SYSTEMIC BIOAVAILABILITY OF PENCLOMEDINE (NSC-338720) FROM OIL-IN-WATER EMULSIONS ADMINISTERED INTRADUODENALLY TO RATS

Penclomedine (NSC-338720) is a low melting point, poorly water-soluble cytotoxic agent with good solubility in triglycerides and a high octanol/water partition coefficient. Its pharmacokinetics in anesthetized rats was studied after i.v. bolus injection of a soybean oil emulsion. Penclomedine displayed biexponential behavior with an apparent t1/2 (+/- SE) of 1.9 +/- 0.3 h and a clearance of 3.3 +/- 0.1 ml/min per kg. After intraduodenal administration to anesthetized rats as either a 10% o/w emulsion of tributyrin, trioctanoin, triolein, soybean oil or mineral oil, or as a suspension, the rank order of absolute bioavailability was trioctanoin > soybean oil almost-equal-to triolein > mineral oil > tributyrin > suspension. The results were rationalized by assuming that drug release from the emulsions was by a combination of vehicle metabolism and diffusional drug release. The poor bioavailability from tributyrin was rationalized by the rapid release of penclomedine resulting in its possible precipitation and subsequent need to redissolve.