Dose‐dependent pharmacokinetics of enprofylline and its renal handling in rats

The effect of dosage on the pharmacokinetics of the potent bronchodilator enprofylline (3‐propylxanthine; PX) and its renal handling were investigated in rats. Enprofylline (PX) was administered iv in dosages of 2.5, 10, 20, and 40 mg/kg, and PX concentration in plasma and urine was determined by HPLC. The pharmacokinetic parameters were estimated by model‐independent methods. The disappearance of PX from plasma was delayed as dosage was increased. The corresponding pharmacokinetic parameters also showed dose dependency; increases in the volume of distribution (Vd) and mean residence time (MRT) and a decrease in total body clearance (CL_T) were observed as dosage was increased from 2.5 to 40 mg/kg. Approximately 80% of the dose, however, was excreted in urine as unchanged PX. Plasma protein binding studies of PX showed concentration dependency and allowed determination of binding parameters, with an apparent dissociation constant (K_d) of 162.50 μM and a binding capacity (nP) of 565.23 μM. Some pharmacokinetic parameters for unbound PX calculated by total plasma concentration and binding parameters also showed dosedependent characteristics. However, no significant change in Vd for unbound PX was observed among administered doses, indicating that the distribution of PX into the body tissues is not changed by an increase in dosage. Renal clearance of unbound PX significantly increased as plasma concentration decreased. The maximum transport capacity (V_max) and the Michaelis‐Menten constant (K_m) for tubular secretion were 60.53 μg/min and 2.27 μg/mL, respectively. The aim of the present study is to demonstrate that both saturable tubular secretion and concentration‐dependent protein binding are responsible for the dose‐dependent pharmacokinetics of PX in rats.