Renal targeting of a non-steroidal antiinflammatory drug: effects on renal prostaglandin synthesis in the rat

1, Renal specific targeting of the non-steroidal anti-inflammatory drug naproxen was obtained by coupling to the low-molecular-mass protein lysozyme. A previous study showed that conjugation to lysozyme resulted in a 70-fold increase of naproxen accumulation in the kidney with a subsequent renal release of the active metabolite naproxen-lysine. 2. In the present study we questioned whether naproxen-lysozyme is active in the rat kidney, inhibiting the urinary excretion of prostaglandin E-2 and renal sodium and water excretion in salt-restricted baseline conditions as well as during frusemide treatment. 3. A high dose of free naproxen (10 mg . day(-1) . kg(-1)) did not affect prostaglandin E-2 excretion in baseline conditions (naproxen, 11 +/- 1 ng/8 h; vehicle, 13 +/- 4 ng/8 h), whereas sodium and water excretion were, respectively, 3.0 and 1.6 times lower in the naproxen group (P < 0.05). Naproxen completely prevented the frusemide-induced increase (3-fold) in prostaglandin E-2 excretion (naproxen 6.6 +/- 1.1 ng/8 h, vehicle 40 +/- 12 ng/8 h, P < 0.005). Frusemide-stimulated natriuresis and diuresis were, respectively, 1.6 (P < 0.05) and 1.8 times (P < 0.005) lower in the naproxen group. 4. A dose of 2 mg . day(-1) . kg(-1) lysozyme-conjugated naproxen did not affect prostaglandin E-2 excretion in baseline conditions (conjugate, 18+/-2 ng/8 h; vehicle, 24+/-5 ng/8 h). The conjugate also had no effect on sodium and water excretion. However, the naproxen conjugate completely prevented the frusemide-induced increase (2-fold) in prostaglandin E-2 excretion (conjugate, 16 +/- 3 ng/8 h; vehicle, 48 +/- 1 3 ng/8 h, P < 0.05). Surprisingly, frusemide-induced natriuresis and diuresis were not affected by the conjugate. 5. In conclusion, a renal specific delivery of the non-steroidal anti-inflammatory drug naproxen using lysozyme results in an inhibitory effect on renal prostaglandin E-2 synthesis but does not affect the excretion of sodium and water, in contrast to free naproxen.