COL-3 is an oral, lipophilic,
tetracycline analog that has been administered to patients with metastatic
cancer. Preliminary assessment of
COL-3 in 35 patients with refractory metastatic
carcinoma demonstrated apparent nonlinear pharmacokinetics with highly variable oral clearance (63.9% coefficient of variance [CV]). To elucidate possible sources of variability of
COL-3 pharmacokinetics in vivo, in vitro
plasma protein binding and in vitro metabolism were explored along with in vivo pharmacokinetics using compartmental modeling. The variability in the overall clearance and urinary excretion of
COL-3 was also assessed.
COL-3 had a long terminal half-life (median = 59.8 h), large apparent volume of distribution (median = 50.2 L), and low apparent clearance (median = 9.93 mL/min). Only adjusted ideal body weight decreased the variability in total apparent clearance. There was nonsaturable
plasma protein binding of
COL-3 (fu = 5.5%), with the majority of binding to
albumin. The renal route of elimination is negligible, with 0.06% of unchanged
COL-3 and 3.31%
COL-3 glucuronide excreted in the first 6 days.
COL-3 is not metabolized by phase I metabolism but does undergo glucuronidation in vitro by UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and in vivo, as evidenced by
COL-3 glucuronides in the urine (median = 13.6% of the total dose).
COL-3 exhibits nonlinear pharmacokinetics, possibly due to dissolution rate-limited absorption.