title: Contribution of lysosomes to concentrative uptake of DX-9065a into rat liver.
abstract: This study evaluates the distribution profile in tissues and concentrative uptake mechanism for a cationic compound of DX-9065a in rats. After a single intravenous dosing of [(14)C]-DX-9065a to male rats, higher levels of radioactivity were observed in kidney and liver. Moreover, the radioactivity in the liver continuously increased up to 6 h after intravenous dosing and a concentrative uptake of the drug against the radioactivity gradient between plasma and liver, showing K(p) value of 90.7. In contrast, carrier-mediated systems did not play a significant role in the uptake of DX-9065a by hepatocytes. A subcellular distribution study was conducted by means of Percoll density gradient centrifugation and revealed a high affinity of the compound with the lysosomes. It was concluded that DX-9065a permeated into hepatocyte across the membrane primarily by passive diffusion, and the consequent process of lysosomal trapping played a major role in the concentrative uptake of the drug into the liver.
authors.affiliation: Drug Metabolism & Physicochemistry Research Laboratory, Daiichi Pharmaceutical Co. Ltd., Edogawa-ku, Tokyo, Japan. muraycjs@daiichipharm.co.jp
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Murayama
authors.forename: Minoru
authors.initials: M
authors.lastname: Nakaoka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sudo
mesh_terms: D000818:Animals; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009281:Naphthalenes / Q000378:metabolism* / Q000494:pharmacology; D009928:Organ Specificity / Q000187:drug effects; D011422:Propionates / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D009281:Naphthalenes; D011422:Propionates