Drug-Induced Dental Caries, Lessons from a Disproportionality Analysis in Vigibase®: Beware of Bisphosphonates, Atropinic, Immunosuppressant and Hyperglycaemic Drugs

Abstract

Background: Accumulating evidence points towards serotonin (5-hydroxytryptamine; 5-HT), melatonin and their metabolites as modulators or markers of a wide range of physiological processes. Literature remains however scarce about their metabolism and usual plasma levels. We developed an analytical method to determine plasma concentrations of 5-HT and 8 of its metabolites: melatonin (Mel), N-acetylserotonin (NAS), 6-hydroxymelatonin (6-OH Mel), 5-methoxytryptamine (5-MT), 5-hydroxyindole-acetic acid (5-HIAA), 5-methoxyindole-acetic acid (5-MIAA), 5-hydroxytryptophol (5-HTP), 5-methoxytryptophol (5-MTP). This work aimed at validating the method and determining physiological ranges for these metabolites in plasma. Methods: Free 5-HT and its 8 metabolites were measured in plasma with a newly developed LC-MS/MS assay. To determine reference plasma concentration ranges, these analytes were measured in 98 healthy subjects (aged 18-70 years, 44 males). Most blood samples (n= 92) were collected between 8h30 and 10 AM to limit the impact of circadian variations, after 24h of abstinence from serotonin rich foods. The study was approved by the local ethics committee and informed consent was obtained according to GCP/ICH requirements. Results: The assay was found linear on calibration curves (0.25 to 400'000 pg/ml) for all analytes with sensitivity (0.25 to 390 pg/ml) depending on the analyte. Intra-and inter-run coefficients of variation were acceptable (0.5% to 22.7%) and no carryover was observed. Free 5-MT, 5-HTP and 5-MTP remained below the quantification limit. Geometric mean values (CV%) were determined for the remaining metabolites (pg/ml): 5-HT: 31829 pg/ml (54%); Mel: 7.4 (110%), NAS: 6.8 (77%), 6-OH-Mel: 0.5 (101%), 5-HIAA: 6018 (28%); 5-MIAA: 55.3 (48%). Significant circadian variations were observed among 21 volunteers monitored over 24h. Conclusions: We developed and validated a robust method for measuring serotonin and 8 metabolites in human plasma. Usual ranges for plasma levels were determined in 98 healthy volunteers. These results afford valuable biomarkers of physiological and pathological serotonin production.