Significant intestinal excretion, one source of variability in pharmacokinetics of COL-3, a chemically modified...

This study was undertaken to examine the disposition of COL-3, a chemically modified tetracycline, in order to elucidate its major route of elimination as one possible source of the variability in pharmacokinetics of COL-3 in vivo.

The disposition profile of COL-3 in vivo was assessed by examining the urinary and fecal excretion of the unchanged drug and/or its metabolites in rats after single intravenous and oral administration. The biliary excretion of COL-3 administered orally in bile duct-cannulated rats was also examined. In addition, plasma protein binding and cytochromes P450-mediated metabolism were explored along with erythrocyte partitioning in vivo. Furthermore, transport of COL-3 across Caco-2 monolayers was performed to elucidate the mechanism of intestinal excretion of COL-3 in vivo.

COL-3 was extensively bound to plasma protein in rat (98%) and human plasma (95%). The affinity of rat blood cells for COL-3, as measured by the ratio of drug concentration in blood cells to that unbound in plasma, was about 36. Of the single intravenous and oral doses, less than 0.2% and 0.03% were excreted unchanged in rat urine, respectively; while 32.1 +/- 9.9% and 38.8 +/- 6.1% were recovered unchanged in rat feces, respectively, within 48 h postdosing. Of the oral dose, 1.36 +/- 0.66% and 2.97 +/- 0.88% were excreted in rat bile as the unchanged COL-3 and the total of COL-3 and its glucuronide conjugate, respectively, within 24 h after dosing. COL-3 had insignificant cytochrome P450-mediated metabolism but underwent phase II metabolism (i.e., glucuronidation) in a minor quantity. COL-3 was not a substrate of P-glycoprotein. Its transport across Caco-2 monolayers was significantly affected by protein binding and pH.

Intestinal excretion, a route different from biliary excretion, is the major route of elimination for COL-3 in rats. Variability in intestinal excretion, due to extreme variable intestinal contents (food and digestive fluids), could be one source of variability in COL-3 pharmacokinetics in vivo in addition to the dissolution rate-limited absorption.