Renal targeting of a non-steroidal anti-inflammatory 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 E2 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 E2 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 E2 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 E2 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 E2 excretion (conjugate, 16+/-3 ng/8 h; vehicle, 48+/-13 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 E2 synthesis but does not affect the excretion of sodium and water, in contrast to free naproxen.
Haas
M
M
Department of Internal Medicine, Division of Nephrology, Groningen Institute for Drug Studies, University Hospital, Hanzeplein 1, NL-9713 GZ Groningen, The Netherlands.
Moolenaar
F
F
Meijer
D K
DK
de Jong
P E
PE
de Zeeuw
D
D
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis* / Q000652:urine; D004232:Diuretics / Q000494:pharmacology; D004337:Drug Carriers; D005665:Furosemide / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009113:Muramidase; D009288:Naproxen / Q000494:pharmacology*; D009318:Natriuresis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014554:Urination / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004232:Diuretics; D004337:Drug Carriers; D009288:Naproxen; D005665:Furosemide; D009113:Muramidase; D015232:Dinoprostone