## 4 Discussion
In general, fungi can use two systems to degrade pharmaceutical compounds; the first is the system related to lignin-modifying (LME) extracellular enzymes (mainly associated with basidiomycetes), and secondly, the detoxification system mediated by CYP450 enzymes. The latter were responsible for the elimination of xenobiotics in fungi lacking an extracellular ligninolytic system [3]. Some aspergillus can remove pharmaceutical compounds under saline conditions [27], and are mediated by LME (esterases, lacases and peroxididases). It has been shown that in most cases both systems act together, regardless of the type of fungus. We reported the importance of CYP enzymes in the biodegradation of DFC in this model [19]. In this work, the obtained results also suggest that this type of enzyme could be implicated in the formation of hydroxylated metabolites (found in the biodegradation of all drugs) as part of the global mechanism. This result, as well as the metabolites observed in the supernatant of the bioreactor inoculated with _P. oxalicum_ in the biodegradation of the complex mix, was consistent with those previously reported [10; 13; 14; 28]. In the bioreactor scaling process, _P. oxalicum_ showed higher efficiency in degradation than at flask scale, evidencing a possible and efficient scaling process. Few studies have focused on the degradation of pharmaceutical compounds at the bioreactor scale with ascomycetes fungi, however, the use of white-rot fungi has been extensively explored. For example, the basidiomycete _T. versicolor_ has been studied for the elimination of carbamazepine in air-bed fluidized bioreactors, in both continuous and discontinuous mode. This ligninolytic fungus removes 200 ug/L in 3 days in continuous mode and 25 days in discontinuous mode [29]. The latter result evidences the high efficiency of the system reaching the total elimination in 8 days of treatment in the same discontinuous mode. Furthermore, another study of T. versicolor in a bioreactor with hospital wastewater showed that diclofenac, ibuprofen, naproxen, paracetamol and phenazone in the form of a complex mixture (initial amount of drugs of 1475 ug/L) were eliminated with an efficacy of 80% after 24 h [17; 30]. It was reported that the main intracellular pathway for the metabolism of drugs in fungi is by the action of CYP450 enzymes. They are a large group of enzymes that are related to many cellular processes, where certain clans have been associated in the degradation of aromatics compounds by hydroxylation of the main ring [3]. In this work, the presence of various mono-, and di-hydroxylated compounds was evidenced (i.e., 3-hydroxy-acetaminophen; 4, 5-dihydroxy-diclofenac; 2-[3-(3,4-dihydroxybenzoyl)] phenyl]-propanoic acid) as the result of the CYP450 enzymes action. The presence of these hydroxylated derivatives has already been discussed previously in works that involve the degradation of NSAIDs by the action of fungi. For example, [PERSON] et al. (2009; 2010a; 2010b) describe the same type of metabolites in the degradation of NPX, IBU and KET by the use of _T. versicolor_ under different conditions [10; 13; 14]. It was demonstrated that _T. versicolor_ possess a versatile system for the degradation of drugs using extracellular (Laccesses) and intracellular (CYP450) enzymes [31]. In the case of _P. oxalicum_, only the CYP450 enzymes seem to participate in the degradation of NSAIDs [19]. Ketoprofen was the most recalcitrant drug and its metabolites accumulated in the medium during biodegradation. This could be the cause of the high toxicity of the medium evaluated, and is suggested by the increase in the EC50 values from the Microtax assay. However, the drug was not toxic to _L. sativum_ at a dilution of 0.1; denoting that the vegetal tissues have a greater tolerance to the effluent composition. This suggests that it would be necessary to evaluate the process under more realistic concentrations of NSAIDs and analgesic and also go deeper into the acute toxicity.