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New data on the metabolism of chloromethylisothiazolinone and methylisothiazolinone in human volunteers after oral dosage: excretion kinetics of a urinary mercapturic acid metabolite ("M-12").

ABSTRACT: Methylisothiazolinone (MI) as well as the mixture of chloromethylisothiazolinone/methylisothiazolinone [MCI/MI (3:1)] are biocides that are used in a variety of products of every-day life. Due to the skin sensitizing properties of these biocides, their use has come under scrutiny. We have previously examined the human metabolism of MI and MCI after oral dosage of isotope-labelled analogues in human volunteers and confirmed N-methylmalonamic acid to be a major, but presumably unspecific human urinary metabolite. In the present study, we have investigated the urinary kinetics of a mercapturic acid metabolite of MI and MCI using the same set of samples. Four human volunteers received 2 mg of isotopically labelled MI and MCI separately and at least 2 weeks apart. Consecutive urine samples were collected over 48 h and were examined for the content of the (labelled) 3-mercapturic acid conjugate of 3-thiomethyl-N-methyl-propionamide ("M-12"), a known metabolite in rats. On a molar basis, M-12 represented 7.1% (3.0-10.1%) of the dose excreted in urine after dosage of MI. Excretion of this mercapturate was fast with a mean half-life of 3.6 h. Surprisingly, for MCI the mercapturate M-12 represented only 0.13% of the dose excreted in urine. Thus, this biomarker is highly specific for exposures to MI and might be used to distinguish between different exposure patterns of these biocides [use of MI or MCI/MI (3:1)] in the general population.

SUBMITTER: Schettgen T

PROVIDER: S-EPMC8298359 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Tebipenem pivoxil (TBPM-PI), an oral carbapenem antibiotic, has shown special advantages in pediatric infections and was in urgent need in China. Although pharmacokinetics, urinary excretion, and metabolite information of its active form tebipenem (TBPM) has been reported, ethnic differences may exist among the Chinese and Japanese population. By now, no systematic pharmacokinetics, urinary excretion, metabolites, or safety information has been revealed to the Chinese population. The purpose of the present work was to investigate abovementioned information of TBPM-PI granules after oral single ascending doses of 100, 200, and 400 mg in Chinese volunteers. Based on the pharmacokinetic study, the urine pharmaco-metabolomic analysis was conducted to reveal metabolomic interruptions and metabolite information. The study design was a single-center, open-label, randomized, single-dose pharmacokinetic study of 36 healthy volunteers (with half of them being male and the other half female). Time to maximum concentration (T max) was reached at 0.50, 0.50, or 0.67 h for 100, 200, or 400 mg, respectively. The linear pharmacokinetic characteristic of maximum plasma concentration (C max) was detected over 100-200 mg. The area under the concentration time curve (AUC) was proportional to the dose in the range of 100-400 mg. The maximum urinary excretion rate was detected at 0-1 or 1-2 h for dose of 100 or 200-400 mg. Cumulative amount of TBPM excreted in urine by 24 h accounted up to 90, 95, and 80% of dose administered for three groups, respectively. The pharmaco-metabolomic analysis revealed urine metabolic trajectory of deviation at 0-1 or 1-2 h and gradually regressing back to the pre-dose group at the following time periods. Urine metabolites from M1 to M4 were identified, indicating ethnic difference in metabolites among the Chinese or Japanese population. The current work proved safety and tolerance of single-dose administration of oral TBPM-PI in Chinese healthy volunteers over doses of 100-400 mg. All these results provide pharmacokinetics, urine excretion, urine metabolomics, urine metabolites, and safety information in healthy Chinese volunteers after oral single ascending doses of TBPM-PI, benefitting further development and clinical utilities.

Project description:Bupropion, widely used as an antidepressant and smoking cessation aid, undergoes complex metabolism to yield numerous metabolites with unique disposition, effect, and drug-drug interactions (DDIs) in humans. The stereoselective plasma and urinary pharmacokinetics of bupropion and its metabolites were evaluated to understand their potential contributions to bupropion effects. Healthy human volunteers (n = 15) were administered a single oral dose of racemic bupropion (100 mg), which was followed by collection of plasma and urine samples and determination of bupropion and metabolite concentrations using novel liquid chromatography-tandem mass spectrometry assays. Time-dependent, elimination rate-limited, stereoselective pharmacokinetics were observed for all bupropion metabolites. Area under the plasma concentration-time curve from zero to infinity ratios were on average approximately 65, 6, 6, and 4 and Cmax ratios were approximately 35, 6, 3, and 0.5 for (2R,3R)-/(2S,3S)-hydroxybupropion, R-/S-bupropion, (1S,2R)-/(1R,2S)-erythrohydrobupropion, and (1R,2R)-/(1S,2S)-threohydrobupropion, respectively. The R-/S-bupropion and (1R,2R)-/(1S,2S)-threohydrobupropion ratios are likely indicative of higher presystemic metabolism of S- versus R-bupropion by carbonyl reductases. Interestingly, the apparent renal clearance of (2S,3S)-hydroxybupropion was almost 10-fold higher than that of (2R,3R)-hydroxybupropion. The prediction of steady-state pharmacokinetics demonstrated differential stereospecific accumulation [partial area under the plasma concentration-time curve after the final simulated bupropion dose (300-312 hours) from 185 to 37,447 nM⋅h] and elimination [terminal half-life of approximately 7-46 hours] of bupropion metabolites, which may explain observed stereoselective differences in bupropion effect and DDI risk with CYP2D6 at steady state. Further elucidation of bupropion and metabolite disposition suggests that bupropion is not a reliable in vivo marker of CYP2B6 activity. In summary, to our knowledge, this is the first comprehensive report to provide novel insight into mechanisms underlying bupropion disposition by detailing the stereoselective pharmacokinetics of individual bupropion metabolites, which will enhance clinical understanding of bupropion's effects and DDIs with CYP2D6.

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New data on the metabolism of chloromethylisothiazolinone and methylisothiazolinone in human volunteers after oral dosage: excretion kinetics of a urinary mercapturic acid metabolite ("M-12").

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