RESUMEN
Edaravone (EDA), an antioxidant drug approved for the treatment of ischemic stroke and amyotrophic lateral sclerosis, was recently proposed as a remyelinating candidate for the treatment of multiple sclerosis. Here, we synthesized twelve EDA analogues 2b-4c showing three substitution patterns A-C, searching for improved remyelinating agents and putative molecular targets responsible for their regenerative activity. We profiled them in three primary assays to determine their stimulation of oligodendrocyte progenitor cell metabolism (tetrazolium MTT assay), their antioxidant potential (2,2-diphenyl-1-picrylhydrazyl-DPPH assay) and to predict their bioavailability (virtual ADME profile). Active 4'-carboxylate 2b, 4'-ester 2c and N1-carbamate-4'-ester 4a were further characterized, justifying their in vitro effects and selecting 4a as a putative EDA 1 prodrug suitable for in vivo testing.
Asunto(s)
Esclerosis Amiotrófica Lateral , Antioxidantes , Humanos , Edaravona/farmacología , Edaravona/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Estrés Oxidativo , Ésteres/farmacologíaRESUMEN
Polycyclic aromatic hydrocarbons (PAHs) are generated by incomplete combustion of organic matter. They have health effects in multiple organs and can cause lung, skin, and bladder cancers in humans. Although data regarding their toxicity is available, information on the absorption, distribution, metabolism, and excretion of PAHs in humans is very limited. In the present study, deuterium-labeled naphthalene (Nap), fluorene (Flu), phenanthrene (Phe), and pyrene (Pyr) were orally administered as a single dose (0.02-0.04 mg/kg) to eight healthy adults. Both serum and urine samples were monitored for 72 h after the exposure. Parent compounds and PAH metabolites (monohydroxy-PAHs; OH-PAHs) were measured by headspace-solid phase microextraction coupled with gas chromatography-mass spectrometry and high-performance liquid chromatography-tandem mass spectrometry, respectively. Based on the time-concentration profiles in serum and urine, non-compartmental analysis was performed, and two-compartment models were constructed and validated for each PAH. Subsequently, all of the parent compounds were rapidly absorbed (Tmax: 0.25 to 1.50 h) after oral administration and excreted in urine with a biological half-life (T1/2) of 1.01 to 2.99 h. The fractional urinary excretion (Fue) of OH-PAHs ranged from 0.07 % to 11.3 %; their T1/2 values ranged from 3.4 to 11.0 h. The two-compartment models successfully described the toxicokinetic characteristics of each PAH and its metabolites. Fue and the two-compartment models could be useful tools for exposure simulation or dose-reconstruction of PAHs. The results of this study will provide useful information for interpreting biomonitoring data of PAHs.
Asunto(s)
Fenantrenos , Hidrocarburos Policíclicos Aromáticos , Adulto , Humanos , Toxicocinética , Pirenos/análisis , Hidrocarburos Policíclicos Aromáticos/análisis , Fenantrenos/toxicidad , Fenantrenos/análisis , Naftalenos/toxicidad , Naftalenos/análisis , Fluorenos , Biomarcadores/orina , Monitoreo del Ambiente/métodosRESUMEN
The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. FTR was administered with and without ritonavir (RTV), a protease inhibitor previously shown to boost TMR exposures. In vitro studies were also used to identify the enzymes responsible for the metabolism of TMR.Total recovery of the administered dose ranged from 78% to 89%. Approximately 44% to 58% of the dose was excreted in urine, 20%-36% in faeces, and 5% in bile, as TMR and metabolites. RTV had no effect on the recovery of radioactivity in any matrix.Compared to FTR alone, pre-treatment of subjects with RTV increased the exposure of TMR by â¼66% and reduced the exposure of plasma total radioactivity by â¼68%.The major route of TMR elimination was through biotransformation. TMR, M28 (N-dealkylation), and M4 (amide hydrolysis) were the major circulating components in plasma. Pre-treatment with RTV increased the amount of TMR present, decreased the amount of circulating M28, and M4 was unchanged.CYP3A4 metabolism accounted for 21% of the dose, forming multiple oxidative metabolites. This pathway was inhibited by coadministration of RTV.
Asunto(s)
Fármacos Anti-VIH , Profármacos , Administración Oral , Amidas , Fármacos Anti-VIH/farmacocinética , Citocromo P-450 CYP3A , Heces , Voluntarios Sanos , Humanos , Masculino , Organofosfatos , Piperazinas , Inhibidores de Proteasas , Ritonavir/farmacocinéticaRESUMEN
Viloxazine is currently being developed as a treatment for attention deficit/hyperactivity disorder (ADHD). The aim of these studies is to update the understanding of the rat and human metabolism and the in vitro drug-drug interaction profile of viloxazine to a degree where it meets current regulatory standards for such investigations. In vivo absorption-distribution-metabolism-excretion (ADME) studies demonstrated that in humans 5-hydroxylation followed by glucuronidation is the major metabolic route. This route was also seen as a minor route in rats where the major route is O-deethylation with subsequent sulfation. In humans, the 5-hydoxylation pathway is mediated by CYP2D6. An estimate for the fraction of the metabolism via this pathway suggests a PM/EM difference of <2-fold, making it highly unlikely that this will be an issue of clinical significance. Viloxazine forms a unique N-carbamoyl glucuronide in humans. The chemical reactivity characteristics of this metabolite are similar to stable glucuronide conjugates and dissimilar from acyl glucuronides; therefore, it is regarded as a stable Phase II conjugate. In vitro drug-drug interaction (DDI) testing indicates that viloxazine is not a significant inhibitor or inducer of CYPs and transporters with the exception of CYP1A2.
Asunto(s)
Antidepresivos de Segunda Generación/farmacología , Interacciones Farmacológicas , Viloxazina/farmacología , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2D6/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Glucurónidos/metabolismo , Humanos , Microsomas Hepáticos/metabolismoRESUMEN
Biological activities of flavonoids in vivo ultimately depend on the systemic bioavailability of the aglycones and their metabolites. We aimed to develop physiologically based kinetic (PBK) models to predict plasma concentrations of the flavonoid quercetin and its metabolites in individual human subjects and to define species differences compared with male rat. The human models were developed based on in vitro metabolic parameters derived from incubations with pooled and 20 individual human tissue fractions and by fitting kinetic parameters to available in vivo data. The outcomes obtained were compared to a previously developed model for quercetin and its metabolites formation in male rat. Quercetin-3'-O-glucuronide was predicted to be the major circulating metabolite in 19 out of 20 individuals, while in male rat di- and tri-conjugates of quercetin containing a glucuronic acid, sulfate and/or methyl moieties are the major metabolites. Significant species differences occur in major circulating metabolites of quercetin suggesting that rat is not an adequate model to study effects of quercetin in man. The defined PBK models can be used to guide the experimental design of in vitro experiments with flavonoids, especially to better take into account the relevance of metabolism and the contribution of metabolites to the biological activity in humans.
Asunto(s)
Modelos Biológicos , Quercetina/sangre , Quercetina/farmacocinética , Adolescente , Adulto , Anciano , Animales , Femenino , Humanos , Insectos , Intestino Delgado/efectos de los fármacos , Intestino Delgado/metabolismo , Cinética , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Quercetina/análogos & derivados , Quercetina/metabolismo , Ratas , Especificidad de la Especie , Adulto JovenRESUMEN
Biological activities of flavonoids in vivo are ultimately dependent on the systemic bioavailability of the aglycones as well as their metabolites. In the present study, a physiologically based kinetic (PBK) model was developed to predict plasma concentrations of the flavonoid quercetin and its metabolites and to tentatively identify the regiospecificity of the major circulating metabolites. The model was developed based on in vitro metabolic parameters and by fitting kinetic parameters to literature available in vivo data. Both exposure to quercetin aglycone and to quercetin-4'-O-glucoside, for which in vivo data were available, were simulated. The predicted plasma concentrations of different metabolites adequately matched literature reported plasma concentrations of these metabolites in rats exposed to 4'-O-glucoside. The bioavailability of aglycone was predicted to be very low ranging from 0.004%-0.1% at different oral doses of quercetin or quercetin-4'-O-glucoside. Glucuronidation was a crucial pathway that limited the bioavailability of the aglycone, with 95-99% of the dose being converted to monoglucuronides within 1.5-2.5h at different dose levels ranging from 0.1 to 50mg/kg bw quercetin or quercetin-4'-O-glucoside. The fast metabolic conversion to monoglucuronides allowed these metabolites to further conjugate to di- and tri-conjugates. The regiospecificity of major circulating metabolites was observed to be dose-dependent. As we still lack in vivo kinetic data for many flavonoids, the developed model has a great potential to be used as a platform to build PBK models for other flavonoids as well as to predict the kinetics of flavonoids in humans.