Study of the Biotransformation of Benfluron Using the Isolated Perfused Rat Liver
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Abstract:
The isolated perfused rat liver method (IPRL) was used to find, isolate and identify further metabolites of Phase I and Phase II biotransformation of the potential cytostatic agent benfluron with special regard to the conjugation processes. Its pharmacokinetic profile during the perfusion was also estimated. The rat liver was isolated from the body and perfused in vitro using a recirculating perfusion system. Benfluron was added to the reservoir as a bolus in doses of 200, 100, 30 mg/kg of body weigh and 1 mg/perfusate volume and also as a continual infusion in a dose of 0.1 mg/min in separate series of experiments. The following metabolites formed during Phase I biotransformation were found in the perfusion liquid as well as in the bile: benfluron N-oxide, 9-hydroxy benfluron, demethylated 9-hydroxy benfluron, demethylated benfluron, and reduced benfluron. The major Phase II metabolite found in the bile samples was the glucuronide of 9-hydroxy benfluron. The pharmacokinetic profile of benfluron in IPRL indicated its main disposition and metabolic pathway, i.e. its rapid extraction from perfusate by the liver (t1/2 alpha = 3.76 min), 9-hydroxylation followed up O-glucuronidation and excretion to the bile. It was revealed that 12% of the total dose of the parent compound was excreted to the bile in the form of conjugates during the first hour of perfusion, 32% during 1.5 hour, and 70% during 2 hours after the administration of benfluron. The conjugates with glucuronic acid represented 96-98% of all metabolites found in the bile.Keywords:
Biotransformation
Glucuronide
Hydroxylation
Bolus (digestion)
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This chapter contains sections titled: Introduction Cytochrome P450-Dependent Steroid Hydroxylase Systems Native Microorganisms in Steroid Biotransformation 11α-Hydroxylation 11β-Hydroxylation 16α-Hydroxylation Conclusions Genetically Modified Microorganisms in Steroid Biotransformation Soluble Cytochromes P450 Membrane-Bound Cytochromes P450 Synopsis and Concluding Remarks References
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Flurbiprofen is a nonsteroidal anti-inflammatory drug used as a racemic mixture. Although glucuronidation is one of its elimination pathways, the role of UDP-glucuronosyltransferase (UGT) in this process remains to be investigated. Thus, the kinetics of the stereoselective glucuronidation of racemic (R,S)-flurbiprofen by recombinant UGT isozymes and human liver microsomes (HLMs) were investigated, and the major human UGT isozymes involved were identified. UGT1A1, 1A3, 1A9, 2B4, and 2B7 showed glucuronidation activity for both (R)- and (S)-glucuronide, with UGT2B7 possessing the highest activity. UGT2B7 formed the (R)-glucuronide at a rate 2.8-fold higher than that for (S)-glucuronide, whereas the other UGTs had similar formation rates. The glucuronidation of racemic flurbiprofen by HLMs also resulted in the formation of (R)-glucuronide as the dominant form, which occurred to a degree similar to that by recombinant UGT2B7 (2.1 versus 2.8). The formation of (R)-glucuronide correlated significantly with morphine 3-OH glucuronidation (r = 0.96, p < 0.0001), morphine 6-OH glucuronidation (r = 0.91, p < 0.0001), and 3′-azido-3′-deoxythymidine glucuronidation (r = 0.85, p < 0.0001), a reaction catalyzed mainly by UGT2B7, in individual HLMs. In addition, the formation of both glucuronides correlated significantly (r = 0.99, p < 0.0001). Mefenamic acid inhibited the formation of both (R)- and (S)-glucuronide in HLMs with similar IC50 values (2.0 and 1.7 μM, respectively), which are close to those in recombinant UGT2B7. In conclusion, these findings suggest that the formation of (R)- and (S)-glucuronide from racemic flurbiprofen is catalyzed by the same UGT isozyme, namely UGT2B7.
UGT2B7
Glucuronide
Glucuronosyltransferase
Flurbiprofen
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Biotransformation
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Biocatalysis
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Biotransformation
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Microbial transformation has been successfully applied in the production of steroid intermediates with therapeutic use and commercial value in pharmaceutical industry due to its high regio- and stereo-selectivity. As such, it is still important to screen microbial strains with novel activity or more efficient abilities in the development of the commercial steroid industry. Biotransformation of steroid: 16α, 17α-epoxyprogesterone (1). using
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