Phase I and pharmacokinetic analysis of high-dose tamoxifen and chemotherapy in normal and tumor-bearing dogs.

Abstract

To determine whether tamoxifen plasma concentrations capable of blocking P-glycoprotein (Pgp) in vitro can be safely achieved in dogs and whether doxorubicin pharmacokinetic alterations occur when tamoxifen is coadministered. Tamoxifen dose escalation studies were conducted in 7 normal dogs and in 19 tumor-bearing dogs receiving full-dose chemotherapy. Plasma tamoxifen and serum doxorubicin disposition were analyzed for putative drug interactions. Steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen (NDMT) were 5-10 microM following oral tamoxifen administration at 600 mg/m2 every 12 h for 7 days to normal and tumor-bearing dogs. Mild-moderate gastrointestinal toxicity (diarrhea, anorexia) and reversible neurotoxicity were observed in dogs receiving chemotherapy plus high-dose tamoxifen. Myelosuppression was not affected by combined treatment in tumor-bearing dogs. High-dose tamoxifen decreased the clearance and volume of distribution of full-dose doxorubicin. Concentrations of tamoxifen/ NDMT sufficient to inhibit Pgp may be achieved in dogs receiving full-dose chemotherapy with a moderate but acceptable increase in gastrointestinal toxicity. Tamoxifen affects doxorubicin metabolism in dogs at high doses resulting in increased serum exposure. Pharmacologic manipulation of Pgp expression or function in normal and tumor tissue in dogs may facilitate investigation of novel anticancer treatment strategies in humans.