Prospective Prediction of Dapaconazole Clinical Drug-Drug Interactions Using an In Vitro to In Vivo Extrapolation Equation and PBPK Modeling.

This study predicted dapaconazole clinical drug−drug interactions (DDIs) over the main Cytochrome P450 (CYP) isoenzymes using static (in vitro to in vivo extrapolation equation, IVIVE) and dynamic (PBPK model) approaches. The in vitro inhibition of main CYP450 isoenzymes by dapaconazole in a human liver microsome incubation medium was evaluated. A dapaconazole PBPK model (Simcyp version 20) in dogs was developed and qualified using observed data and was scaled up for humans. Static and dynamic models to predict DDIs following current FDA guidelines were applied. The in vitro dapaconazole inhibition was observed for all isoforms investigated, including CYP1A2 (IC50 of 3.68 µM), CYP2A6 (20.7 µM), 2C8 (104.1 µM), 2C9 (0.22 µM), 2C19 (0.05 µM), 2D6 (0.87 µM), and 3A4 (0.008−0.03 µM). The dynamic (PBPK) and static DDI mechanistic model-based analyses suggest that dapaconazole is a weak inhibitor (AUCR > 1.25 and <2) of CYP1A2 and CYP2C9, a moderate inhibitor (AUCR > 2 and <5) of CYP2C8 and CYP2D6, and a strong inhibitor (AUCR ≥ 5) of CYP2C19 and CYP3A, considering a clinical scenario. The results presented may be a useful guide for future in vivo and clinical dapaconazole studies.

Mussels get higher: A study on the occurrence of cocaine and benzoylecgonine in seawater, sediment and mussels from a subtropical ecosystem (Santos Bay, Brazil).

Data on the occurrence of cocaine (COC) and benzoylecgonine (BE) in marine environmental compartments are still limited, with few studies reporting superficial water contamination, mainly in tropical zones. In this sense, environmental data of these substances are essential to identify potential polluting sources, as well as their impact in costal ecosystems. The aim of this study was to evaluate the occurrence of COC and BE in seawater, sediment and mussels from a subtropical coastal zone (Santos Bay, São Paulo, Brazil), as well as to determine a field measured Bioaccumulation Factor (BAF). COC and BE were detected in all water samples in concentrations ranging from 1.91 ng·L-1 to 12.52 ng·L-1 and 9.88 ng·L-1 to 28.53 ng·L-1, respectively. In sediments, only COC was quantified in concentrations ranging from 0.94 ng·g-1 to 46.85 ng·g-1. Similarly, only COC was detected in tissues of mussels 0.914 µg·kg-1 to 4.58 µg·kg-1 (ww). The field-measured BAF ranged from 163 to 1454 (L·kg-1). Our results pointed out a widespread contamination by cocaine and its main human metabolite benzoylecgonine in Santos Bay. Mussels were able to accumulate COC in areas used by residents and tourists for bathing, fishing, and harvest, denoting concern to human health. Therefore, our data can be considered a preliminary assessment, which indicates the need to evaluate drugs (including illicit as COC) in environmental and seafood monitoring programs, in order to understand their risks on the ecosystem and human health.

Seasonal monitoring of cocaine and benzoylecgonine in a subtropical coastal zone (Santos Bay, Brazil).

Illicit drugs and their metabolites represent a new class of emerging contaminants. These substances are continuously discharged into wastewater which have been detected in the aquatic environment in concentrations ranging from ng.L-1 to µg.L-1. Our study detected the occurrence of cocaine (COC) and benzoylecgonine (BE) in a subtropical coastal zone (Santos Bay, SP, Brazil) within one year. Water samples (surface and bottom) were collected from the Santos Submarine Sewage Outfall (SSOS) area. COC and BE were measured in the samples using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-ESI-MS/MS). Concentrations ranged from 12.18 to 203.6 ng.L-1 (COC) and 8.20 to 38.59 ng.L-1 (BE). Higher concentrations of COC were observed during the end of spring, following the population increase at summer season. COC and its metabolite occurrence in this coastal zone represent a threat to coastal organisms.

Detoxification, oxidative stress, and cytogenotoxicity of crack cocaine in the brown mussel Perna perna.

The presence of cocaine and its metabolites and by-products has been identified in different aquatic matrices, making crack cocaine the target of recent studies. The aim of this study was to evaluate the sublethal effects of crack on the brown mussel Perna perna. Mussels were exposed to three concentrations of crack cocaine (0.5, 5.0, and 50.0 µg L-1) for 168 h. Gills, digestive glands, and hemolymph were extracted and analyzed after three different exposure times using a suite of biomarkers (EROD, DBF, GST, GPX, LPO, DNA damage, ChE, and lysosomal membrane stability [LMS]). After 48 and 96 h of exposure, EROD, DBF, GST, GPX activities and DNA strand breaks in the gills increased significantly after 48 and 96 h of exposure. Alterations in LMS were also observed in the mussels exposed to all crack concentrations after 96 and 168 h. Our results demonstrated that crack cocaine is metabolized by CYP-like and GST activities in the gills. GPX was not able to prevent primary genetic damage, and cytotoxic effects in the hemocytes were also observed in a dose- and time-dependent response. Our study shows that the introduction of illicit drugs into coastal ecosystems must be considered a threat to marine organisms.