N-phosphoryl derivatives of bisantrene. Antitumor prodrugs with enhanced solubility and reduced potential for toxicity.

The selective phosphorylation of bisantrene (1) affords bis(phosphonoguanidinic acid) 6, a prodrug with enhanced aqueous solubility (as sodium salt 7) at physiological pH. Unlike 1, in a rat tail vein model, no precipitation was observed when bis(phosphonoguanidinic acid) 6 was injected. While in rats 6 hydrolyzed to monophosphonoguanidinic acid 9 with a half-life of ca. 12 min., complete hydrolysis to bisantrene required several hours. The corresponding monophosphonoguanidinic acid 9 was synthesized from bisantrene and also showed good solubility and antitumor activity. While the antitumor activities of 6 in mice were comparable to bisantrene against B-16 melanoma and P-388 and L-1210 leukemias, it was inactive in vitro vs several tumor cell types. Thus, its activity in vivo resulted from its ability to serve as a prodrug for bisantrene.

Skin metabolism and transdermal absorption of viprostol, a synthetic PGE2 analog, in the rat: effect of vehicle.

The effects of three formulations on the transdermal absorption and antihypertensive activity of 14C-viprostol were investigated in the spontaneously hypertensive rat. Single doses of 14C-viprostol were administered topically to rats in three formulations: silicone oil, petrolatum base, and triethyl citrate (TEC). Mean arterial blood pressure (MABP) and blood concentrations of radioactivity were measured over 24 h. Metabolic profiles in the skin were determined by HPLC; in vitro skin metabolism was also investigated. Following topical dosing with 14C-viprostol in petrolatum and silicone oil, substantial systemic concentrations of radioactivity and decreases in MABP were observed. In contrast, administration of 14C-viprostol in TEC led to negligible blood concentrations of radioactivity and the lowering of MABP was diminished. Metabolic profiles in skin at the application site from rats dosed with viprostol in petrolatum and silicone oil indicated rapid hydrolysis of the viprostol methyl ester to the active free acid, CL 115,129. When TEC was used as the dosing vehicle, the conversion of viprostol to the free acid appeared to be slower. TEC (an ester itself) was also found to reduce the rate of hydrolysis of viprostol in rat skin 10,000-g supernatants.