DOSE-DEPENDENT PHARMACOKINETICS OF RAPAMYCIN-28-N,N-DIMETHYLGLYCINATEIN THE MOUSE

Rapamycin-28-N,N-dimethylglycinate methanesulfonate salt (RG), synthes ized as a potential water-soluble prodrug to facilitate parenteral adm inistration of the antineoplastic macrolide rapamycin (RA), is active against intracranially implanted human glioma in mice. Preclinical pha rmacokinetic studies to evaluate the prodrug were conducted in male CD 2F1 mice treated with 10, 25, 50 and 100 mg/kg doses of RG by rapid i. v. injection. The plasma concentration of RG decayed in a distinctly t riphasic manner following treatment with the 100 mg/kg dose; however, prodrug disposition was apparent biexponential at each of the lower do ses. RG exhibited dose-dependent pharmacokinetics, characterized by an increase in the total plasma clearance from 12.5 to 39.3 ml.min-1 . k g-1 for dosage escalations in the range 10-50 mg/kg, while clearance v alues at doses of 50 and 100 mg/kg were similar. The terminal rate con stants decreased linearly as the dose was increased from 10 to 100 mg/ kg, eliciting an apparent prolongation of the biological half-life fro m 2.1 to 4.8 h. There was also a sequential increase in the steady sta te apparent volume of distribution from 1.73 to 8.75 1/kg. These obser vations are consistent with saturable binding of RG to plasma proteins while binding to tissue remains linear. Nevertheless, conversion to R A appeared to represent a prominent route of RG elimination. The molar plasma concentration of RA exceeded that of the prodrug within 30-90 min after i.v. treatment and declined very slowly thereafter, with pla sma levels sustained between 0.1 and 10 mum for 48 h at each of the do ses evaluated. Thus, RG effectively served as a slow release delivery system for RA, implying the possibility of maintaining therapeutic pla sma levels of the drug from a more convenient dosing regimen than a co ntinuous infusion schedule. The present findings, coupled with the dem onstrated in vivo activity of RG against human brain tumor models, war rant its continued development as a much needed chemotherapeutic agent for the treatment of brain neoplasms.