Pharmaceuticals (PhCs) are organic contaminants that have been detected in wastewater, surface water, and soils throughout the world. The presence of 10 commonly used PhCs in Spain (azithromycin, benzylpenicillin, citalopram, fluconazole, fluoxetine, ibuprofen, irbesartan, olanzapine, telmisartan, and venlafaxine) was analysed at four wastewater treatment plants, and the changes in their concentrations during treatment were assessed. Although certain some PhCs were degraded in the treated water, their presence in sewage sludge increased in all cases. The sewage sludge was composted using rice straw to degrade the PhCs, and the composting efficiency was modified by changes in the relative C/N ratio of the composting blend. Using a simple microbiological culture process for enrichment, 11 different strains of microorganisms that degraded specific PhCs were identified. Ibuprofen and azithromycin were metabolized by one and four strains, respectively, and both PhCs were used as a carbon source; in addition, six strains used irbesartan as a nitrogen source.

The ATP-binding cassette transporter ABCG2 (BCRP and MXR) is involved in the absorption, distribution, and elimination of numerous drugs. Thus, drugs that are able to reduce the activity of ABCG2, e.g., antihypertensive AT1 receptor antagonists (ARBs), may cause drug-drug interactions and compromise drug safety and efficacy. In addition, genetic variability within the ABCG2 gene may influence the ability of the transporter to interact with ARBs. Thus, the aim of this study was to characterize the ARB-ABCG2 interaction in the light of naturally occurring variations (F489L, R482G) or amino acid substitutions with in silico-predicted relevance for the ARB-ABCG2 interaction (Y469A; M483F; Y570A). For this purpose, ABCG2 variants were expressed in HEK293 cells and the impact of ARBs on ABCG2 activity was studied in vitro using the pheophorbide A (PhA) efflux assay. First, we demonstrated that both the F489L and the Y469A substitution, respectively, reduced ABCG2 protein levels in these cells. Moreover, both substitutions enhanced the inhibitory effect of candesartan cilexetil, irbesartan, losartan, and telmisartan on ABCG2-mediated PhA efflux, whereas the R482G substitution blunted the inhibitory effect of candesartan cilexetil and telmisartan in this regard. In contrast, the ARB-ABCG2 interaction was not altered in cells expressing either the M483F or the Y570A variant, respectively. In conclusion, our data indicate that the third transmembrane helix and adjacent regions of ABCG2 may be of major importance for the interaction of ARBs with the ABC transporter. Moreover, we conclude from our data that individuals carrying the F489L polymorphism may be at increased risk of developing ABCG2-related drug-drug interactions in multi-drug regimens involving ARBs.

To assess the stability of Irbesartan under stress conditions, and identify the degradation products, it was subjected to hydrolytic and oxidative stress, according to ICH guideline Q1A (R2). The drug showed degradation only in basic conditions, while it was stable to other stress conditions. Three degradation products were formed, which were separated on a C-8 column employing prep HPLC using gradient elution. The structures were established by extensive 1D and 2D NMR spectroscopic studies and mass spectra. The products were identified as (2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methanamine (DP-1), N-((2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)pentanamide (DP-2) and N-((2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1-pentanamidocyclopentane-1-carboxamide (DP-3). One of the three, DP-1, was reported earlier. However, its structure has not been elucidated by NMR. The other two degradants are novel and are being reported here for the first time.

Poor drug adherence in hypertensive patients can lead to treatment failure and increased cardiovascular morbidity, as well as increased costs to society. An analytical method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MSMS) was developed and validated for use in routine therapeutic drug monitoring (TDM). The method includes 21 antihypertensive drugs or active metabolites from the groups beta blockers (n=5), calcium antagonists (n=5), angiotensin II receptor antagonists (n=4), angiotensin converting enzyme (ACE) inhibitors (n=3) and diuretics (n = 3), in addition to one α1-selective alpha blocker.

The calibration of two passive samplers for the determination of 20 emerging organic compounds in seawater is described in this work: i) a new version of polar organic chemical integrative sampler (POCIS) containing 100 mg of mixed-mode anion exchanger (Strata X-AW) and 100 mg of polymeric HLB (Plexa) sorbent materials and using a highly porous Nylon membrane (30-μm pore size) and ii) polyethersulfone (PES) hollow fibre. Among the studied contaminants, herbicides, hormones, life style products (stimulants and artificial sweeteners), industrial chemicals (corrosion inhibitor and fluorinated compounds), personal care products and several pharmaceuticals were included. In the case of POCIS, both the sorbents and the Nylon membranes were extracted and analysed independently. The calibration set up consisted on a continuous-flow tank that was fed with a continuous flow of seawater (2 L/h) and a stock mixture of contaminants (20 mL/h), assuring a nominal concentration of ~ 600 ng/L (each analyte) in the tank. The uptake was linear in POCIS sorbent and Nylon membranes but exponential for PES hollow fibres. Furthermore, the highest sampling rates (Rs) values were obtained in POCIS sorbent (between 2.7 for acetaminophen and 491 mL/day for perfluoro-n-octanoic acid, PFOA) followed by Nylon membranes (between 3.6 for OBT and 50 mL/day for telmisartan) and the lowest were those from PES fibres (between 1.7 for bezafibrate and 157 mL/day for butylparaben). Additionally, five deuterated compounds ([2H5]-atrazine, [2H3]-amitriptyline, [2H7]-irbesartan, [2H3]-ketoprofen and [2H9]-progesterone) were studied as candidates for performance reference compounds (PRCs) in both POCIS and PES, and though [2H5]-atrazine, [2H9]-progesterone and [2H3]-amitriptyline showed acceptable results in the case of POCIS, only [2H5]-atrazine provided a good validation. In the case of PES fibres, the PRC corrections did not provide acceptable results due to a low dissipation of the PRCs. Finally, POCIS were deployed in two sites of the low part of the estuary of Bilbao (northern Spain) from where water samples were also taken and analysed. As a result, in addition to the overall good agreement between the passive and active samplings, passive samplers allowed the determination of several compounds that were below the detection limits in the active sampling.

Doxorubicin (DOX) is an anthracycline antibiotic that is used frequently for treatment of various types of malignancies. Hepatotoxicity is one of the serious complications of DOX. The aim of this study was to explore the effect of different doses of irbesartan on doxorubicin-induced hepatotoxicity in mice. Sixty male BALB/c mice were divided into six equal groups as follows: Control group; DOX group; Irbesartan (Small dose) group; Irbesartan (Large dose) group; DOX + Irbesartan (Small dose) group and DOX + Irbesartan (Large dose) group. Liver weight/body weight ratio, food intake, serum albumin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and total bilirubin were measured. Also, tissue antioxidant enzymes, transforming growth factor beta 1 (TGF-β1), nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 (Nrf2/HO-1) content, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and signal transducer and activator of transcription-3 (STAT-3) were assessed. Parts of the hepatic tissues were subjected to histopathological examination. Irbesartan administration to DOX-treated mice induced significant decrease in serum ALT, AST, ALP, total bilirubin, tissue TGF-β1, TNF-α, IL-6 and liver weight/body weight ratio associated with significant increase in food intake, serum albumin, tissue Nrf2/HO-1 content, STAT-3 and antioxidant enzymes and significant improvement in the histopathological picture compared to DOX group. This improvement was significant with DOX + Irbesartan large dose compared to DOX + Irbesartan small dose. In conclusion, irbesartan - in a dose-dependent manner - might represent a promising hope for cancer patients to ameliorate DOX-induced hepatotoxicity.

In vitro-in vivo extrapolation based on uptake clearance determined in human hepatocytes has been used to predict in vivo hepatic clearance of organic anion transporting polypeptide (OATP) substrates. This study evaluated the relative activity factor (RAF) approach to extrapolate active uptake clearance in transporter-transfected cell systems (CLuptake) to that in human hepatocyte suspensions (PSinf,act). RAF values for OATP1B1 and OATP1B3 were determined in two batches of cryopreserved human hepatocytes using estrone-3-sulfate and cholecystokinin octapeptide as reference substrates, respectively. Fourteen OATP1B substrate drugs selected (atorvastatin, bosentan, cerivastatin, fexofenadine, fluvastatin, glibenclamide, irbesartan, nateglinide, pitavastatin, pravastatin, rosuvastatin, telmisartan, torasemide, and valsartan) showed temperature-dependent uptake in human hepatocytes. In transporter-transfected cells, OATP1B1- and OATP1B3-mediated uptake was observed in all compounds except for telmisartan. RAF-based net CLuptake was mainly accounted for by OATP1B1 (72.3-99.7%) and fell within the 3-fold of PSinf,act observed in human hepatocytes in 11 out of 13 compounds (excluding telmisartan). This study demonstrated that the RAF approach provides a quantitative index of OATP1B1- and OATP1B3-mediated PSinf,act in human hepatocytes, which will facilitate the optimization of the pharmacokinetic properties of OATP1B substrates at nonclinical stages of drug development.

The occurrence of illicit drugs (cocaine, opioids, amphetamines and cannabis derivatives), some of their metabolites and 48 pharmaceuticals, was investigated in pool and source waters in ten Italian indoor swimming pools. The samples were analyzed by highperformance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), after solid phase extraction (SPE). Cocaine and its metabolites were found in nine swimming pools, at concentrations from 0.3 to 4.2 ng/L for cocaine, 1.1 to 48.7 ng/L for norcocaine, 0.7 to 21.4 ng/L for benzoylecgonine and 0.1 to 7.3 ng/L for norbenzoylecgonine. Opioids, amphetamines and cannabis derivatives were never detected. The most frequent pharmaceuticals were anti-inflammatory drugs: ibuprofen was found in all the pool waters, with a maximum 197 ng/L and ketoprofen was detected in 9/10 samples (maximum 127 ng/L). Among anticonvulsants, carbamazepine and its metabolite, 10,11-dihydro-10,11dihydroxycarbamazepine, were frequent in swimming pool water (8/10 samples) at concentrations up to 62 ng/L. The cardiovascular drug valsartan was also found frequently (8/10 samples), but at lower concentrations (up to 9 ng/L). Other pharmaceuticals were detected occasionally and at lower concentrations (atenolol, enalapril, paracetamol, hydroclorothiazide, irbesartan and dehydro-erythromycin). Carbamazepine, irbesartan and dehydroerythromycin were detected at very low levels (up to 5 ng/L) in only one of the four source water samples. A quantitative risk assessment showed that the health risk for humans to these substance in swimming pool waters was generally negligible, even for vulnerable subpopulations such as children and adolescents.