Dextran–methylprednisolone succinate as a prodrug of methylprednisolone: Plasma and tissue disposition**A preliminary account of this study was presented at the Twelfth Annual Meeting of the American Association of Pharmaceutical Sciences, Boston, MA, November 2–6, 1997 (Mehvar R. 1997. Targeted delivery of methylprednisolone using a dextran prodrug. Pharm Res 14:S336).

Liquid chromatography–tandem mass spectrometry for the determination of methylprednisolone in rat plasma and liver after intravenous administration of its liver-targeted dextran prodrug

“…Additionally, the concentrations of regenerated MP in the liver at 8 hr following the administration of DMP were 573 and 707 ng/g in two rats. In contrast, no MP is measurable in the liver 8 hr after the administration of the parent drug, consistent with the rapid decline of the liver concentration of the drug after the parent drug administration [7]. …”

“…Because of the relatively high in vivo concentrations of dextran prodrugs of MP in plasma and/or liver, compared with the regenerated MP [7], even a small degradation of the conjugate in vitro can significantly overestimate the MP concentrations regenerated from the conjugate in vivo. A previous work on the in vitro stability of dextran-peptide-MP prodrugs showed that the conjugates are more stable when acetic acid was added to the samples [11].…”

“…However, the use of steroids and other immunosuppressants in organ transplantation has been associated with significant toxicity, such as diabetes, hypertension, Cushing syndrome, and osteoporosis [3–5]. Recently, we synthesized a macromolecular prodrug of MP using dextran as a carrier and succinic acid as a linker, and investigated its hydrolysis kinetics [6], pharmacokinetics [7], and pharmacodynamics [8,9] in rats. It was demonstrated that the prodrug would selectively accumulate and gradually release MP in the liver and spleen, resulting in a more intense and sustained immunosuppressive activity in these organs, compared to administration of an equal dose of the parent drug.…”

Hepatic immunosuppressive effects of systemically administered novel dextran–methylprednisolone prodrugs with peptide linkers in rats

“…The differences among MPS, DMP1, and/or DMP5 in terms of their AUECs or liver AUCs, C 1 , C 2 , k 1 , and k 2 were analyzed using a two-sided Z-test after Bonferroni adjustment for the appropriate number of comparisons, as described in detail before. 23 All comparisons were performed at a significance level (α) of 0.05 after Bonferroni adjustment, if applicable. The data are presented as mean ± SD for parameters that could be estimated for individual animals (e.g., TNF-α AUC, bile flow rate, maximum effect, and maximum liver concentration) and as mean ± SE for population parameters (e.g., AUEC and liver AUC and bi-exponential parameters of prodrugs).…”

“…First, a conjugate linking MP to a 70 kDa dextran using a succinate linker was synthesized, and its pharmacokinetics 23 and pharmacodynamics 24–26 were characterized in rats. After the systemic administration, the conjugate selectively accumulated in the rat liver 23 and was much more effective than the parent drug in suppression of immune events in the liver. 24,26 However, the release of MP from the conjugate was slow and incomplete.…”