Miproxifene phosphate

To evaluate the potential of phosphate ester prodrugs to significantly improve the absorptive flux of poorly soluble parent drugs.

Absorptive transport studies of parent drugs and their prodrugs were carried out in Caco-2 cells. Prodrugs of parent drugs with variable aqueous solubilities were tested: Hydrocortisone-phosphate/Hydrocortisone, Fosphenytoin/phenytoin, TAT-59/DP-TAT-59, and Entacapone phosphate/Entacapone. Additional absorption studies were carried out in rats.

Absorptive fluxes of DP-TAT-59 and phenytoin increased 9.8 or 3.3-fold after dosing TAT-59 and 500 microM fosphenytoin, respectively. Hydrocortisone's flux did not increase with hydrocortisone-phosphate at 100 microM. Permeability of the highly lipophilic and protein bound compound, DP-TAT-59, was significantly increased with serosal albumin. No permeability increase was observed for the other drugs with albumin. Entacapone phosphate failed to improve the flux of entacapone compared to an entacapone solution, but the prodrug solution did yield higher entacapone plasma levels in rats when compared with an entacapone suspension.

Ideal phosphate prodrug candidates are characterized by high permeability and low solubility (BCS Class II drugs). For low dose BCS Class II drug candidates, however, no biopharmaceutical advantage may be gained. Phosphate prodrugs of parent drugs with limited permeability may fail. When screening highly lipophilic parent drugs transport studies should be done with albumin.

Experimental and epidemiological studies have pointed to a major role of estrogens in the pathogenesis of human breast cancer. The Oxford meta-analysis (1998) once again confirmed the efficacy of antiestrogens (tamoxifen) as adjuvant therapy. We need to know whether the new non-steroid antiestrogens (idoxifen, droloxifen and TAT-59) and selective estrogen receptor modulator (raloxifen), whith preclinical characteristics better than those of tamoxifen will be more efficient clinically. Large-scale trials to compare the new drugs with tamoxifen are under way. Faslodex, a pure antiestrogen, looks highly promising, too. Zoladex, a luteinising hormone-releasing hormone agonist, is looking as a better choice than ovariectomy or irradiation of the pelvis for ovarian ablation in premenopausal breast cancer. New aromatase inhibitors are more efficient than progestins and much safer than aminoglutethimide. It has been shown recently that these inhibitors keep metastatic breast cancer at bay longer, and with longer survival. The non-steroid inhibitors (anastrozole and letrozole) and the steroid oral drug exemestane are undergoing clinical trials as means of adjuvant treatment of breast cancer. The trial of arimidex and tamoxifen administered alone or in combination (ATAC) is unique since it is using a combination of tamoxifen and an aromatase inhibitor (anastrozole). New methods of endocrine therapy have resulted in less toxic and more convenient procedures. Also, longer therapeutic effects and survival are becoming more apparent.