Medicamentos peligrosos: resumen normativo / Hazardous drugs: regulatory summary

Las propiedades tóxicas de los medicamentos citostáticos son bien conocidas desde que en los años 40 empezaron a utilizarse en el ámbito oncológico. (AU)

Use of commercial pharmaceutical drug (Daktarin®) for retrospective/accidental/forensic thermoluminescence dosimetry.

Retrospective/accidental dosimetry seeks for materials that can be used as probes for the dose assessment by means of several methods when there is no dose data available (e.g. from personal dosimeters). In the same respect, researchers also seek materials appropriate for forensic purposes, which would allow to identify the prior presence of radioactive materials at buildings, sites or even vehicles. To this direction, several solid-state drugs, which are ubiquitous, have also been studied as probes for the dose estimation in emergency situations. However, due to their heat-sensitive character, measurements were possible only with OSL. The scope of the present work is to identify a heat-resistant drug (Daktarin) and conduct, for the first time, a detailed study of the thermoluminescence properties of it along with computerized curve deconvolution analysis which would shed light on the traps involved. Results indicate that the glow curve of Daktarin has at least three peaks that can be used for dosimetric purposes, since they exhibit linear dose response for doses up to 20 Gy, do not exhibit any sensitization, have high lifetime and their stability with time is good, since an appreciable signal remains unaffected even 3 months post irradiation. All the above were validated conducting dose recovery tests and successfully calculating the unknown delivered dose for various periods after the irradiation of the samples. The new findings are very supportive and point towards the efficient use of commercial pharmaceuticals as probes for retrospective/accidental/forensic dosimetry using thermoluminescence.

Effects of Glycan Structure on the Stability and Receptor Binding of an IgG4-Fc.

A series of well-defined N-glycosylated IgG4-Fc variants were utilized to investigate the effect of glycan structure on their physicochemical properties (conformational stability and photostability) and interactions with an Fc γ receptor IIIA (FcγRIIIA). High mannose (HM, GlcNAc2Man(8+n) [n = 0-4]), Man5 (GlcNAc2Man5), GlcNAc1, and N297Q IgG4-Fc were prepared in good quality. The physical stability of these IgG4-Fc variants was examined with differential scanning calorimetry and intrinsic fluorescence spectroscopy. Photostability was assessed after photoirradiation between 295 and 340 nm (λ max = 305 nm), and HPLC-MS/MS analysis of specific products was performed. The size of glycans at Asn297 affects the yields of light-induced Tyr side-chain fragmentation products, where the yields decreased in the following order: N297Q > GlcNAc1 > Man5 > HM. These yields correlate with the thermal stability of the glycoforms. The HM and Man5 glycoforms display increased affinity for FcγRIIIA by at least 14.7-fold compared with GlcNAc1 IgG4-Fc. The affinities measured for the HM and Man5 IgG4-Fc (0.39-0.52 µM) are similar to those measured for fucosylated IgG1. Dependent on the mechanisms of action of IgG4 therapeutics, such glycoforms may need to be carefully monitored. The nonglycosylated N297Q IgG4-Fc did not present measurable affinity to FcγRIIIA.

Implementation of a mathematical model for the photochemical kinetics of a solid form active pharmaceutical ingredient.

We present here the development of a photochemical model used to quantify the risk to photodegradation of a solid drug substance. A key feature of the proposed model development is streamlined estimation of the dependence of the absorption spectra and the quantum yield to the wavelength. A mathematical description of the relationship between the quantum yield and the wavelength enables estimation of photodegradation kinetics under any light anticipated to be encountered in the manufacturing environment. The system studied here consisted of a first order irreversible transformation (A → B(1Φ)) and the formalism strongly suggested the quantum yield was constant over the relevant wavelength range. The predictive power of the model enabled the design of a control strategy to limit the formation of the photo-degradant to very low levels. Also presented are insights obtained from quantum mechanical modeling of the electronic transitions associated with the UV absorption spectra.

Effects of Radiation on Drug Metabolism: A Review.

BACKGROUND: Radiation is the fourth most prevalent type of pollution following the water, air and noise pollution. It can adversely affect normal bodily functions. Radiation alters the protein and mRNA expression of drugmetabolizing enzymes and drug transporters and the pharmacokinetic characteristics of drugs, thereby affecting drug absorption, distribution, metabolism, and excretion. Therefore, it is important to study the pharmacokinetic changes in drugs under radiation. METHODS: To update data on the effects of ionizing radiation and non-ionizing radiation caused by environmental pollution or clinical treatments on the protein and mRNA expression of drug-metabolizing enzymes and drug transporters. Data and information on pharmacokinetic changes in drugs under radiation were analyzed and summarized. RESULTS: The effect of radiation on cytochrome P450 is still a subject of debate. The widespread belief is that higherdose radiation increased the expression of CYP1A1 and CYP1B1 of rat, zebrafish or human, CYP1A2, CYP2B1, and CYP3A1 of rat, and CYP2E1 of mouse or rat, and decreased that of rat's CYP2C11 and CYP2D1. Radiation increased the expression of multidrug resistance protein, multidrug resistance-associated protein, and breast cancer resistance protein. The metabolism of some drugs, as well as the clearance, increased during concurrent chemoradiation therapy, whereas the half-life, mean residence time, and area under the curve decreased. Changes in the expression of cytochrome P450 and drug transporters were consistent with the changes in the pharmacokinetics of some drugs under radiation. CONCLUSION: The findings of this review indicated that radiation caused by environmental pollution or clinical treatments can alter the pharmacokinetic characteristics of drugs. Thus, the pharmacokinetics of drugs should be rechecked and the optimal dose should be re-evaluated after radiation.

In-Use Photostability Practice and Regulatory Evaluation for Pharmaceutical Products in an Age of Light-Emitting Diode Light Sources.

This article describes how the increased use of energy-efficient solid-state light sources (e.g., light-emitting diode [LED]-based illumination) in hospitals, pharmacies, and at home can help alleviate concerns of photodegradation for pharmaceuticals. LED light sources, unlike fluorescent ones, do not have spurious spectral contributions <400 nm. Because photostability is primarily evaluated in the International Council of Harmonization Q1B tests with older fluorescent bulb standards (International Organization for Standardization 10977), the amount of photodegradation observed can over-predict what happens in reality, as products are increasingly being stored and used in environments fitted with LED bulbs. Because photodegradation is premised on light absorption by a compound of interest (or a photosensitizer), one can use the overlap between the spectral distribution of a light source and the absorption spectra of a given compound to estimate if photodegradation is a possibility. Based on the absorption spectra of a sample of 150 pharmaceutical compounds in development, only 15% would meet the required overlap to be a candidate to undergo direct photodegradation in the presence of LED lights, against a baseline of 55% of compounds that would, when considering regular fluorescent lights. Biological drug products such as peptides and monoclonal antibodies are also expected to benefit from the use of more efficient solid-state lighting.

Unveiling the important roles of coexisting contaminants on photochemical transformations of pharmaceuticals: Fibrate drugs as a case study.

Pharmaceuticals are a group of ubiquitous emerging pollutants, many of which have been shown to undergo efficient photolysis in the environment. Photochemically produced reactive intermediates (PPRIs) sensitized by the pharmaceuticals in sunlit natural waters may induce photodegradation of coexisting compounds. In this study, the roles of coexisting contaminants on the phototransformation of pharmaceuticals were unveiled with the fibrate drugs gemfibrozil (GMF), fenofibrate (FNF), and fenofibric acid (FNFA) as model compounds. GMF undergoes initial concentration dependent photodegradation due to the involvement of singlet oxygen (1O2) initiated self-sensitized photolysis, and undergoes pH dependent photodegradation due to dissociation and hydroxyl radical (OH) generation. The decarboxylated intermediates of GMF and coexisting FNFA significantly accelerated the photodegradation of GMF. The promotional effects of the decarboxylated intermediates are attributed to generation of PPRIs, e.g. 1O2, superoxide (O2-), that subsequently react with GMF. Besides, FNFA can also promote the photodegradation of GMF through the electron transfer reaction from ground state GMF to excited state FNFA, leading to the formation of decarboxylated intermediates. The formed intermediates can subsequently also facilitate GMF photodegradation. The results presented here provided valuable novel insights into the effects of coexisting contaminants on the photodegradation of pharmaceuticals in polluted waters.

Fate and distribution of pharmaceutically active compounds in mesocosm constructed wetlands.

Removal of pharmaceutically active compounds (PhACs) in constructed wetlands (CWs) is a complex interplay of different processes. We studied fate and distribution of seven PhACs (caffeine, CAF; naproxen, NAP; metoprolol, MET; propranolol, PRO; ibuprofen, IBP; carbamazepine, CBZ; diclofenac, DFC) in mesocosm CWs and effects of irradiation via pre-photocatalysis, substrate composition (mainly sediment) through addition of litter (dead plant biomass), and plants. CWs showed high removal of CAF, NAP, MET, PRO, and IBP (79-99%). All seven PhACs were detected in substrate and plant tissues as well as IBP intermediates. Estimated PhAC mass balance showed that sorption dominated PRO removal in CWs while other PhACs were mainly removed by biodegradation and/or phytodegradation. Pre-photocatalysis significantly increased removal of PhACs except for CAF and IBP, and decreased accumulation of PhACs in substrate and plant tissues of the following wetland compartment. Litter addition in CW significantly enhanced removal of PRO and CBZ via biodegradation and/or phytodegradation. Plants played an essential and positive role in removing PhACs, resulting from direct phytoremediation and indirectly enhancing sorption and biodegradation. Our study provides knowledge to understand removal mechanisms of PhACs in CWs and to potentially enhance PhAC removal by developing pre-photocatalysis, adding dead plant biomass, and optimizing vegetation.

Pilot-scale evaluation of micropollutant abatements by conventional ozonation, UV/O3, and an electro-peroxone process.

The electro-peroxone (E-peroxone) process is an emerging ozone-based advanced oxidation process (AOP) that has shown large potential for micropollutant abatement in water treatment. To evaluate its performance under more realistic conditions of water treatment, a continuous-flow pilot E-peroxone system was developed and compared with conventional ozonation and a UV/O3 process for micropollutant abatements in various water matrices (groundwater, surface water, and secondary wastewater effluent) in this study. With a specific ozone dose of 1.5 mg O3/mg DOC, micropollutants that have high and moderate reactivity with ozone (O3) (diclofenac, naproxen, gemfibrozil, and bezafibrate) could be sufficiently abated (>90% abatement) in the various waters by all three processes. However, ozone-resistant micropollutants (ibuprofen, clofibric acid, and chloramphenicol) were abated only by ∼32-68%, 68-91%, and 73-90% during conventional ozonation of the selected groundwater, surface water, and secondary wastewater effluent, respectively. By electro-generating H2O2 or applying UV irradiation to enhance O3 transformation to •OH during ozonation, the E-peroxone and UV/O3 processes similarly enhanced the abatement efficiencies of ozone-resistant micropollutants by ∼15-43%, ∼5-15%, and ∼5-10% in the groundwater, surface water, and secondary wastewater effluent, respectively. In addition, the E-peroxone and UV/O3 processes significantly reduced bromate formation during the treatment of the three waters compared to conventional ozonation. Due to its higher efficiency, the E-peroxone process reduced ∼10-53% of the energy consumption required to abate the concentration of chloramphenicol (the most ozone-resistant micropollutant spiked in the waters) by 1 order of magnitude in the three waters compared to conventional ozonation. In contrast, the UV/O3 process consumed approximately 4-10 times higher energy than conventional ozonation. This pilot-scale study demonstrates that the E-peroxone process can provide a feasible, effective, and energy-efficient alternative for micropollutant abatement and bromate control in water and wastewater treatment.

Photostability Issues in Pharmaceutical Dosage Forms and Photostabilization.

Photodegradation is one of the major pathways of the degradation of drugs. Some therapeutic agents and excipients are highly sensitive to light and undergo significant degradation, challenging the quality and the stability of the final product. The adequate knowledge of photodegradation mechanisms and kinetics of photosensitive therapeutic entities or excipients is a pivotal aspect in the product development phase. Hence, various pharmaceutical regulatory agencies, across the world, mandated the industries to assess the photodegradation of pharmaceutical products from manufacturing stage till storage, as per the guidelines given in the International Conference on Harmonization (ICH). Recently, numerous formulation and/or manufacturing strategies has been investigated for preventing the photodegradation and enhancing the photostability of photolabile components in the pharmaceutical dosage forms. The primary focus of this review is to discuss various photodegradation mechanisms, rate kinetics, and the factors that influence the rate of photodegradation. We also discuss light-induced degradation of photosensitive lipids and polymers. We conclude with a brief note on different approaches to improve the photostability of photosensitive products.

Influence of process parameters on the effectiveness of photooxidative treatment of pharmaceuticals.

In this study, UV-C/H2O2 and UV-C/[Formula: see text] processes as photooxidative Advanced oxidation processes were applied for the treatment of seven pharmaceuticals, either already included in the Directive 2013/39/EU "watch list" (17α- ethynylestradiol, 17ß-estradiol) or with potential to be added in the near future due to environmental properties and increasing consumption (azithromycin, carbamazepine, dexamethasone, erythromycin and oxytetracycline). The influence of process parameters (pH, oxidant concentration and type) on the pharmaceuticals degradation was studied through employed response surface modelling approach. It was established that degradation obeys first-order kinetic regime regardless structural differences and over entire range of studied process parameters. The results revealed that the effectiveness of UV-C/H2O2 process is highly dependent on both initial pH and oxidant concentration. It was found that UV-C/[Formula: see text] process, exhibiting several times faster degradation of studied pharmaceuticals, is less sensitive to pH changes providing practical benefit to its utilization. The influence of water matrix on degradation kinetics of studied pharmaceuticals was studied through natural organic matter effects on single component and mixture systems.

A preformulation evaluation of a photosensitive surface active compound, explaining concentration dependent degradation.

A candidate drug within the cardiovascular area was identified during early research and evaluated for further development. The aim was to understand and explain the degradation mechanisms for the present compound. The stability of the active pharmaceutical ingredient (API) in solution and solid state was studied during different conditions. The bulk compound was exposed to elevated temperatures, increased relative humidity and stressed light conditions. Degradation of the drug in solutions was followed in the presence versus absence of ethylenediaminetetraacetic acid (EDTA), during aerobic versus anaerobic conditions, stored protected from light versus exposed to light and as a function of pH and concentration. It was possible to improve the stability by adding EDTA and completely abolish degradation by storing dissolved compound at anaerobic conditions. Solutions of API were stable between pH3 and 7, with some degradation at pH1, when stored protected from light and at 22°C, but degrade rapidly when exposed to ambient light conditions. The degradation products were identified by mass spectroscopy. Degradation schemes were drawn. There was concentration dependence in the degradation of dissolved drug when exposed to light, showing a titration behavior that concurred with the measured critical micelle/aggregation concentration (CMC/CAC) of the compound. The compound was stable in solution during the investigated time period, at concentrations above CMC/CAC, where the molecule was protected from photodegradation when the compound aggregated. Below CMC/CAC, a significant degradation of the API occurred. This may be a potential explanation why other surface active compounds show concentration dependent degradation. The photosensitivity was also observed for the neutral compound in crystalline and amorphous form, as well as for the crystalline chloride salt of the drug. However, the degradation of amorphous form was faster compared to crystalline material. No difference was observed in the degradation pattern between the neutral form of the compound and the salt form of the drug.

Removal of 30 active pharmaceutical ingredients in surface water under long-term artificial UV irradiation.

This study investigated the i) kinetics, and ii) proportion of photolysis of 30 relatively stable active pharmaceutical ingredients (APIs) during artificial UV irradiation for 28 d in ammonium acetate buffer, filtered and unfiltered river water. Buffer was included to control removal kinetics under stable pH conditions and without particulate matter. Dark controls were used to determine removal due to other processes than photolysis and calculate the proportion of photolysis of the total removal. The removal of each API in each matrix was determined using online solid phase extraction/liquid chromatography tandem mass spectrometry (online SPE/LC-MS/MS). Most APIs transformed during the 28 d of UV irradiation and the dark controls showed that photolysis was the major removal process for the majority of the APIs studied. The half-lives ranged from 6 h (amitriptyline) in unfiltered river water to 884 h (37 d, carbamazepine) in buffer. In unfiltered river water, the proportion of APIs with short half-lives (<48 h) was much higher (29%) than in the other matrices (4%), probably due to additional organic carbon, which could have promoted indirect photolysis. Furthermore, two APIs, memantine and fluconazole, were stable in all three matrices, while alprazolam was stable in buffer and unfiltered river water and four additional APIs were stable in buffer. Considering the relatively long-term UV-exposure, this study enabled the investigation of environmentally relevant half-lives in natural waters. Many APIs showed high persistence, which is environmentally concerning and emphasizes the importance of further studies on their environmental fate and effects.

A new efficient method of generating photoaffinity beads for drug target identification.

Affinity purification is one of the most prevalent methods for the target identification of small molecules. Preparation of an appropriate chemical for immobilization, however, is a tedious and time-consuming process. A decade ago, a photoreaction method for generating affinity beads was reported, where compounds are mixed with agarose beads carrying a photoreactive group (aryldiazirine) and then irradiated with ultraviolet light under dry conditions to form covalent attachment. Although the method has proven useful for identifying drug targets, the beads suffer from inefficient ligand incorporation and tend to shrink and aggregate, which can cause nonspecific binding and low reproducibility. We therefore decided to craft affinity beads free from these shortcomings without compromising the ease of preparation. We herein report a modified method; first, a compound of interest is mixed with a crosslinker having an activated ester and a photoreactive moiety on each end. This mixture is then dried in a glass tube and irradiated with ultraviolet light. Finally, the conjugates are dissolved and reacted with agarose beads with a primary amine. This protocol enabled us to immobilize compounds more efficiently (approximately 500-fold per bead compared to the original method) and generated beads without physical deterioration. We herein demonstrated that the new FK506-immobilized beads specifically isolated more FKBP12 than the original beads, thereby proving our method to be applicable to target identification experiments.

Impact of space environment on stability of medicines: Challenges and prospects.

To upkeep health of astronauts in a unique, isolated, and extreme environment of space is the primary goal for a successful space mission, hence, safe and efficacious medications are essential for the wellness of astronauts. Space medication has been challenged with problems related to efficacy. Along with altered physiology, one of the possible reasons could be instability of space medications in the presence of harsh spaceflight environmental conditions. Altered physical and chemical stability can result in reduced potency which can result in reduced efficacy. Right now, medicines from the International Space Station are replaced before their expiration. But, for longer duration missions to Mars or any other asteroid, there will not be any chance of replacement of medicines. Hence, it is desired that medicines maintain the shelf-life throughout the space mission. Stability of medicines used for short term or long term space missions cannot be judged by drug stability guidelines based on terrestrial environmental factors. Unique environmental conditions related to spaceflight include microgravity, excessive vibration, hard vacuum, humidity variation, temperature differences and excessive radiation, which may cause instability of medicines. This write-up provides a review of the problem and countermeasure approaches for pharmaceuticals exposed to the space environment. The first part of the article discusses thought processes behind outlining of International Conference on Harmonization drug stability guidelines, Q1A (R2) and Q1B, and its acceptance limits for accelerated stability study. The second part of the article describes the difference in the radiation environment of deep space compared to radiation environment inside the space shuttle based on penetration power of different types of radiation. In the third part of the article, various promising approaches are listed which can be used for assurance of space medicine stability. One of the approaches is the use of ground-based space simulation analogues and statistical treatment to data to calculate failure rate of drugs and probabilistic risk assessment. Another approach is to innovate storage and packaging technology using radiation harden polymer or using cryogenic temperatures.

Decomposition of Iodinated Pharmaceuticals by UV-254 nm-assisted Advanced Oxidation Processes.

Iodinated pharmaceuticals, thyroxine (a thyroid hormone) and diatrizoate (an iodinated X-ray contrast medium), are among the most prescribed active pharmaceutical ingredients. Both of them have been reported to potentially disrupt thyroid homeostasis even at very low concentrations. In this study, UV-254 nm-based photolysis and photochemical processes, i.e., UV only, UV/H2O2, and UV/S2O82-, were evaluated for the destruction of these two pharmaceuticals. Approximately 40% of 0.5µM thyroxine or diatrizoate was degraded through direct photolysis at UV fluence of 160mJcm-2, probably resulting from the photosensitive cleavage of C-I bonds. While the addition of H2O2 only accelerated the degradation efficiency to a low degree, the destruction rates of both chemicals were significantly enhanced in the UV/S2O82- system, suggesting the potential vulnerability of the iodinated chemicals toward UV/S2O82- treatment. Such efficient destruction also occurred in the presence of radical scavengers when biologically treated wastewater samples were used as reaction matrices. The effects of initial oxidant concentrations, solution pH, as well as the presence of natural organic matter (humic acid or fulvic acid) and alkalinity were also investigated in this study. These results provide insights for the removal of iodinated pharmaceuticals in water and/or wastewater using UV-based photochemical processes.

High throughput screening of photocatalytic conversion of pharmaceutical contaminants in water.

The susceptibility for photon-induced degradation of over 800 pharmaceutical compounds present in the LOPAC1280 library, was analyzed by UV/Vis spectroscopy in the absence or presence of TiO2 P25 in water. In general, few compounds were effectively degraded in the absence of the TiO2 photocatalyst (3% of all compounds tested), while in the presence of TiO2, the majority of compounds was converted, often to a large degree. Differences in degree of degradation are evaluated on the basis of molecular weight, as well as the chemical nature of the drug compounds (functional groups and pharmacological classes). In general, if the molecular weight increases, the degradation efficacy decreases. Relatively high degrees of conversion can be achieved for (relatively small) molecules with functional groups such as aldehydes, alcohols, ketones and nitriles. A low degree of conversion was observed for compounds composed of conjugated aromatic systems. Trends in degradation efficacy on the basis of pharmacological class, e.g. comparing hormones and opioids, are not obvious.

Assessment of light stability of drugs in blood and plasma.

AIM: A procedure was developed for the assessment of photochemical stability of drugs in blood and plasma under standardized conditions. The procedure avoids a variable outcome of photochemical stability experiments and tests relevant worst case conditions so that unnecessary light protection is avoided. Results/methodology: Blood and plasma were spiked with a mixture of drugs and incubated in a Suntest CPS(+), in the laboratory on the bench and near the window on a sunny summer day. The results were compared. DISCUSSION/CONCLUSION: No protection from light, limited protection from light and full protection from light are advised for drugs that are stable in plasma in the Suntest CPS(+) at 250 W/m(2) for at least 30 min, for 5-30 min and for <5 min, respectively.

Adsorption and photocatalytic degradation of pharmaceuticals and pesticides by carbon doped-TiO2 coated on zeolites under solar light irradiation.

To evaluate the performance of zeolite-supported carbon-doped TiO(2) composite catalysts toward target pollutants under solar light irradiation, the adsorption and photocatalytic degradation of 18 pharmaceuticals and pesticides with distinguishing features (molecular size and volume, and photolysis) were investigated using mordenite zeolites with SiO(2)/Al(2)O(3) ratios of 18 and 240. Different quantities of carbon-doped TiO(2) were coated on the zeolites, and then the finished composite catalysts were tested in demineralized, surface, and hospital wastewater samples, respectively. The composite photocatalysts were characterized by X-ray diffraction, field emission scanning electron microscopy, and surface area and porosity analyses. Results showed that a dispersed layer of carbon-doped TiO(2) is formed on the zeolite surface; this layer blocks the micropores of zeolites and reduces their surface area. However, these reductions did not significantly affect adsorption onto the zeolites. Our results demonstrated that zeolite-supported carbon-doped TiO(2) systems can effectively degrade 18 pharmaceuticals and pesticides in demineralized water under natural and simulated solar light irradiation. In surface and hospital wastewaters, zeolite-supported carbon-doped TiO(2) systems present excellent anti-interference capability against radical scavengers and competitive organics for pollutants removal, and higher pollutants adsorption on zeolites evidently enhances the removal rate of target pollutants in surface and hospital wastewater samples with a complicated matrix.

Assessing the potential of pharmaceuticals and their transformation products to cause mutagenic effects: Implications for gene expression profiling.

The selection and prioritization of pharmaceuticals and their transformation products for evaluating effects on the environment and human health is a challenging task. One common approach is based on compounds (e.g., mixture composition, concentrations), and another on biology (e.g., relevant endpoint, biological organizational level). Both of these approaches often resemble a Lernaean Hydra-they can create more questions than answers. The present study embraces this complexity, providing an integrated approach toward assessing the potential effects of transformation products of pharmaceuticals by means of mutagenicity, estrogenicity, and differences in the gene expression profiles. Mutagenicity using the tk kinase assay was applied to assess a list of 11 priority pharmaceuticals, namely, atenolol, azithromycin, carbamazepine, diclofenac, ibuprofen, erythromycin, metoprolol, ofloxacin, propranolol, sulfamethoxazole, and trimethoprim. The most mutagenic compounds were found to be ß-blockers. In parallel, the photolabile pharmaceuticals were assessed for their mixture effects on mutagenicity (tk assay), estrogenicity (T47D- KBluc assay), and gene expression (microarrays). Interestingly, the mixtures were mutagenic at the µg/L level, indicating a synergistic effect. None of the photolysed mixtures were statistically significantly estrogenic. Gene expression profiling revealed effects related mainly to certain pathways, those of the p53 gene, mitogen-activated protein kinase, alanine, aspartate, and glutamate metabolism, and translation-related (spliceosome). Fourteen phototransformation products are proposed based on the m/z values found through ultra-performance liquid chromatography-tandem mass spectrometry analysis. The transformation routes of the photolysed mixtures indicate a strong similarity with those obtained for each pharmaceutical separately. This finding reinforces the view that transformation products are to be expected in naturally occurring mixtures. Environ Toxicol Chem 2016;35:2753-2764. © 2016 SETAC.