The stereospecificity of flobufen metabolism in isolated guinea pig hepatocytes

Král, Radim; Skálová, Lenka; Szotáková, Barbora; Velík, J.; Schroterova, Ladislava; Babú, Yogeeta N.; Wsól, Vladimı́r

doi:10.1186/1471-2210-3-5

Cited by 4 publications

(1 citation statement)

References 19 publications

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“…Only hepatocytes with viability >75% were used for the experiments. Isolated hepatocytes suspended in culture medium [ 18 , 19 ] were seeded into 96 well plates precoated with collagen, with the density of the hepatocytes at 50 000 cells per well. After four hours of pre-incubation in a humid atmosphere with 5% of CO 2 at 37 °C, the hepatocytes were treated with culture medium containing SRT (0, 1, 10, 25, 50, 75, 100 µM pre-dissolved in DMSO) and incubated for 24 h in the same conditions.…”

Section: Methodsmentioning

confidence: 99%

Sertraline as a new potential anthelmintic against Haemonchus contortus: toxicity, efficacy, and biotransformation

Zajíčková

Prchal

Navrátilová

et al. 2021

Vet Res

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Haemonchus contortus is a parasitic nematode of ruminants which causes significant losses to many farmers worldwide. Since the drugs currently in use for the treatment of haemonchosis are losing their effectiveness due to the drug-resistance of this nematode, a new or repurposed drug is highly needed. As the antipsychotic drug sertraline (SRT) has been shown to be effective against the parasitic nematodes Trichuris muris, Ancylostoma caninum and Schistosoma mansoni, the aim of the present study was to evaluate the possible effect of SRT on H. contortus. The potential hepatotoxicity of SRT was tested in sheep, a common H. contortus host. In addition, the main metabolic pathways of SRT in H. contortus and the ovine liver were identified. While no effect of SRT on H. contortus egg hatching was observed, SRT was found to significantly decrease the viability of H. contortus adults in drug-sensitive and resistant strains, with its effect comparable to the commonly used anthelmintics levamisole and monepantel. Moreover, SRT in anthelmintically active concentrations showed no toxicity to the ovine liver. Biotransformation of SRT in H. contortus was weak, with most of the drug remaining unmetabolized. Production of the main metabolite hydroxy-SRT did not differ significantly between strains. Other minor metabolites such as SRT-O-glucoside, dihydroxy-SRT, and SRT-ketone were also identified in H. contorts adults. Compared to H. contortus, the ovine liver metabolized SRT more extensively, mainly via desmethylation and glucuronidation. In conclusion, the potency of SRT against H. contortus was proven, and it should be tested further toward possible repurposing.

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Section: Methodsmentioning

confidence: 99%

Sertraline as a new potential anthelmintic against Haemonchus contortus: toxicity, efficacy, and biotransformation

Zajíčková

Prchal

Navrátilová

et al. 2021

Vet Res

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Stereospecificity of flobufen metabolism in guinea pigs in vitro and in vivo: Phase I of biotransformation

et al. 2003

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Flobufen (F) is an original nonsteroidal antiinflammatory drug that exists in two enantiomeric forms. Its biotransformation was investigated in male guinea pigs because of the similarities shown in a preliminary F metabolic study between guinea pig and man. Stereospecificity of the respective enzymes was studied in vitro, using microsomes and cytosol, and in vivo, in urine and feces. Rac-F, R-F, and S-F served as substrates. The amount of 4-dihydroflobufen stereoisomers (DHF) and other metabolites (M-17203 and UM-2) was determined by chiral HPLC using an R,R-ULMO column. It was observed that F reductases were distributed differently in microsomes and cytosol. The microsomal fraction showed higher activity and different stereospecificity in rac-F, R-F, and S-F reduction compared to cytosol. (2R;4S)-DHF was the principle metabolite in microsomes and (2S;4S)-DHF was the principle metabolite in cytosol. In vivo experiments revealed the excretion of a main metabolite UM-2 in addition to other metabolites M-17203 and DHF stereoisomers. UM-2 was predominantly excreted after S-F administration. Stereoselectivity of DHF stereoisomers excretion was different in urine and in feces. The absence of UM-2 and M-17203 in microsomes and cytosol and their presence in urine and feces showed that both could arise in some other extrahepatic tissue or cell compartment or that their formation depends on liver cell integrity.

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Pharmacokinetic study of benzoylmesaconine in rats using an enzyme immunoassay system

et al. 2006

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A highly sensitive enzyme immunoassay (EIA) system for quantitative determination of benzoylmesaconine (BM) in biological samples was developed. The sensitivity of an antiserum towards bgalactosidase (b-gal)-labeled antigen was in the range of 10 -1 -10 5 ng/ml of BM in rat serum. Under the same conditions, the antiserum had quite weak cross-reactivity with related alkaloids in the aconite tuber. The coefficients of variance (CV) of intra-and interday assays were 6.4 and 10.2%, and 3.4 and 14.8% in the presence of high and low concentrations, respectively, of BM in rat serum. The concentration versus time curve of BM after intravenous administration corresponded to a two-compartment model, and that after oral administration corresponded to a one-compartment model. Benzoylmesaconine was identified as two peaks in serum at 48 h after oral administration; consequently its area under the serum concentration-time curve (AUC 0-48 ) and mean residence time (MRT) values were significantly high. Hydrolysis by intestinal

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The stereospecificity of flobufen metabolism in isolated guinea pig hepatocytes

Cited by 4 publications

References 19 publications

Sertraline as a new potential anthelmintic against Haemonchus contortus: toxicity, efficacy, and biotransformation

Sertraline as a new potential anthelmintic against Haemonchus contortus: toxicity, efficacy, and biotransformation

Stereospecificity of flobufen metabolism in guinea pigs in vitro and in vivo: Phase I of biotransformation

Pharmacokinetic study of benzoylmesaconine in rats using an enzyme immunoassay system

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