Library

X
feed icon rss

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of a novel protein kinase inhibitor, UCN-01 (1999)
    Springer
    Cancer chemotherapy and pharmacology 44 (1999), S. 12-18 
    Details
    ISSN: 1432-0843
    Keywords: Key words 7-Hydroxystaurosporine (UCN-01) ; Pharmacokinetics ; Pharmacodynamics ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: 7-Hydroxystaurosporine (UCN-01) is a potent protein kinase inhibitor and is being developed as a novel anticancer agent. We describe here its pharmacokinetics and pharmacodynamics in experimental animals. Methods: The pharmacokinetics of UCN-01 were studied following intravenous (i.v.) administration to mice, rats and dogs at doses of 1–9, 0.35–3.5 and 0.5 mg/kg, respectively. We also studied the pharmacodynamics of UCN-01 (9 mg/kg per day) during and after five consecutive i.v. administrations to nude mice bearing xenografted human pancreatic tumor cells (PSN-1). The concentrations of UCN-01 in plasma and tumor were measured by HPLC using a fluorescence detector. Results: UCN-01 in plasma after i.v. administration was eliminated biphasically in mice and rats, and triphasically in dogs. The elimination half-lives in mice, rats and dogs were 3.00–3.98, 4.02–4.46 and 11.6 h, respectively. The total clearance (Cltotal) values in mice, rats and dogs were high (1.93–2.64, 2.82–3.86 and 0.616 l/h per kg, respectively). The hepatic clearance (Clhepatic) in rats represented 54.0–81.3% of Cltotal. The volumes of distribution at steady-state in mice, rats and dogs were large (7.89–8.42, 13.0–16.9 and 6.09 l/kg, respectively). These pharmacokinetic parameters were dose-independent in mice and rats. UCN-01 produced significant inhibition of tumor growth during five consecutive i.v. administrations in mice bearing the xenografted PSN-1 cells, and the inhibitory effect continued for 3 days after the final administration. UCN-01 concentrations in tumor tissue were much higher than those in the plasma, and the ratio of tumor to plasma concentrations was about 500 at 24 h after five consecutive doses. Conclusions: The pharmacokinetic studies showed that UCN-01 has a high clearance and large distribution volume in various experimental animals, and its disposition is linear over the range of doses tested. The pharmacodynamic study showed that UCN-01 is distributed at much higher concentrations in tumor than those in plasma and that it significantly inhibits tumor growth. The high distribution of UCN-01 into tumor cells may contribute to the potent inhibition of tumor growth in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050939
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 2
    Electronic Resource
    Electronic Resource
    Phase I and pharmacologic study of oral (E)-2′-deoxy-2′-(fluoromethylene) cytidine: on a daily × 5-day schedule (1998)
    Springer
    Investigational new drugs 16 (1998), S. 245-254 
    Details
    ISSN: 1573-0646
    Keywords: phase I trial ; ribonucleoside diphosphate reductase inhibitor ; deoxytidine analog ; FMdC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract (E)-2′-deoxy-2′-(fluoromethylene)cytidine (FMdC), one of the most potent inhibitors of ribonucleoside diphosphate reductase, was selected for clinical development because of its novel mechanisms of action, and strong antitumor activity against experimental tumor models. This study was designed to determine the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic profile of FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 weeks in patients with advanced solid tumors. The starting dose was 8 mg/m2/day. Pharmacokinetic studies were carried out on days 1 through 5 of the first cycle. Ten patients with non-small cell lung cancer received 15 courses of FMdC at doses which were de-escalated from 8 mg/m2/day to 2 mg/m2/day because of unexpected severe toxicities at the starting dose level. Neutropenia was the dose-limiting toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were the common non-hematologic toxicities. The MTD was 4 mg/m2/day, since four of six patients developed grade 3–4 neutropenia. At the 4 mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), plasma clearance, and mean residence time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h, respectively. The recommended dose for phase II studies with this schedule is also 4 mg/m2/day for 5 days. Further investigations are necessary to establish optimal dosing schedules and routes for the administration of FMdC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006126212481
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...