Methyl methacrylate and respiratory sensitization: A Critical review

Methyl methacrylate (MMA) is a respiratory irritant and dermal sensitizer that has been associated with occupational asthma in a small number of case reports. Those reports have raised concern that it might be a respiratory sensitizer. To better understand that possibility, we reviewed the in silico, in chemico, in vitro, and in vivo toxicology literature, and also epidemiologic and occupational medicine reports related to the respiratory effects of MMA. Numerous in silico and in chemico studies indicate that MMA is unlikely to be a respiratory sensitizer. The few in vitro studies suggest that MMA has generally weak effects. In vivo studies have documented contact skin sensitization, nonspecific cytotoxicity, and weakly positive responses on local lymph node assay; guinea pig and mouse inhalation sensitization tests have not been performed. Cohort and cross-sectional worker studies reported irritation of eyes, nose, and upper respiratory tract associated with short-term peaks exposures, but little evidence for respiratory sensitization or asthma. Nineteen case reports described asthma, laryngitis, or hypersensitivity pneumonitis in MMA-exposed workers; however, exposures were either not well described or involved mixtures containing more reactive respiratory sensitizers and irritants.The weight of evidence, both experimental and observational, argues that MMA is not a respiratory sensitizer

METABOLISM OF 3 PHARMACOLOGICALLY ACTIVE-DRUGS IN ISOLATED HUMAN AND RAT HEPATOCYTES - ANALYSIS OF INTERSPECIES VARIABILITY AND COMPARISON WITH METABOLISM IN-VIVO

1. The metabolism of the three drugs (Org GB 94, Org 3770 and Org OD 14) was studied in isolated human and rat hepatocytes. The metabolic profiles in rat and human hepatocytes were compared with the available in vivo data in both species. 2. All three drugs were metabolized extensively under the conditions used, both in human and rat hepatocytes, showing both extensive phase I and II metabolism. 3. During 3-h incubation with rat hepatocytes the three compounds were metabolized completely, whereas incubation with human hepatocytes only resulted in partial metabolism, amounting for 58% (Org GB 94), 36% (Org 3770) and 94% (Org OD 14) of the dose. In addition, rat hepatocytes excreted relatively more of the formed metabolites than human hepatocytes. 4. For both species, the metabolites formed in the isolated cells were quite similar to those found in vivo. With respect to Org GB 94 and Org 3770, metabolites were detected in man in vivo and in isolated human hepatocytes that were not found in any of the animal species studied previously. 5. The reflection of interspecies differences in isolated hepatocytes, with respect to both metabolite profiles and human-specific metabolites, renders isolated human hepatocytes a very valuable tool during preclinical drug development

Disposition kinetics and bioavailability of the glucosidase inhibitor N-benzyl-1-deoxynojirimycin after various routes of administration in mice

Pharmacokinetics, biodistribution, and excretion of the alpha-glucosidase inhibitor and antiviral compound N-benzyl-1-deoxynojirimycin (BndNM) were studied in mice, after intravenous, subcutaneous, and oral administration of a single radiolabeled dose, No metabolites were detected in plasma, urine, or feces extracts, BndNM, a lipophilic derivative of 1-deoxynojirimycin (dNM), showed a biexponential plasma decay with an initial half-life (t(1/2)) of 9 min and an apparent terminal t(1/2) of 62 min, The mean bioavailability was 89% after subcutaneous and on the average 82% after oral dosing to fed mice, Decay curves of BndNM in plasma and total blood coincided exactly for all routes of administration, indicating equal concentrations in plasma and blood cells, Tissue concentrations of BndNM were higher than plasma concentrations at all time points (0.5-24 h) in all collected tissues (kidney, liver, large and small intestines, and stomach) but especially in kidney, where tissue/plasma concentration ratios of 10 to 15 were reached, Only small amounts of BndNM were recovered from collected gallbladders, not exceeding 0.1% of the dose. Recovery of BndNM in urine and feces was quite similar to that of N-methyl-dNM, a more hydrophilic dNM derivative that is not metabolized either, After 24 h, only small fractions of the dose of BndNM were recovered from feces: 1.2% after subcutaneous dosing, 4.2% after oral dosing, and 4.9% after intravenous dosing, Much higher amounts were recovered from the urine: 91% of the dose after subcutaneous administration, 89% after oral dosing, and 75% after intravenous injection. It is concluded that elimination including tubular secretion represents the major elimination route for BndNM and that significant tissue retention of the drug occurs even 24 h after administration