Nonclinical pharmacokinetics of BMS‐292655, a water‐soluble prodrug of the antifungal ravuconazole

Abstract

The phosphate ester, BMS-292655, was developed as a water-soluble prodrug of the antifungal agent, ravuconazole (BMS-207147). BMS-292655 was comparatively stable in rat, beagle dog, cynomolgus monkey and human plasma, but was hydrolysed upon incubation with liver S9 preparations from all species. The major product in rat, monkey and human S9 was BMS-207147, while in dog S9, the intermediate ester, BMS-300043, predominated. BMS-300043 itself was more stable in dog S9 than in S9 preparations from the other species. Intravenous administration of BMS-292655 to rats, beagle dogs and cynomolgus monkeys indicated species differences in the extent of formation of BMS-207147 (monkeys>rats>dogs). The lower overall generation of BMS-207147 in dogs was consistent with the presence of circulating plasma levels of BMS-300043. BMS-300043 was present in monkey plasma but not detectable in rat plasma. The conversion of BMS-292655 to BMS-207147 in the presence of human S9 indicated the potential for BMS-292655 to function as a BMS-207147 prodrug in humans. The similarity in the hydrolysis of BMS-292655 when incubated with human and monkey S9 in vitro, coupled with the effective release of BMS-207147 from BMS-292655 upon i.v. administration to monkeys, is consistent with this conclusion.

Nanofiber-Based Delivery of Therapeutic Peptides to the Brain

“…Our conclusion that the activity that we are seeing is due to the dalargin originating from the pDal nanofibers stems from the delayed response and the fact that we know that palmitoyl tyrosine ester prodrugs of leucine 5 -enkephalin give rise to leucine 5 enkephalin in vivo. 28 Ester prodrugs are rapidly cleaved to the parent drug: being completely cleaved within 30 min in the case of the phosphate ester prodrug of the antifungal agent, ravuconazole, 42 or the (glycyl, glutamyl)diethyl ester prodrug of the antitumor agent, S-(N-pchlorophenyl-N-hydroxycarbamoyl)glutathione. 43 Additionally, it is also possible that the prolonged duration of activity of pDal nanofibers could indicate that the receptorÀagonist dissociation kinetics are slow.…”

Efficacy comparison of the novel water-soluble propofol prodrug HX0969w and fospropofol in mice and rats

“…The mismatch between the conditions of in vitro and in vivo release from this class of compounds (phosphate ester prodrugs) was reported in a previous article. 27 The reason might be that HX0969w was mainly metabolized by tissue alkaline phosphatase rather than plasma alkaline phosphatase. Thus, further studies are required to fully explore the metabolic characteristics of HX0969w.…”

Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration

“…The delayed pharmacodynamic response is further evidence that TPLENK is indeed acting as a prodrug. Ester prodrugs are rapidly cleaved to the parent drug: being completely cleaved within 30 min in the case of the phosphate ester prodrug of the anti-fungal agent, ravuconazole [36], or the (glycyl, glutamyl)diethyl ester prodrug of the anti-tumour agent, S-(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione [37].…”