Microbial process for preparation of glucuronides of raloxifene

“…Human serum albumin (HSA) (200 g/l) was obtained from Octapharma (Ljubljana, Slovenia). Raloxifene metabolites M1, M2, and M3 were synthesized as authentic standards by incubating raloxifene hydrochloride with the bacterial cell line Streptomyces sp.-ATCC 55043 by a modification of the method that was published by Lilly Research Laboratories (Briggs et al, 1999), followed by purification. The details of this synthesis are described elsewhere (Trdan et al, 2011).…”

Section: Methodsmentioning

confidence: 99%

Raloxifene Glucuronidation in Human Intestine, Kidney, and Liver Microsomes and in Human Liver Microsomes Genotyped for theUGT1A1*28Polymorphism

Lušin

Trontelj²,

Mrhar³

2011

Drug Metab Dispos

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ABSTRACT:Raloxifene, a selective estrogen receptor modulator, exhibits quite large interindividual variability in pharmacokinetics and pharmacodynamics. In women, raloxifene is metabolized extensively by different isoforms of UDP-glucuronosyltransferase (UGT) to its glucuronides. To gain an insight into intestine, kidney, liver, and lung glucuronidation of raloxifene, human microsomes of all tested organs were used. Raloxifene-6-␤-glucuronide (M1) formation followed the Michaelis-Menten kinetics in intestinal, kidney, and liver microsomes; meanwhile, raloxifene-4-␤-glucuronide (M2) formation followed the substrate inhibition kinetics. Human lung microsomes did not show any glucuronidation activity. The tissue intrinsic clearances for kidney, intestine, and liver were 3.4, 28.1, and 39.6 ml ⅐ min ؊1 ⅐ kg ؊1, respectively. The aim of our in vitro study was to explain the mechanism behind the observed influence of UGT1A1*28 polymorphism on raloxifene pharmacokinetics in a small-sized in vivo study (Br J Clin Pharmacol 67:437-444, 2009). Incubation of raloxifene with human liver microsomes genotyped for UGT1A1*28 showed a significantly reduced metabolic clearance toward M1 in microsomes from donors with *28 allele. On the contrary, no significant genotype influence was observed on the formation of M2 because of the high variability in estimated apparent kinetic parameters, although a clear trend toward lower glucuronidation activities was observed when UGT1A1*28 polymorphism was present. The liver intrinsic clearances of both homozygotes differed significantly, whereas the clearance of heterozygotes did not differ from the wild-type and the mutated homozygotes. In conclusion, our results show the high importance of the liver and intestine in raloxifene glucuronidation. Moreover, the significant influence of UGT1A1*28 polymorphism on metabolism of raloxifene was confirmed.

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“…The organic phase was washed once with brine (50 ml), dried (Na 2 SO 4 ), and concentrated. (11). A mixture of monosilylated acolbifene 7 and 8 (8.00 g, 14.0 mmol) was azeotroped twice with dry benzene (100 ml) to ensure dryness and removal of residual ethanol.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and deuterium labelling of the pure selective estrogen receptor modulator (SERM) acolbifene glucuronides

Sancéau

Larouche

Caron

et al. 2007

Labelled Comp Radiopharmac

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Acolbifene (EM-652 Á HCl, SCH 57068 Á HCl), a highly potent and orally active selective estrogen receptor modulator (SERM), is at late stage clinical development for the treatment of estrogen-sensitive breast cancer. Acolbifene-7-glucuronide 1 (major) and acolbifene-4 0 -glucuronide 2 (minor) were identified as metabolites of acolbifene in the human. The two monoglucuronides and a diglucuronide 3 as well as the corresponding 2 H-labelled derivatives 4-6 were synthesised for use as preclinical and clinical standards for LC-MS/MS analysis. All glucuronides were prepared by the Schmidt glycosylation of monoprotected acolbifene with a glucuronyl imidate at À108C to prevent epimerisation at the C-2 position. The two monoglucuronides 1 and 2 of acolbifene were separated by semi-preparative HPLC. Incorporation of three deuteriums was achieved by alkylation of chromanone 15 with C 2 H 3 MgI followed by dehydration with C

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Microbial process for preparation of glucuronides of raloxifene

Cited by 8 publications

References 6 publications

Determination of raloxifene and its glucuronides in human urine by liquid chromatography–tandem mass spectrometry assay

Determination of raloxifene and its glucuronides in human urine by liquid chromatography–tandem mass spectrometry assay

Raloxifene Glucuronidation in Human Intestine, Kidney, and Liver Microsomes and in Human Liver Microsomes Genotyped for theUGT1A1*28Polymorphism

Synthesis and deuterium labelling of the pure selective estrogen receptor modulator (SERM) acolbifene glucuronides

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