L-693612

The disposition of L-693,612, a carbonic anhydrase inhibitor, was examined in rats following oral doses of 0.05 to 25 mg/kg. Area under the blood concentration-time curve (AUC) increased linearly with dose up to 0.25 mg/kg. However, the linear range did not extend to 5 and 25 mg/kg doses; AUC rose only 10-fold overall despite a 500-fold increase in dose. A similar pattern of disproportionality occurring after i.v. administration indicated that the nonlinear behavior after oral doses was not due to dose-limited absorption, but rather it arose because blood clearance increased with dose. Concentration-dependent erythrocyte/plasma partitioning arising from saturation of binding to erythrocyte carbonic anhydrase could explain the dose-dependent blood clearance. At blood concentrations (< 25 microM) achieved in the linear dose range, L-693,612 was extensively sequestered in red blood cells, bound to carbonic anhydrase, with a constant low free fraction in plasma available for elimination. At doses which saturated the binding capacity of carbonic anhydrase, blood clearance increased, since for low hepatic extraction compounds, the rate of elimination is dependent upon the free fraction in blood. Dose-dependent increases in distribution volumes were consistent with the view that high-affinity binding to carbonic anhydrase confined this compound largely to blood volume at low doses, but saturation of binding sites increased availability to peripheral tissues after high doses. Increasing the dose had a minimal effect on terminal half-life because it reflected the concentration-time profile during a period of linear distribution into erythrocytes.