glucuronidation
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Pochopení cest metabolizace inhibitorů SGLT2 (gliflozinů) je jednou z podmínek bezpečné terapie těmito léčivy. Glifloziny se v organismu metabolizují prakticky jen glukuronidací, což je velmi neobvyklé a lékaři i farmaceuti s tím musejí počítat. Největší část všech gliflozinů se metabolizuje cestou UGT1A9, v případě dapagliflozinu je tato cesta rozhodující, naopak empagliflozin je metabolizován hned čtyřmi izoenzymy UGT, což se projevuje zanedbatelným vlivem jejich polymorfismů a lékových interakcí. Glukuronidy vzniklé metabolizací gliflozinů jsou dobře rozpustné ve vodě, a jsou proto eliminovány ledvinami aktivním transportem. Míra glukuronidace jednotlivých gliflozinů je různá, nejnižší je v případě empagliflozinu a nejvyšší u dapagliflozinu.
Understanding the metabolism pathways of SGLT2 inhibitors (gliflozins) is one of the conditions for safe therapy with these drugs. Gliflozins are metabolized in the body practically only by glucuronidation, which is very unusual. Both doctors and pharmacists must count it in. Most gliflozins are metabolized by UGT1A9. In the case of dapagliflozin, this is the decisive pathway, whereas empagliflozin is metabolized by four UGT isoenzymes, which manifests as a negligible effect of their polymorphisms and drug interactions. Glucuronides formed by the metabolism of gliflozins are readily soluble in water and are therefore eliminated by active renal transport. The degree of glucuronidation of individual gliflozins is different; the lowest is in the case of empagliflozin and the highest in the case of dapagliflozin.
OBJECTIVES: The study of interspecies differences in glucuronidation processes in the man, monkey, pig, dog and rat using liver microsomal fraction. The study is focused on determination of the enzyme activity of UGT1A6 (having also a toxicological importance) in microsomes of different species. METHODS: For determination of glucuronides formed, an HPLC method with UV detection and LC-MS characterization was used. p-Nitrophenol and 4-methylumbelliferon and silybin were chosen as model substrates. RESULTS: The data presented in this paper show an overall similarity in kinetic parameters of the UGT1A6 with p-nitrophenol and 4-methylumbelliferon for man, pig and monkey. The pattern of silybin glucuronides formed in monkey and dog samples are relatively close to this of the man. CONCLUSIONS: For studies of glucuronidation of xenobiotics where the role UGT1A6 is expected, the use of pig and monkey microsomes should be considered. As an optimal model for study of silybin glucuronidation, both the rhesus monkey and dog (Beagle) seem to be the best models. To elucidate the role of the UGT forms involved in metabolism of silybin, the experiments with recombinant UGT enzymes are needed.
- MeSH
- druhová specificita MeSH
- glukuronidy metabolismus MeSH
- glukuronosyltransferasa metabolismus MeSH
- Haplorrhini MeSH
- jaterní mikrozomy enzymologie MeSH
- kinetika MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- ochranné látky metabolismus MeSH
- prasata MeSH
- psi MeSH
- silymarin metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
The flavonolignan silybin, the main component of silymarin, extract from the seeds of Silybum marianum, is used mostly as a hepatoprotectant. Silybin is almost 1:1 mixture of two diastereomers A and B. The individual UDP-glucuronosyltransferases (UGTs) contributing to the metabolism of silybin diastereomers have not been identified yet. In this study, the contribution of UGTs to silybin metabolism was examined. The potential silybin metabolites were formed in vitro by incubating silybin (i) with the human liver microsomal fraction, (ii) with human hepatocytes and finally (iii) with 12 recombinant UGTs (UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15 and 2B17). High-performance liquid chromatographic (HPLC) techniques with UV detection and additionally MS detection were used for metabolite identification. Hepatocytes and microsomes formed silybin A-7-O-β-D-glucuronides, B-7-O-β-D-glucuronides, A-20-O-β-D-glucuronides and B-20-O-β-D-glucuronides. With recombinant UGTs, the major role of the UGT1A1, 1A3, 1A8 and 1A10 enzymes but also of the UGT1A6, 1A7, 1A9, 2B7 and 2B15 in the stereoselective reactions leading to the respective silybin glucuronides was confirmed. UGT1A4, UGT2B4 and UGT2B17 did not participate in silybin glucuronidation. The predominant formation of 7-O-β-D-glucuronides and the preferential glucuronidation of silybin B diastereomer in vitro by human UGTs were confirmed.
- MeSH
- glukuronidy metabolismus MeSH
- glukuronosyltransferasa metabolismus MeSH
- hepatocyty metabolismus MeSH
- jaterní mikrozomy enzymologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- ostropestřec mariánský chemie MeSH
- rekombinantní proteiny metabolismus MeSH
- silymarin chemie metabolismus MeSH
- stereoizomerie MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Pharmacology and toxicology ; Supplement Vol. 73. 1
[1st ed.] 23 s. : tab., lit. ; 28 cm
- MeSH
- glukuronáty MeSH
- oxazepam farmakokinetika MeSH
- uridyltransferasa MeSH
- xenobiotika farmakokinetika MeSH
- Konspekt
- Farmacie. Farmakologie
- NLK Obory
- farmacie a farmakologie
- MeSH
- aldosteron moč sekrece MeSH
- dítě MeSH
- draslík fyziologie moč MeSH
- glukuronidy moč sekrece MeSH
- moč fyziologie MeSH
- sodík fyziologie moč MeSH
- Check Tag
- dítě MeSH
