Decrease In Renal Content Research Articles

Drug-targeting to the kidney: Renal delivery and degradation of a naproxen-lysozyme conjugate in vivo

A renal-specific controlled release of an active drug may enable a reduction of the required dose and may provide a reduction of extra-renal toxicity. To achieve renal specific targeting of the NSAID naproxen, the low-molecular-weight protein (LMWP) lysozyme was employed as carrier since it is mainly taken up and catabolized in the proximal tubules of the kidney. A conjugate was synthesized with an average coupling degree of 2 mol naproxen per 1 mol lysozyme in which the drug was directly coupled to the protein via a peptide bond. First, we investigated whether naproxen conjugation affects the renal disposition of lysozyme. As native lysozyme, the conjugate was predominantly and rapidly (within 20 min) taken up by the kidney. The subsequent decrease in renal content reflecting the renal degradation of the conjugated lysozyme molecules appeared also to be similar to that of native lysozyme with a half life of four hours. Second, the effect of lysozyme conjugation on the body distribution of naproxen was studied. An important observation with regard to the aimed reduction in extra-renal side effects was that no detectable amounts of free naproxen were present in the plasma after administration of conjugate. Conjugation of naproxen to lysozyme resulted in a pronounced (70-fold) increase of naproxen accumulation in the kidney. In agreement with the protein disposition study, the conjugate was rapidly taken up by the kidney and subsequently degraded. In conclusion, renal selective targeting of the NSAID naproxen can be obtained by conjugation with the LMWP lysozyme. This concept of drug delivery to the kidney has the potential to improve drug efficacy and safety.

Adrenal cortex and renal pressor function.

The pressor response of the nephrectomized rat to the injection of kidney extracts and to a renal graft, was used as an index of the renal content and secretion of pressor substances during adrenal insufficiency or treatment with corticosteroids. Adrenalectomy caused an elevation of both content and secretion, which was best demonstrated after two to three weeks of maintenance therapy. Treatment with cortisone and cortisol decreased slightly but significantly the secretion of pressor substances without altering renal content. ACTH had no effect on either function. Sequential studies of content and secretion of pressor substances during treatment with DCA plus salt showed first a rapid disappearance of prossor activity from renal vein blood followed by a decrease in renal content to near zero levels; DCA without excess salt elicited the same effects but more gradually; administration of 1% saline alone decreased secretion without altering content. It is concluded that salt active corticosteroids specifically inhibit the formation and secretion of renal pressor substances and that determination of the index of secretion constitutes a more reliable and sensitive indicator of the renal pressor function than determination of the pressor activity in kidney extracts.