Dose-dependent pharmacokinetics of rapamycin-28-N,N-dimethylglycinate in the mouse.

Rapamycin-28-N,N-dimethylglycinate methanesulfonate salt (RG), synthesized as a potential water-soluble prodrug to facilitate parenteral administration of the antineoplastic macrolide rapamycin (RA), is active against intracranially implanted human glioma in mice. Preclinical pharmacokinetic studies to evaluate the prodrug were conducted in male CD2F1 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 triphasic manner following treatment with the 100 mg/kg dose; however, prodrug disposition was apparent biexponential at each of the lower doses. RG exhibited dose-dependent pharmacokinetics, characterized by an increase in the total plasma clearance from 12.5 to 39.3 ml.min-1.kg-1 for dosage escalations in the range 10-50 mg/kg, while clearance values at doses of 50 and 100 mg/kg were similar. The terminal rate constants decreased linearly as the dose was increased from 10 to 100 mg/kg, eliciting an apparent prolongation of the biological half-life from 2.1 to 4.8 h. There was also a sequential increase in the steady state apparent volume of distribution from 1.73 to 8.75 l/kg. These observations are consistent with saturable binding of RG to plasma proteins while binding to tissue remains linear. Nevertheless, conversion to RA 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 plasma levels sustained between 0.1 and 10 microM for 48 h at each of the doses evaluated. Thus, RG effectively served as a slow release delivery system for RA, implying the possibility of maintaining therapeutic plasma levels of the drug from a more convenient dosing regimen than a continuous infusion schedule. The present findings, coupled with the demonstrated in vivo activity of RG against human brain tumor models, warrant its continued development as a much needed chemotherapeutic agent for the treatment of brain neoplasms.