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

Purpose: To determine whether tamoxifen plasma concentrations capable of bl ocking P-glycoprotein (Pgp) in vitro can be safely achieved in dogs and whe ther doxorubicin pharmacokinetic alterations occur when tamoxifen is coadmi nistered. Methods: Tamoxifen dose escalation studies were conducted in 7 no rmal dogs and in 19 tumor-bearing dogs receiving full-dose chemotherapy. Pl asma tamoxifen and serum doxorubicin disposition were analyzed for putative drug interactions. Results: Steady-state plasma concentrations of tamoxife n and N-desmethyl tamoxifen (NDMT) were 5-10 mu M following oral tamoxifen administration at 600 mg/m(2) every 12 h for 7 days to normal and tumor-bea ring 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 treatme nt in tumor-bearing dogs. High-dose tamoxifen decreased the clearance and v olume of distribution of full-dose doxorubicin. Conclusions: Concentrations of tamoxifen/ NDMT sufficient to inhibit Pgp may be achieved in dogs recei ving full-dose chemotherapy with a moderate but acceptable increase in gast rointestinal toxicity. Tamoxifen affects doxorubicin metabolism in dogs at high doses resulting in increased serum exposure. Pharmacologic manipulatio n of Pgp expression or function in normal and tumor tissue in dogs may faci litate investigation of novel anticancer treatment strategies in humans.