Synthesis of acylglucuronides of drugs using immobilized dog liver microsomes octadecylsilica particles coated with phospholipid.
Immobilized dog liver microsome octadecylsilica (ODS) particles coated with phospholipid were developed for the synthesis of acylglucuronides of drugs. The phospholipid-coated ODS particles were readily prepared by stirring a solution containing L-alpha-dipalmitoylphosphatidylcholine with the ODS particles, in which the phospholipid was absorbed on the ODS surfaces by hydrophobic interaction between the acyl group of phospholipid and the otcadecyl group of the ODS particles. Similarly, the microsome-immobilized particles were readily prepared by stirring a buffer solution containing dog liver microsomes with the phospholipid-coated ODS particles, in which the microsomes were immobilized on the phospholipid-coated ODS particles by hydrophobic binding. The microsome-immobilized particles exhibited UDP-glucuronosyltransferase activity which catalyzed the glucuronidation of ketoprofen and a nonpeptide endothelin receptor antagonist, S-1255 ([R]-[+]-2-[benzo(1,3)dioxol-5-yl]-6-isopropyl-4-[4-methoxyphenyl]-2H-chromene-3-carboxylic acid), to the corresponding acylglucuronide in the presence of uridine 5(')-diphosphate (UDP)-glucuronic acid, and two acylglucuronides of ketoprofen and S-1255 were synthesized using the microsome-immobilized particles. These acylglucuronides were synthesized by simply shaking the microsome-immobilized particles adsorbed on the substrate in a buffer solution containing UDP-glucuronic acid with a thermostated mixer. The molecular weights and chemical structures of the synthesized acylglucuronides were identified by mass spectrometry and nuclear magnetic resonance, respectively. The productivity of S-1255 acylglucuronide using microsome-immobilized particles was approximately threefold higher than that observed with free microsomes, whereas the ketoprofen acylglucuronide productivity was slightly lower than that observed with free microsomes. The present method should be very useful for the synthesis of acylglucuronides of drugs, which are slightly soluble aqueous solutions in the drug development stage.
Kamimori
Hiroshi
H
Shionogi Research Laboratories, Shionogi & Co, Ltd, 12-4, Sagisu 5-chome, Osaka, Fukushima-ku 553-0002, Japan. hiroshi.kamimori@shionogi.co.jp
Ozaki
Yoshihisa
Y
Okabayashi
Yoshito
Y
Ueno
Kyoji
K
Narita
Shigeru
S
D000215:Acylation; D000327:Adsorption; D000818:Animals; D004285:Dogs; D005260:Female; D020719:Glucuronides / Q000096:biosynthesis* / Q000138:chemical synthesis; D007660:Ketoprofen / Q000031:analogs & derivatives / Q000378:metabolism; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010743:Phospholipids / Q000737:chemistry*; D015203:Reproducibility of Results; D012822:Silicon Dioxide / Q000737:chemistry*; D013379:Substrate Specificity; D013997:Time Factors; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D020719:Glucuronides; D010743:Phospholipids; C026679:octadecylsilica; D014535:Uridine Diphosphate Glucuronic Acid; D012822:Silicon Dioxide; D007660:Ketoprofen