PRECLINICAL PHARMACOLOGY OF THE NATURAL PRODUCT ANTICANCER AGENT BRYOSTATIN-1, AN ACTIVATOR OF PROTEIN-KINASE-C

Bryostatin 1, a natural product anticancer agent isolated from a marin e bryozoan, has been shown in tissue culture to activate protein kinas e C. This agent has recently undergone Phase I testing in humans given either as a bolus i.v. injection or a continuous infusion. To underst and how bryostatin 1 might be used best as an anticancer agent, a stud y of the pharmacokinetics, tissue distribution, metabolism, and elimin ation of bryostatin 1 in mice was undertaken, using [C26-H-3]-labeled bryostatin 1. Following i.v. administration, the plasma disappearance curve for bryostatin 1 could be described by a two-compartment model, with half-lives of 1.05 and 22.97 h, respectively. In contrast, the pl asma disappearance curve for bryostatin 1 administered i.p. was better described by a first order absorption one-compartment model, with an absorption half-life of 0.81 h and an elimination half-life of 28.76 h , respectively. The majority of radioactivity in plasma was associated with the intact drug for up to 24 h after dosing. In the first 12 h a fter i.v administration, urinary excretion represented the major pathw ay of elimination, with 23.0 +/- 1.9% (mean +/- SD) of the administere d dose excreted. Within 72 h after i.v. administration, approximately equal amounts of radioactivity (40%) were excreted in feces compared t o urine. Bryostatin 1 was widely distributed in many organs hut concen trated in the lung, liver, gastrointestinal tract, and fatty tissue. T he concentration in the gastrointestinal tract, along with the fecal e xcretion, suggests the possibility of enterohepatic circulation of thi s drug. In summary, this study demonstrates that bryostatin 1 is relat ively stable in vivo, widely distributed but concentrated in some majo r tissues, and rapidly excreted first through urine and at later times through the feces. The data from this animal study should be useful i n the design of future human trials with this anticancer drug.