- Preparative Enzymatic Synthesis of the Acylglucuronide of Mycophenolic Acid
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The acylglucuronide (3) of mycophenolic acid (1) was enzymatically synthesised on a preparative scale (450 mg substrate) under optimised reaction conditions with 51% conversion. By screening 9 liver homogenates from 8 vertebrate species, it was shown that only with liver homogenate from horse as the catalyst were the acyl- (3) and the O-glucuronide (2) were formed in a ca. 1:1 ratio. With homogenates from other sources, the O-glucuronide (2) was produced in high excess. By optimising the concentration of the co-substrate UDP-glucuronic acid and the reaction temperature, the conversion to the acylglucuronide (3) was increased from initially 34 to 55% and the ratio of acyl- (3) to O-glucuronide (2) from 1.5:1 to 3.9:1. The reaction was also performed continuously in an enzyme membrane reactor, however, with lower conversion yield and therefore, higher specific UDP-glucuronic acid consumption.
- Kittelmann, Matthias,Rheinegger, Urs,Espigat, Aude,Oberer, Lukas,Aichholz, Reiner,Francotte, Eric,Ghisalba, Oreste
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- Pharmacokinetics and pharmacodynamics of mycophenolic acid in Nagase analbuminemic rats: Evaluation of protein binding effects using the modeling and simulation approach
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This study aimed to examine the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA) in Nagase analbuminemic rats (NARs) to evaluate the effect of protein binding on the associated inosine-5-monophosphate dehydrogenase (IMPDH) activity. Free fractions of MPA in the control rats and NARs were 2.09 and 24.8%, respectively. Pharmacokinetic and pharmacodynamic parameters simultaneously obtained by the nonlinear mixed effects modeling program NONMEM explained reasonably well the concentrations of MPA and MPA glucuronide as well as IMPDH activity in both rats. NARs showed a higher clearance and a smaller volume of distribution based on the free MPA concentration than the controls did, besides the increase in free fraction. The half-maximal inhibitory concentration based on free MPA was estimated as 163 ng/mL for both rats. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters showed that the area under the IMPDH activity-time curve decreased non-linearly according to the increase in free fraction of MPA. In conclusion, the experimental data obtained from NARs followed by the modeling and simulation approach quantitatively clarified that the free MPA concentration was suitable for the biomarker of immunosuppressive effect of MPA. Dose adjustments based on the total MPA may cause unnecessary overexposure to MPA in patients with hypoalbuminemia.
- Yoshimura, Kazuaki,Yano, Ikuko,Kawanishi, Misaki,Nakagawa, Shunsaku,Yonezawa, Atsushi,Matsubara, Kazuo
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- Inhibition of intestinal and hepatic glucuronidation of mycophenolic acid by Ginkgo biloba extract and flavonoids
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Herb-drug interactions have received more attention in recent years because of the widespread popularity of herbal supplements. However, there are limited data on the effect of herbs on glucuronidation in humans. The goal of this work was to examine the effect of Ginkgo biloba extract and its main flavonoid and terpene lactone constituents on mycophenolic acid (MPA) 7-Oglucuronidation. Human liver (HLM) and intestinal (HIM) microsomes were incubated with MPA and G. biloba extract (unhydrolyzed or acid-hydrolyzed), quercetin, kaempferol, ginkgolide A, ginkgolide B, or bilobalide. MPA-7-O-glucuronide formation was inhibited in HLM and HIM incubations by unhydrolyzed [IC50 = 84.3 (HLM) and 6.9 (HIM) μg/ml] and hydrolyzed [IC50 = 20.9 (HLM) and 4.3 (HIM) μg/ml] G. biloba extracts, quercetin [IC50 = 19.1 (HLM) and 5.8 (HIM) μM], and kaempferol [IC50 = 23.1 (HLM) and 7.7 (HIM) μM]. Terpene lactones did not show inhibition of MPA glucuronidation. Quercetin was a mixed-type inhibitor in HLM and HIM incubations [Ki = 11.3 (HLM) and 2.8 (HLM) μM], whereas kaempferol was a noncompetitive inhibitor in HLM (Ki = 33.7 μM) and a mixed-type inhibitor in HIM (Ki = 4.5 μM). These results indicate that G. biloba extract or quercetin-and kaempferol-rich supplements may inhibit intestinal and hepatic glucuronidation of MPA. Future studies are needed to evaluate the clinical significance of this interaction. Copyright
- Mohamed, Mohamed-Eslam F.,Frye, Reginald F.
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- Accurate prediction of glucuronidation of structurally diverse phenolics by human UGT1A9 using combined experimental and in silico approaches
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Purpose: Catalytic selectivity of human UGT1A9, an important membrane-bound enzyme catalyzing glucuronidation of xenobiotics, was determined experimentally using 145 phenolics and analyzed by 3D-QSAR methods. Methods: Catalytic efficiency of UGT1A9 was determined by kinetic profiling. Quantitative structure activity relationships were analyzed using CoMFA and CoMSIA techniques. Molecular alignment of substrate structures was made by superimposing the glucuronidation site and its adjacent aromatic ring to achieve maximal steric overlap. For a substrate with multiple active glucuronidation sites, each site was considered a separate substrate. Results: 3D-QSAR analyses produced statistically reliable models with good predictive power (CoMFA: q 2=0.548, r2=0.949, r pred 2 =0.775; CoMSIA: q2=0.579, r2=0.876, rpred2 =0.700). Contour coefficient maps were applied to elucidate structural features among substrates that are responsible for selectivity differences. Contour coefficient maps were overlaid in the catalytic pocket of a homology model of UGT1A9, enabling identification of the UGT1A9 catalytic pocket with a high degree of confidence. Conclusion: CoMFA/CoMSIA models can predict substrate selectivity and in vitro clearance of UGT1A9. Our findings also provide a possible molecular basis for understanding UGT1A9 functions and substrate selectivity.
- Wu, Baojian,Wang, Xiaoqiang,Zhang, Shuxing,Hu, Ming
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experimental part
p. 1544 - 1561
(2012/07/27)
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- Convenient syntheses of the in vivo carbohydrate metabolites of mycophenolic acid: reactivity of the acyl glucuronide
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Following in vivo use of mycophenolic acid, the O-aryl and O-acyl glucuronides, as well as the recently discovered O-aryl glucoside (Scheme 1), are all found as metabolites. We describe convenient preparations of all three derivatives. The phenolic glycos
- Jones, Amy E.,Wilson, Helen K.,Meath, Paul,Meng, Xiaoli,Holt, David W.,Johnston, Atholl,Oellerich, Michael,Armstrong, Victor W.,Stachulski, Andrew V.
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supporting information; experimental part
p. 4973 - 4977
(2009/12/05)
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