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  • The in vitro enantioselective metabolism of pesticides


    The in vitro enantioselective metabolism of pesticides has been investigated by employing human liver microsomes, which are a reliable resource to perform MCL enantioselective risk assessment in humans (Carrão et al., 2019; de Albuquerque et al., 2018, 2016; Yao et al., 2016). The enantioselective metabolism of a racemic MCL mixture has already been evaluated in vitro by using rat liver microsomes (Yan et al., 2014) and rat hepatocytes (Wang et al., 2015). Yan et al. reported significant metabolism differences between MCL enantiomers: the (−)-MCL half-life was more than 10-fold higher than the (+)-MCL half-life, which suggested that rat liver microsomes preferentially degraded (+)-MCL (Yan et al., 2014). Wang et al. also reported significant differences after incubation for 24 h, the (−)-MCL concentration was 1.6 times higher than the (+)-MCL concentration, which suggested that rat hepatocytes preferentially degraded (+)-MCL (Wang et al., 2015). Hao et al. evaluated the enantioselective MCL absorption, distribution, and metabolism in vivo following a single-dose in rats (Hao et al., 2018). Their results suggested preferential (−)-MCL enrichment in the liver, kidney, heart, lung, and testis (Hao et al., 2018). Besides that, (+)-MCL was converted into (−)-MCL in the liver and kidney after 6 h (Hao et al., 2018). Furthermore, the racemic mixture and the individual enantiomers differed both in terms of enrichment and degradation, which suggested enantiomer-specific bioaccumulation (Hao et al., 2018). Finally, five chiral metabolites were detected, and the metabolite pathway was proposed (Hao et al., 2018). In this scenario, the present work aimed to evaluate the enantioselective MCL metabolism and CYP450 inhibitory potential in vitro by investigating a MCL racemic mixture and its individual enantiomers in a human model. For the first time, the enzymatic kinetic parameters of in vitro MCL metabolism have been characterized, the main CYP450 sphingosine responsible for MCL metabolism have been determined, the in vivo toxicokinetic parameters have been predicted, and the MCL inhibitory potential over the main CYP450 enzymes has been investigated to predict pesticide-drug interactions.
    Materials and methods
    Results and discussion
    Conclusion The enantioselective MCL metabolism by CYP450 enzymes present in human liver microsomes has been evaluated for the first time; rac-MCL and the isolated enantiomers, S-(+)-MCL and R-(−)-MCL have been employed. The MCL enantiomers have significantly different metabolism: CYP450 enzymes only metabolize S-(+)-MCL was metabolized by human. The VMAX and KMapp values obtained for the incubation of isolated S-(+)-MCL are approximately 4.6-fold and 1.9-fold higher than the VMAX and KMapp values obtained for rac-MCL respectively. The predicted in vivo toxicokinetic parameters indicate that S-(+)-myclobutanil may be preferentially eliminated by the liver and may suffer the first-pass metabolism effect. However, because CYP450 does not metabolize R-(−)-myclobutanil, the latter enantiomer may reach the systemic circulation, thereby sphingosine remaining longer in the human body and possibly causing toxic effects. Although there are differences in the metabolism of myclobutanil enantiomers, in vitro inhibition studies do not show significant enantioselective differences. The studies suggest that myclobutanil can inhibit CYP2D6 and CYP2C9 moderately and CYP3A and CYP2C19 strongly. These results provide useful scientific information for myclobutanil risk assessment in humans.
    Introduction Aspirin and ibuprofen are among the most widely used non-steroidal anti- inflammatory drugs (NSAIDs) in the world. Aspirin, also called acetylsalicylic acid, is used to treat certain types of pain, fever and inflammation, including neuropathic pain [1], migraine and episodic tension-type headache [2] and rheumatoid arthritis [3,4]. Long-term aspirin use prevents heart attacks and strokes [5]. For example, administration of 75–1500 mg/d of aspirin has substantial benefits for the prevention of myocardial infarction [6]. Furthermore, aspirin reduces the risk of colorectal cancer [7], breast cancer [8] and endometrial cancer [9]. Ibuprofen [2-(4-isobutylphenyl)- propionic acid], had effects similar to those of aspirin, but had better effect in treatment of fever, pain, and inflammation, including post immunization fever, painful menstruation, osteoarthritis and headaches [10]. Ibuprofen can also be used to close patent ductus arteriosus [11] and to enhance pyrazinamide treatment of murine tuberculosis [12].