evaluation. After pedigree analysis with her brother and parents, this proband showed to harbor a new allele p.(P73L; E158K; E308G) FMO3 in trans configuration with the second new one p.(F140S) FMO3. Recombinant FMO3 proteins of the wild-type and the novel two variants underwent kinetic analyses of their trimethylamine N-oxygenation activities. P73L; E158K; E308G and F140S FMO3 proteins exhibited moderately and severely decreased trimethylamine N-oxygenation capacities (∼50% and ∼10% of wild-type FMO3, respectively). Amino acids P73 and F140 were located on the outer surface region in a crystallographic structure recently reported of a FMO3 analog. Changes in these positions would indirectly impact on key FAD-binding residues. This is the first report and characterization of a patient of fish odor syndrome caused by genetic aberrations leading to impaired FMO3-dependent N-oxygenation of trimethylamine found in the Argentinian population. We found novel structural determinants of FAD-binding domains, expanding the list of known disease-causing mutations of FMO3. Our results suggest that individuals homozygous for any of these new variants would develop a severe form of this disorder. Fil: Dionisio, Leonardo Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina Fil: Shimizu, Makiko. Showa Pharmaceutical University; Japón Fil: Stupniki, Sofia. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina Fil: Oyama, Saki. Showa Pharmaceutical University; Japón Fil: Aztiria, Eugenio Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina Fil: Alda, Maximiliano. Instituto de Diagnóstico Infantil; Argentina Fil: Yamazaki, Hiroshi. Showa Pharmaceutical University; Japón Fil: Spitzmaul, Guillermo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina

Aims:: Base dissociation constants of 30 model chemicals were investigated to constitute potential determinant factors predicting the contributions of flavin-containing monooxygenases (FMOs). Background:: The contributions of FMOs to the metabolic elimination of new drug candidates could be underestimated under certain experimental conditions during drug development. Objective:: A method for predicting metabolic sites and the contributions of FMOs to N-oxygenations is proposed using a molecular descriptor, the base dissociation constant (pKa base), which can be estimated in silico using commonly available chemoinformatic prediction systems. Methods:: Model drugs and their oxidative pathways were surveyed in the literature to investigate the roles of FMOs in their N-oxygenations. The acid and base dissociation constants of the nitrogen moieties of 30 model substrates were estimated using well-established chemoinformatic software. Results:: The base dissociation constants of 30 model chemicals were classified into two groups based on the reported optimal in vitro pH of 8.4 for FMO enzymes as a key determinant factor. Among 18 substrates (e.g., trimethylamine, benzydamine, and itopride) with pKa (base) values in the range of 8.4-9.8, all N-oxygenated metabolites were reported to be predominantly catalyzed by FMOs. Except for three cases (xanomeline; L-775,606; and tozasertib), the nine substrates with pKa (base) values in the range 2.7-7.9 were only moderately or minorly N-oxygenated by FMOs in addition to their major metabolic pathway of oxidation mediated by cytochrome P450s. N-Oxygenation of T-1032 (with a pKa of 4.8) is mediated predominantly by P450 3A5, but not by FMO1/3. Conclusion:: The predicted contributions of FMOs to the N-oxygenation of drug candidates can be simply estimated using classic base dissociation constants.

1. Flavin-containing monooxygenase 3 (FMO3) in humans is polymorphic in several ethnic groups, including Caucasians, Africans and Asians. Some FMO3 variants are associated with a disorder trimethylaminuria. 2. In the current study, we used the results from urinary phenotyping assays to identify 63 subjects with

BACKGROUND The effect of smoking on mortality in working-age adults remains unclear. Accordingly, we compared the effects of cigarette smoking and smoking cessation on total and cause-specific mortality in a Japanese working population. Methods and Results: This study included 79,114 Japanese workers aged 20-85 years who participated in the Japan Epidemiology Collaboration on Occupational Health Study. Deaths and causes of death were identified from death certificates, sick leave documents, family confirmation, and other sources. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated via Cox proportional hazards regression. During a maximum 6-year follow-up, there were 252 deaths in total. Multivariable-adjusted HRs (95% CIs) for total mortality, cardiovascular disease (CVD) mortality, and tobacco-related cancer mortality were 1.49 (1.10-2.01), 1.79 (0.99-3.24), and 1.80 (1.02-3.19), respectively, in current vs. never smokers. Among current smokers, the risks of total, tobacco-related cancer, and CVD mortality increased with increasing cigarette consumption (Ptrend

Background: Biomarkers of tobacco exposure have a central role in studies of tobacco use and nicotine intake. The most significant exposure markers are nicotine itself and its metabolites in urine. Therefore, it is important to evaluate the performance of laboratories conducting these biomarker measurements. Methods: This report presents the results from a method performance study involving 11 laboratories from 6 countries that are currently active in this area. Each laboratory assayed blind replicates of seven human urine pools at various concentrations on three separate days. The samples included five pools blended from smoker and nonsmoker urine sources, and two additional blank urine samples fortified with pure nicotine, cotinine, and hydroxycotinine standards. All laboratories used their own methods, and all were based on some form of liquid chromatography/tandem mass spectrometry. Results: Overall, good agreement was found among the laboratories in this study. Intralaboratory precision was good, and in the fortified pools, the mean bias observed was < + 3.5% for nicotine, approximately 1.2% for hydroxycotinine, and less than 1% for cotinine (1 outlier excluded in each case). Both indirect and direct methods for analyzing the glucuronides gave comparable results. Conclusions: This evaluation indicates that the experienced laboratories participating in this study can produce reliable and comparable human urinary nicotine metabolic profiles in samples from people with significant recent exposure to nicotine. Impact: This work supports the reliability and agreement of an international group of established laboratories measuring nicotine and its metabolites in urine in support of nicotine exposure studies. Cancer Epidemiol Biomarkers Prev; 27(9); 1083–90. ©2018 AACR.

In vitro permeability and in vivo pharmacokinetics of pemafibrate were investigated in human intestinal and animal models untreated or pretreated with cyclosporine A or rifampicin to evaluate any drug interactions. Ratios of basal to apical apparent permeability (Papp) over apical to basal Papp in the presence of pH gradients decreased from 0.37 to 0.080 on rifampicin co-incubation, suggesting active transport of pemafibrate from basal to apical sides in intestinal models. Plasma concentrations of intravenously administered pemafibrate were enhanced moderately in control mice but only marginally in humanized-liver mice by oral pretreatment with rifampicin [an organic anion transporting polypeptide (OATP) 1B1 inhibitor] 1 h before the administration of pemafibrate. In three cynomolgus monkeys genotyped as wild-type OATP1B1 (2 homozygous and 1 heterozygous), oral dosing of cyclosporine A 4 h or rifampicin 1 h before pemafibrate administration significantly increased the areas under the plasma concentration–time curves (AUC) of intravenously administered pemafibrate by 4.9- and 7.4-fold, respectively. Plasma AUC values of three pemafibrate metabolites in cynomolgus monkeys were also increased by cyclosporine A or rifampicin. These results suggested that pemafibrate was actively uptaken in livers and rapidly cleared from plasma in cynomolgus monkeys; this rapid clearance was suppressible by OATP1B1 inhibitors.

Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. An anti-inflammatory drug, diclofenac is reportedly metabolized mainly by human cytochrome P450 (P450) 2C9 to 4′-hydroxydiclofenac and minorly by P450 3A4 to 5-hydroxydiclofenac that leads to reactive intermediates. In this study, in vivo pharmacokinetics in six marmosets and in vitro metabolism in nine marmoset liver microsomes were analyzed using diclofenac to evaluate marmosets as preclinical drug metabolism models. In wild-type marmosets genotyped for P450 2C19 p.[(Phe7Leu; Ser254Leu; Ile469Thr)], plasma levels of 5-hydroxydiclofenac and 4′-hydroxydiclofenac were roughly similar, but the homozygotes showed approximately three-times higher plasma levels of 5-hydroxydiclofenac than those of 4′-hydroxydiclofenac after oral administrations of diclofenac (50 mg/kg). Nine marmoset liver microsomes catalyzed mainly diclofenac 5-hydroxylation with no significant effects of the the P450 2C19 genotype, and partly diclofenac 4′-hydroxylation that depended on the P450 2C19 genotype, at substrate concentrations of 10 µM and 100 µM. Both Michaels-Menten constant Km values for diclofenac 4′-hydroxylation in human and marmoset liver microsomes were ∼30 μM and those for diclofenac 5-hydroxylation were ∼120 μM. Ketoconazole significantly suppressed only diclofenac 5-hydroxylation in marmoset or human liver microsomes at 0.030 μM, indicating main contribution of P450 3A enzymes, which were found to be P450 3A5/90 using recombinant marmoset P450 3A enzymes. These results suggest that marmosets would be a functional animal model for in vivo and in vitro metabolites likely generated via arene oxide intermediates of diclofenac by P450 3A enzymes in humans, primarily because marmosets lack the ortholog of human P450 2C9.

Diisononyl phthalate (DINP) used as a plasticizer is a mixture of compounds consisting of isononyl esters of phthalic acid. There are concerns about the bioaccumulation of such esters in humans. A [phenyl-U-14C]DINP mixture was synthesized and orally administered (50 mg/kg body weight) to control and humanized-liver mice and their pharmacokinetics were determined. Monoisononyl phthalate (MINP, a primary metabolite of DINP), oxidized MINP (isomers with hydroxy, carbonyl, and carboxy functional groups), and their glucuronides were detected in plasma from control and humanized-liver mice. Biphasic plasma concentration-time curves of MINP and its glucuronide were seen in control mice. In contrast, no such biphasic relationship was seen in humanized-liver mice, in which MINP and oxidized MINP were extensively excreted in the urine within 48 h. Animal biomonitoring equivalents of MINP and oxidized MINP from humanized-liver mice studies were scaled to human equivalents using known species allometric scaling factors with a simple physiologically based pharmacokinetic (PBPK) model. Estimated urinary oxidized MINP concentrations in humans were roughly consistent with reported concentrations of MINP (with a different side chain). The simplified PBPK model could estimate human urinary concentrations of MINP after ingestion of DINP and was capable of both forward and reverse dosimetry.

INTRODUCTION We aimed to determine the prospective association of smoking status, smoking intensity, and smoking cessation with the risk of hearing loss in a large Japanese cohort. METHODS The cohort study included 50195 employees, who were aged 20-64 years and free of hearing loss at baseline. Participants were followed up for a maximum of 8 years. Pure-tone audiometric testing was performed annually to identify hearing loss at 1 and 4 kHz. Cox proportional hazards regression models were used to investigate the association between smoking and hearing loss. RESULTS During follow-up, 3532 individuals developed high-frequency hearing loss, and 1575 developed low-frequency hearing loss. The hazard ratio (HR) associated with current smokers was 1.6 (95% confidence interval [CI] = 1.5 to 1.7) and 1.2 (95% CI = 1.1 to 1.4) for high- and low-frequency hearing loss, respectively, as compared with never smokers. The risk of high- and low-frequency hearing loss increased with the number of cigarettes smoked per day (both p for trend

Aims/Introduction We previously developed a 3‐year diabetes risk score in the working population. The objective of the present study was to develop and validate flexible risk models that can predict the risk of diabetes for any arbitrary time‐point during 7 years. Materials and Methods The participants were 46,198 Japanese employees aged 30–59 years, without diabetes at baseline and with a maximum follow‐up period of 8 years. Incident diabetes was defined according to the American Diabetes Association criteria. With routine health checkup data (age, sex, abdominal obesity, body mass index, smoking status, hypertension status, dyslipidemia, glycated hemoglobin and fasting plasma glucose), we developed non‐invasive and invasive risk models based on the Cox proportional hazards regression model among a random two‐thirds of the participants, and used another one‐third for validation. Results The range of the area under the receiver operating characteristic curve increased from 0.73 (95% confidence interval 0.72–0.74) for the non‐invasive prediction model to 0.89 (95% confidence interval 0.89–0.90) for the invasive prediction model containing dyslipidemia, glycated hemoglobin and fasting plasma glucose. The invasive models showed improved integrated discrimination and reclassification performance, as compared with the non‐invasive model. Calibration appeared good between the predicted and observed risks. These models performed well in the validation cohort. Conclusions The present non‐invasive and invasive models for the prediction of diabetes risk up to 7 years showed fair and excellent performance, respectively. The invasive models can be used to identify high‐risk individuals, who would benefit greatly from lifestyle modification for the prevention or delay of diabetes.

Lenalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species. Screening for thalidomide analogs devoid of teratogenicity/toxicity-attributable to drug metabolism and disposition, but having immunomodulatory properties-is a strategic pathway towards development of new anticancer drugs. Plasma concentrations of lenalidomide were investigated in immunodeficient control and humanized-liver mice following oral administration of lenalidomide (50 mg/kg). Plasma concentrations of lenalidomide (1-2 hr after administration) were slightly but significantly higher in humanized-liver mice than in control mice (p < 0.05). Human albumin mRNA, a liver-specific toxicity marker, was found in the blood of humanized-liver mice 24 hr after lenalidomide administration. Simulations of human plasma concentrations of lenalidomide were achieved with simplified physiologically-based pharmacokinetic models in control and humanized-liver mice or by the direct fitting analysis of reported human data, in accordance with reported lenalidomide concentrations after low dose administration in humans. The results indicate that pharmacokinetic profiles of lenalidomide, a compound resulting from introducing one aromatic amino group into thalidomide and removing one keto group, resulted in less species variation in in vivo pharmacokinetics in control and humanized-liver mice and that immunodeficient humanized-liver mice can serve as experimental model animals for human liver injury in drug development at high doses, with human albumin RNA analysis in plasma.

BACKGROUND We investigated the risk of cardiovascular disease (CVD) with duration of metabolic syndrome (MetS) for the past 4 years before the CVD event.Methods and Results:We performed a nested case-control study within the Japan Epidemiology Collaboration on Occupational Health Study. A total of 139 registered cases of CVD and 561 self-reported cases of CVD were identified and matched individually on age, sex, and worksite with 695 and 2,803 controls, respectively. MetS was defined by the Joint Interim Statement definition. The odds ratio (95% confidence interval) for registered CVD was 4.7 (2.9, 7.5) for people with persistent MetS (positive for MetS for ≥3 assessments) and 1.9 (1.1, 3.3) for those with intermittent MetS (positive for MetS for 1-2 assessments), compared with people without MetS during the past 4 years before the event/index date (P for trend

Background Long-term sick-leave is a major public health problem, but data on its incidence in Japan are scarce. We aimed to present reference data for long-term sick-leave among private sector employees in Japan. Methods The study population comprised employees of 12 companies that participated in the Japan Epidemiology Collaboration on Occupational Health Study. Details on medically certified sick-leave lasting ≥30 days were collected from each company. Age- and sex-specific incidence rate of sick-leave was calculated for the period of April 2012 to March 2014. Results A total of 1422 spells in men and 289 in women occurred during 162,989 and 30,645 person-years of observation, respectively. The three leading causes of sick-leave (percentage of total spells) were mental disorders (52%), neoplasms (12%), and injury (8%) for men; and mental disorders (35%), neoplasms (20%), and pregnancy-related disease (14%) for women. Incidence rate of sick-leave due to mental disorders was relatively high among men in their 20s–40s but tended to decrease with age among women. Incidence rate of sick-leave due to neoplasms started to increase after age 50 in men and after age 40 in women, making neoplasms the leading cause of sick-leave after age 50 for women and after age 60 for men and the second leading cause after age 40 for women and after age 50 for men. Pregnancy-related disease was the second leading cause of sick-leave among women aged 20–39 years. Conclusions These results suggest that mental disorder, neoplasms, and pregnancy-related disease are the major causes of long-term sick-leave among private sector employees in Japan., Highlights • Incidence rate of sick-leave lasting ≥30 days was studied in 12 Japanese companies. • The major causes were mental disorder, neoplasms, and pregnancy-related disease. • Mental disorder and pregnancy-related disease were common in women aged 30–39 years.

The predicted contributions of flavin-containing monooxygenase 3 (FMO3) to drug candidate N-oxygenations can be estimated using classic base dissociation constants of the N-containing moiety. In this study, metabolic clearance values in human liver microsomes were experimentally determined for available model drugs. Typical metabolic clearance values (34-96 μL/min/mg protein) at pH 8.4 of trimethylamine, benzydamine, and itopride were two-to fourfold higher than those at pH 7.4. In contrast, the metabolic clearance of control drug midazolam at pH 8.4 was half that at pH 7.4. The ratios of clearance values at pH 8.4 to those at pH 7.4 and the substrate pKa (base) values of reported metabolic N-oxygenation sites of trimethylamine, benzydamine, clomipramine, chlorpromazine, tamoxifen, itopride, loxapine, xanomeline, tozasertib, dasatinib, and clozapine were significantly correlated (r = 0.60, p 0.05, n = 11). These results suggested that the simple comparison of metabolic clearance values at pH 8.4 and at pH 7.4 could be useful for predicting the contributions of FMO3 to the N-oxygenations of new drug candidates. This method, along with in silico pKa (base) values 8.4, could prove useful for predicting the contributions of FMO3 to N-oxygenations as part of drug development.

Paraoxonase (PON) plays roles in the metabolism of organophosphate xenobiotics and drugs. Despite the importance of marmosets for research into drug metabolism and pharmacokinetics, marmoset paraoxonase has not yet been fully characterized. Consequently, we identified the PON1 gene in the marmoset genome by sequence homology analysis. Marmoset PON1 cDNA containing an open reading frame (1065 bp) was successfully cloned from marmoset liver by reverse transcription-polymerase chain reaction. The deduced amino acid sequence (355 amino acids) has approximately 93% identity with the human ortholog and contains important amino acid residues for substrate binding and calcium ion coordination. According to a phylogenetic tree of PON1 amino acid sequences constructed using data from seven animal species, marmoset PON1 is closer to human PON1 than it is to the PON1 orthologs of experimental animals such as pigs, rabbits, rats, and mice. Marmoset PON1 mRNA was predominantly expressed in liver among the five tissues examined. Marmoset PON1 protein secreted into plasma was detected by immunoblotting. The paraoxon-hydrolyzing activity in plasma was higher in marmosets than in humans. Based on these data, we concluded that marmoset and human PON1 have similar characteristics with regard to genomic structure, amino acid sequences, and tissue distribution.

1. Simulated clearances of R-warfarin and efavirenz were recently reported for individual cynomolgus monkeys genotyped for cytochrome P450 2C19 and 2C9, respectively. To expand and verify this modeling procedure, simulations of R/S-omeprazole and R/S-warfarin clearances after oral administrations in individual marmosets were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling consisting of gut, liver and central compartments. 2. Pharmacokinetics of R/S-omeprazole were chirally determined using the previously reported plasma microsamples in this study. The areas under the plasma concentration/time curves (AUC) of R-omeprazole and S-warfarin, but not S-omeprazole and R-warfarin, after oral administrations in the P450 2C19 homozygous mutant group were significantly higher than those in the wild-type group. These modeled hepatic intrinsic clearances were also significantly associated with the marmoset P450 2C19 genotypes. Other parameter values, e.g. absorption rate constants or systemic circulation volumes, were not likely determining factors. 3. The reported individual AUC values measured in 4-6 marmosets after oral R-omeprazole and S-warfarin administrations were significantly correlated with the AUC values predicted using the PBPK models after virtual administrations. 4. This study indicates that clearances of R-omeprazole, S-warfarin and related medicines associated with polymorphic P450 2C19 in individual marmosets can be simulated using simplified individual PBPK models.

Background We prospectively examined the association of diabetes risk with the number of metabolic abnormalities, as well as their combinations, according to the presence or absence of impaired fasting glucose (IFG) in a large-scale Japanese working population. Methods Participants included 55,271 workers at 11 companies who received periodic health check-ups between 2008 and 2013. The metabolic syndrome (MetS) components were defined using the 2009 Joint Interim Statement. IFG was defined as fasting plasma glucose 5.6–6.9 mmol/L. Diabetes newly diagnosed after the baseline examination was defined according to the American Diabetes Association criteria. We calculated the hazard ratios (HRs) for diabetes incidence using the Cox proportional hazards model. Results During the follow-up period (median 4.95 years), 3183 subjects developed diabetes. In individuals with normal fasting glucose levels, the risk of diabetes increased steadily with the increasing number of MetS components; the multivariable-adjusted HRs for incident diabetes for the number of MetS components were 2.0, 4.3, 7.0, and 10.0 for one, two, three, or four MetS components, respectively, compared with the absence of components. A similar association was observed among individuals with IFG; the corresponding HRs were 17.6, 23.8, 33.9, and 40.7. The combinations that included central obesity appeared to be more strongly associated with diabetes risk than other combinations with the same number of MetS components within the same glucose status. Conclusions Our findings indicate that risk stratification of individuals by the presence or absence of IFG and the number of MetS components can detect individuals with a high risk of diabetes., Highlights • We examined diabetes risk by the number and combination of metabolic abnormalities. • Diabetes risk increased with the number of abnormalities for a given glucose status. • The combinations that included central obesity were strongly associated with diabetes.

Common marmosets (Callithrix jacchus) are potentially primate models for preclinical drug metabolism studies because there are similarities in the molecular characteristics of cytochrome P450 enzymes between this species and humans. However, characterization of non–cytochrome P450 enzymes has not been clarified in marmosets. Here, we report characterization of flavin-containing monooxygenases FMO1–FMO5 identified in marmoset tissues. Marmoset FMO forms shared high amino acid sequence identities (93%–95%) and phylogenetic closeness with human homologous FMO forms. FMO1 and FMO3 mRNA were abundantly expressed in the liver and kidneys among five marmoset tissues examined, where FMO3 protein was detected by immunoblotting. FMO inhibition assays using preheated tissue microsomes indicated that benzydamine N-oxygenation and sulindac sulfide S-oxygenation in the marmoset liver was mainly catalyzed by FMO3, the major hepatic FMO. Marmoset FMO3 protein heterologously expressed in Escherichia coli effectively catalyzed benzydamine N-oxygenation and sulindac sulfide S-oxygenation comparable to marmoset liver microsomes. These results indicate that the FMO3 enzyme expressed in marmoset livers mainly metabolizes benzydamine and sulindac sulfide (typical human FMO substrates), suggesting its importance for FMO-dependent drug metabolism in marmosets.

1. Benzydamine is used clinically as a nonsteroidal anti-inflammatory drug in oral rinses and is employed in preclinical research as a flavin-containing monooxygenase (FMO) probe substrate. In this study, plasma concentrations of benzydamine and its primary N-oxide and N-demethylated metabolites were investigated in control TK-NOG mice, in humanized-liver mice, and in mice whose liver cells had been ablated with ganciclovir. 2. Following oral administration of benzydamine (10 mg/kg) in humanized-liver TK-NOG mice, plasma concentrations of benzydamine N-oxide were slightly higher than those of demethyl benzydamine. In contrast, in control and ganciclovir-treated TK-NOG mice, concentrations of demethyl benzydamine were slightly higher than those of benzydamine N-oxide. 3. Simulations of human plasma concentrations of benzydamine and its N-oxide were achieved using simplified physiologically based pharmacokinetic models based on data from control TK-NOG mice and from reported benzydamine concentrations after low-dose administration in humans. Estimated clearance rates based on data from humanized-liver and ganciclovir-treated TK-NOG mice were two orders magnitude high. 4. The pharmacokinetic profiles of benzydamine were different for control and humanized-liver TK-NOG mice. Humanized-liver mice are generally accepted human models; however, drug oxidation in mouse kidney might need to be considered when probe substrates undergo FMO-dependent drug oxidation in mouse liver and kidney.

1. Cynomolgus monkey cytochrome P450 2C19 (formerly known as P450 2C75), homologous to human P450 2C19, has been identified as R-warfarin 7-hydroxylase. In this study, simulations of R-warfarin clearance in individual cynomolgus monkeys genotyped for P450 2C19 p.[(Phe100Asn; Ala103Val; Ile112Leu)] were performed using individual simplified physiologically based pharmacokinetic (PBPK) modeling. 2. Pharmacokinetic parameters and absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearances for individual PBPK models were estimated for eleven cynomolgus monkeys. 3. One-way ANOVA revealed significant effects of the genotype (p 0.01) on the observed elimination half-lives and areas under the curves of R-warfarin among the homozygous mutant, heterozygous mutant, and wild-type groups. R-Warfarin clearances in individual cynomolgus monkeys genotyped for P450 2C19 were simulated by simplified PBPK modeling. The modeled hepatic intrinsic clearances were significantly associated with the P450 2C19 genotypes. The liver microsomal elimination rates of R-warfarin for individual animals after in vivo administration showed significant reductions associated with the genotype (p 0.01). 4. This study provides important information to help simulate clearances of R-warfarin and related medicines associated with polymorphic P450 2C19 in individual cynomolgus monkeys, thereby facilitating calculation of the fraction of hepatic clearance.

Trimethylamine, a dietary- and medicinal carnitine-derived amine, is extensively metabolized by liver to non-malodorous trimethylamine N-oxide. Although trimethylamine and trimethylamine N-oxide under daily dietary consumption or carnitine treatment are generally regarded as nontoxic, they have been, and remain, of toxicological and clinical interest because of their potential association with atherosclerosis. The aim of the current study was to model the pharmacokinetics of trimethylamine after oral administration of trimethylamine in humans and compare the results with reported measured values. Adjusted biomonitoring equivalents from rat studies based on reported plasma concentrations were scaled to human equivalents using known species allometric scaling factors. In vitro metabolic clearance data were obtained using rat and human liver microsomal preparations. Renal clearances in humans for trimethylamine and trimethylamine N-oxide were calculated with a clearance concept approach using reported 24-hr urinary excretion rates and assumed areas under plasma concentration curves. The resulting modeled plasma and urinary concentration curves by simple physiologically based pharmacokinetic models (or semi-physiological pharmacokinetic models) were consistent with reported concentrations. This study provides important information to help simulate human plasma levels of trimethylamine and trimethylamine N-oxide in trimethylamine loading tests and during treatment with prescribed medicinal l-carnitine, showing the similar range as that resulting from daily dietary foodstuff consumption along with little toxicological impacts. The present models could estimate relationship between plasma and urine concentrations of trimethylamine or trimethylamine N-oxide and the daily oral doses by both forward and reverse dosimetry from viewpoint of human risk assessment.

The relationships among meat consumption, smoking habits, and phenotypic cytochrome P450 2A6 variation with respect to colorectal cancer risk remain unclear. In this study, the relationships among colorectal tumour risk, meat consumption by questionnaire, and phenotypic P450 2A6 activity by genotyping in a case-control study (299 cases and 170 controls) were analyzed for never-smokers and ever-smokers. In never-smokers consuming ≥1 serving per day of total meat, a significant odds ratio of 4.42 (95% confidence interval, 1.29 - 15.2), adjusted by logistic regression for age and gender, was observed, compared with the group consuming ≤2 servings per week. Furthermore, in Japanese never-smokers, the susceptibility to colorectal tumours was dependent on the frequency of meat intake (trend test p = 0.011). In never-smokers who were P450 2A6 poor metabolizers and had a high frequency of meat intake, the apparent odds ratio was 3.57 (95% confidence interval, 0.30 - 42.2) compared with the P450 2A6 normal group with a low meat intake frequency. These results suggested that colorectal tumour risk was inversely associated with the phenotypic P450 2A6 activities in Japanese never-smokers with a high meat intake.