Application to a cartilage targeting strategy: synthesis and in vivo biodistribution of (14)C-labeled quaternary ammonium-glucosamine conjugates.

摘要: As part of a cartilage targeting program based on the affinity quaternary ammonium (QA) moiety for cartilage, QA derivatives D-glucosamine (DG), an antirheumatic drug exhibiting natural tropism cartilaginous tissues, were designed and evaluated by pharmacokinetic studies. Two QA-DG conjugates synthesized labeled with (14)C cross-linking entity (trimethylammonium or pyridinium) to [(14)C]DG via amide bond in two-step procedure. After intravenous injection male Sprague-Dawley rats, two (14)C-labeled exhibited similar profiles, but their behavior clearly differed from that unconjugated DG several ways. (i) The tissue distribution was more restricted, decreased radioactivity level whole tissues except kidney, skin. (ii) concentrated rapidly strongly than short times after injection; other hand, 1 h administration, higher DG, this result being consistent already observed compound. (iii) Both eliminated predominantly urinary route (85%); urine lower (45% injected dose), significant (14)CO(2) found expired air, indicating metabolization utilization energy-consuming processes. (iv) Blood plasma kinetics studies displayed enterohepatic cycle whereas conjugates, rapid disappearance observed. (v) HPLC analyses indicated low degree most recovered corresponding unchanged molecule. This study demonstrates introduction modifies its biodistribution lends it greater specificity at least injection. These findings justify further work agents.