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| Titel: |
Rationale for the Chemical-Specific Adjustment Factors Used to Derive an Occupational Exposure Limit for Timolol Maleate |
| Auteur: |
Naumann, Bruce D. Dolan, David G. Sargent, Edward V. |
| Verschenen in: |
Human and ecological risk assessment |
| Paginering: | Jaargang 10 (2004) nr. 1 pagina's 99-111 |
| Jaar: |
2004-02 |
| Inhoud: |
Timolol maleate is a non-selective beta-adrenergic blocking agent currently used primarily to reduce intraocular pressure in the treatment of glaucoma. It also produces effects on the heart and bronchial smooth muscle and all of these effects are of potential concern in workers handling this active pharmaceutical ingredient. The disposition of timolol maleate is influenced by a polymorphism in oxidative metabolism by CYP2D6 and two distinct phenotypes have been identified (i.e., poor and extensive metabolizers). These properties of timolol maleate provided an opportunity to use the compound as a case study to demonstrate the derivation of chemical-specific adjustment factors for pharmacokinetics and pharmacodynamics to replace the default uncertainty factor for interindividual variability. Overall, the available data on the pharmacodynamic endpoints showed very little variability and most pharmacokinetic studies failed to discern significant differences in relatively small groups of healthy volunteers or patients. Reports of bradycardia and bronchoconstriction in patients receiving therapeutic doses are relatively rare. In one study, there was a significant reduction in heart rate 24 hours post-dose that was associated with elevated area under the curve (AUC) values. A chemical-specific adjustment factor (CSAF) for kinetics of 9.8 based on these AUC data was combined with a CSAF for dynamics of 1.2 and applied to the extrapolated no-effect level for clinically significant cardiovascular effects (with correction for oral bioavailability) to establish an occupational exposure limit (OEL) for timolol maleate which is expected to be protective of workers that may be poor metabolizers or asthmatics. |
| Uitgever: |
Taylor & Francis |
| Bronbestand: |
Elektronische Wetenschappelijke Tijdschriften |
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