Interaction of Intestinal Nucleoside Transporter hCNT2 with Amino Acid Ester Prodrugs of Floxuridine and 2-Bromo-5,6-dichloro-1-β-D-ribofuranosylbenzimidazole

• Shin Ho-Chul

  Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University

• Kim Jin-Suk

  Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University

• Vig Balvinder Singh

  Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan

• Song Xueqin

  Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan

• Drach John Charles

  Department of Biologic and Materials Sciences, School of Dentistry and Department of Medicinal Chemistry, College of Pharmacy, University of Michigan

• Amidon Gordon Lewis

  Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan

書誌事項

タイトル別名

• Interaction of Intestinal Nucleoside Transporter hCNT2 with Amino Acid Ester Prodrugs of Floxuridine and 2-Bromo-5,6-dichloro-1-.BETA.-D-ribofuranosylbenzimidazole
• Interaction of Intestinal Nucleoside Transporter hCNT2 with Amino Acid Ester Prodrugs of Floxuridine and 2 Bromo 5 6 dichloro 1 ベータ D ribofuranosylbenzimidazole

抄録

Amino acid ester prodrugs of antiviral and anticancer nucleoside drugs were developed to improve oral bioavailability or to reduce systemic toxicity. We studied the interaction of human concentrative nucleoside transporter (hCNT2) cloned from intestine with various amino acid ester prodrugs of floxuridine (FUdR) and 5,6-dichloro-2-bromo-1-β-D-ribofuranosylbenzimidazole (BDCRB). Na⁺-dependent uptakes of [³H]-inosine and [³H]-adenosine were measured in U251 cells transiently expressing intestinal hCNT2. FUdR significantly inhibited the uptake of both [³H]-inosine and [³H]-adenosine (60—70% of control), while its amino acid ester prodrugs including Val, Phe, Pro, Asp, and Lys esters exhibited markedly decreased inhibition potency (10—30% of control). On the other hand, BDCRB and its amino acid prodrugs markedly inhibited the uptake of both [³H]-inosine and [³H]-adenosine. Val, Phe, and Pro ester prodrugs of BDCRB showed similar inhibition capacities as parent compound BDCRB (80—90% for adenosine and 60—80% for inosine). The amino acid site of attachment (3′- and 5′-monoesters) and stereochemistry (L- and D-amino acid esters), did not significantly affect the uptake of [³H]-inosine and [³H]-adenosine. These results demonstrate that the hCNT2 favorably interacts with BDCRB and its amino acid prodrugs, compared to those of FUdR, and that neutral amino acid esters of BDCRB have a high affinity toward this transporter. Therefore, the intestinal hCNT2 may be a target transporter as a factor for modulating oral pharmacokinetics of BDCRB prodrugs.

収録刊行物

• Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ

  Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ 29 (2), 247-252, 2006

  公益社団法人 日本薬学会

キーワード

• nucleoside transporter hCNT2
• U251
• amino acid ester prodrug
• BDCRB
• floxuridine

詳細情報

• CRID: 1390001204624674560
• NII論文ID: 110005663953
• NII書誌ID: AA10885497
• DOI: 10.1248/bpb.29.247
• ISSN: 13475215
• ISSN: 09186158
• NDL書誌ID: 7791597
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I7791597
• Web Site: http://www.jstage.jst.go.jp/article/bpb/29/2/29_2_247/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2006310163
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可