Renal Accumulation of Salicylate and Phenacetin: Possible Mechanisms in the Nephropathy of Analgesic Abuse
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Renal accumulation of salicylate and phenacetin: possible mechanisms in the nephropathy of analgesic abuse Lewis W. Bluemle Jr., Martin Goldberg J Clin Invest. 1968;47(11):2507-2514. https://doi.org/10.1172/JCI105932. Research Article Since either aspirin or phenacetin might be causative in the nephropathy of analgesic abuse, studies were designed to examine the renal accumulation and distribution of the major metabolic products of these compounds, salicylate and N- acetyl-p-aminophenol (APAP) respectively, in dogs. Nineteen hydropenic animals were studied, of which seven were given phenacetin, nine received acetyl salicylic acid, two were given both aspirin and phenacetin, and one received APAP directly. Two of three hydrated animals were given phenacetin and one was given aspirin. During peak blood levels of salicylate and (or) APAP, the kidneys were rapidly removed, frozen, sliced from cortex to papillary tip, and analyzed for water, urea, APAP, and salicylate. No renal medullary gradient for salicylate was demonstrable during both hydropenic and hydrated states. In contrast, both free and conjugated APAP concentrations rose sharply in the inner medulla during hydropenia, reaching a mean maximal value at the papillary tip exceeding 10 times the cortical concentration (P < 0.001), a distribution similar to that of urea. Salicylate had no effect on the APAP gradient, but hydration markedly reduced both the APAP and urea gradients in the medulla. The data indicate that APAP probably shares the same renal mechanisms of transport and accumulation as urea and acetamide, and that papillary necrosis from excessive phenacetin may be related to high papillary concentration of APAP. Find the latest version: https://jci.me/105932/pdf Renal Accumulation of Salicylate and Phenacetin: Possible Mechanisms in the Nephropathy of Analgesic Abuse LEWIS W. BLuIEwnE, JR. and MARTIN GOLDBERG From the Renal-Electrolyte Section, Department of Medicine and the General Clinical Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 A B S T R A C T Since either aspirin or phenacetin probably shares the same renal mechanisms of might be causative in the nephropathy of anal- transport and accumulation as urea and acetamide, gesic abuse, studies were designed to examine the and that papillary necrosis from excessive phena- renal accumulation and distribution of the major cetin may be related to high papillary concentra- metabolic products of these compounds, salicylate tion of APAP. and N-acetyl-p-aminophenol (APAP) respectively, in dogs. Nineteen hydropenic animals were stud- INTRODUCTION ied, of which seven were given phenacetin, nine received acetyl salicylic acid, two were given both Since 1953 when Spuhler and Zollinger (1) re- aspirin and phenacetin, and one received APAP ported a series of cases in which chronic inter- directly. Two of three hydrated animals were given stitial nephritis was associated with a high in- phenacetin and one was given aspirin. During take of certain analgesic compounds, many papers peak blood levels of salicylate and (or) APAP, have appeared on the subject of the nephropathy the kidneys were rapidly removed, frozen, sliced of analgesic abuse. Renal failure is commonly from cortex to papillary tip, and analyzed for associated with this condition, and pathologically, water, urea, APAP, and salicylate. an almost uniform finding is necrosis of the renal No renal medullary gradient for salicylate was papilla (2). Recently, Kincaid-Smith (3) has demonstrable during both hydropenic and hy- suggested that papillary necrosis is the primary drated states. In contrast, both free and conju- factor in the pathogenesis of this disease. gated APAP concentrations rose sharply in the Many questions remain, however, regarding the inner medulla during hydropenia, reaching a mean etiologic agents involved and the mechanisms of maximal value at the papillary tip exceeding 10 the renal tissue damage resulting from them. The times the cortical concentration (P < 0.001), a clinical evidence for the entity, analgesic-induced distribution similar to that of urea. Salicylate had nephropathy, while highly suggestive, is largely no effect on the APAP gradient, but hydration inferential, and the results of toxicity studies in markedly reduced both the APAP and urea gradi- animals have been both inconsistent and incon- ents in the medulla. The data indicate that APAP clusive (4-6). There are still conflicting opin- ions as to whether aspirin or phenacetin is the A preliminary report of this work has been presented important offending agent. Gilman (7) has postu- (Clin. Res. 1967. 15: 351). lated that salicylate might diffuse back through . Address requests for reprints to Dr. Martin Goldberg, 860 Gates Building, Hospital of the University of Penn- renal tubular epithelial cells at medullary sites sylvania, Philadelphia, Pa. 19104. where tubular pH is low, favoring the diffusion Received for publication 16 May 1968. of the undissociated and presumably freely dif- The Journal of Clinical Investigation Volume 47 1968 '.2507 fusible form of salicylate. Hence, theoretically, a 0 mechanism is possible which can lead to the ,ICs C... medullary accumulation of salicylate. On the other NH2 NH2 CH3 NH2 hand, an inspection of the chemical structure of Urea Acetamide phenacetin and its major metabolic product, N-acetyl-p-aminophenol (APAP) (8), reveals ol oH ,C.. ",C a close resemblance to acetamide, an analogue of CH3 NH N H urea (see Fig. 1), which has been shown to con- CH3 centrate preferentially in the renal papilla (9). The present study was therefore undertaken to 0C2H5 OH determine whether salicylate or APAP, or both, Phenacetin N- acetyl -p- aminophenol might be distributed in the kidney to form an in- FIGURE 1 Comparison of the chemical formulas of urea, creasing concentration gradient from cortex to acetamide, phenacetin, and N-acetyl-p-aminophenol. See papillary tip. The rationale for this was based on text. the following two assumptions: (a) insofar as any component of analgesic mixtures might be nephro- bladder was emptied by the air washout technique. In toxic, the degree of injury it produces should be the hypdropenic animals, when urine osmolality exceeded related to its tissue concentration, and (b) the 1400 mOsm/kg a final urine specimen was collected and correlate with the blood samples were obtained. Both kidneys were then site of maximum injury should quickly removed after clamping the renal pedicles. The site of maximum concentration. Hence since the kidneys were immediately frozen in acetone and dry ice. main site of injury in the nephropathy of anal- In the hydrated animals the kidneys were similarly re- gesic abuse is the medulla, with papillary necrosis moved 1 hr after institution of the water load. being the characteristic feature (3), it seemed Two cross-sectional slices, i inch thick, were cut from each frozen kidney by band saw. From each slice at reasonable to ask whether the main metabolic least two series of tissue samples, each weighing from products of aspirin (salicylate) or of phenacetin 75 to 500 mg, were cut at the levels of the cortex, the (APAP) might tend to concentrate in these re- outer papilla (the outer portion of the "white medulla" gions of the kidney. adjacent to the outer red zone of the medulla), and the papillary tip. One series of samples from each kidney METHODS was used to determine tissue water content by drying in an oven at 103-105'C for 48 hr. Another series was used Mongrel female dogs weighing between 14 and 30 kg for analysis of salicylate and APAP. In six experiments were used for all experiments. Hydropenia was induced with aspirin and three with phenacetin an additional se- by water deprivation for 18-X24 hr. 5 units of pitressin ries from each kidney was used for urea analysis by a tannate in oil was given 16 hr before each experiment. modification of the Conway microdiffusion technique Control urine samples for use as blanks were obtained (10). Five hydropenic animals which were given no by direct bladder puncture. The analgesic agent being drug were used to obtain control levels of urea from studied was given by mouth in gelatin capsules with up cortex to papillary tip. These data were reported else- to 75 ml of milk or water to aid absorption. Nine dogs where as part of another study (11), but they are uti- received phenacetin alone (300 mg/kg body weight). Of lized here as controls because the experimental prepara- these, seven were hydropenic until removal of the kidney tion and methods of analyses were identical with those and two received an acute water load (30 ml/kg) as 5% of the present study. glucose in water administered over a period of 30 min Salicylate levels were determined on nitric acid di- before the kidneys were removed during the ensuing diu- gests of tissue and in blood and urine by the method of resis. In these latter animals pitressin was omitted. Trinder (12). Concentrations of free and conjugated Nine dogs received aspirin alone in dosages of 170- APAP were determined in all plasma and urine samples 330 mg/kg body weight. Eight of these were hydro- of the phenacetin-loaded dogs by the extraction and penic and one received a water load as described above, spectrophotometric assay of Brodie and Axelrod (13). before removal of the kidneys. Two additional hydro- In two phenacetin-loaded dogs, one hydropenic and the penic animals were given both aspirin (170 mg/kg) and other hydrated, independent determinations were made phenacetin (300 mg/kg) simultaneously. One additional of free and conjugated APAP concentrations in kidney hydropenic animal was given APAP directly (150 samples, also by the method of Brodie and Axelrod (13). mg/kg). Recovery studies were done by adding known amounts 2-3 hr after drug administration, anesthesia was in- of salicylate and APAP to minced beef and dog kidney.