Vancomycin: Predictive risk factors for nephrotoxicity and implication for monitoring

The increased use of vancomycin in hospitals has resulted in a standard practice to monitor serum vancomycin levels because of possible nephrotoxicity. However, the routine monitoring of vancomycin serum concentration is under criticism and the cost effectiveness of such routine monitoring is in question because frequent monitoring neither results in increase efficacy nor decrease nephrotoxicity. The purpose of the present study is to determine factors that may place patients at increased risk of developing vancomycin induced nephrotoxicity and for whom monitoring may be most beneficial.^ From September to December 1992, 752 consecutive in patients at The University of Texas M. D. Anderson Cancer Center, Houston, were prospectively evaluated for nephrotoxicity in order to describe predictive risk factors for developing vancomycin related nephrotoxicity. Ninety-five patients (13 percent) developed nephrotoxicity. A total of 299 patients (40 percent) were considered monitored (vancomycin serum levels determined during the course of therapy), and 346 patients (46 percent) were receiving concurrent moderate to highly nephrotoxic drugs.^ Factors that were found to be significantly associated with nephrotoxicity in univariate analysis were: gender, base serum creatinine greater than 1.5mg/dl, monitor, leukemia, concurrent moderate to highly nephrotoxic drugs, and APACHE III scores of 40 or more. Significant factors in the univariate analysis were then entered into a stepwise logistic regression analysis to determine independent predictive risk factors for vancomycin induced nephrotoxicity.^ Factors, with their corresponding odds ratios and 95% confidence limits, selected by stepwise logistic regression analysis to be predictive of vancomycin induced nephrotoxicity were: Concurrent therapy with moderate to highly nephrotoxic drugs (2.89; 1.76-4.74), APACHE III scores of 40 or more (1.98; 1.16-3.38), and male gender (1.98; 1.04-2.71).^ Subgroup (monitor and non-monitor) analysis showed that male (OR = 1.87; 95% CI = 1.01, 3.45) and moderate to highly nephrotoxic drugs (OR = 4.58; 95% CI = 2.11, 9.94) were significant for nephrotoxicity in monitored patients. However, only APACHE III score (OR = 2.67; 95% CI = 1.13,6.29) was significant for nephrotoxicity in non-monitored patients.^ The conclusion drawn from this study is that not every patient receiving vancomycin therapy needs frequent monitoring of vancomycin serum levels. Such routine monitoring may be appropriate in patients with one or more of the identified risk factors and low risk patients do not need to be subjected to the discomfort and added cost of multiple blood sampling. Such prudent selection of patients to monitor may decrease cost to patients and hospital. ^

IN VITRO METABOLISM OF 6-THIOGUANINE IN RAT SUBCELLULAR FRACTIONS

The metabolism of the antitumor agent 6-thioguanine (TG, NSC-752) by rat liver was studied in vitro. Livers from adult male Sprague-Dawley rats were homogenized and the "liver homogenate" was subjected to differential centrifugation to obtain the "10,000 x g pellet", the "post-mitochondrial fraction", the "cytosol fraction", and the "microsomes". The homogenity of each fraction was estimated by appropriate marker enzyme assays. To delineate the in vitro metabolism of TG by rat liver, 0.2 mM of {8-('14)C}TG was incubated with different subcellular fractions in KCl-Tris-MgCl(,2) buffer, pH 7.4 at 37(DEGREES). The metabolites formed were identified by chromatography, UV spectrometry, as well as mass spectrometry. After a 1 hr incubation, TG was metabolized by the liver homogenate, the 10,000 x g pellet and the post-mitochondrial fraction mainly to 6-thioguanosine (TGR), accompanied by varying lesser amounts of 6-thiouric acid (TUA), allantoin, guanine-6-sulfinic acid (G-SO(,2)H) and an unknown product. In comparison, the cytosal fraction converted TG almost entirely to TGR and TUA in equal amounts. The formation of TGR from TG was limited by the endogenous supply of ribose-1-phosphate. With the microsomal fraction, however, TG was metabolized significantly to G-SO(,2)H and the unknown, accompanied with some TGR. After a 5 hr incubation the metabolism of TG was changed to favor the catabolic route, yielding mostly TUA in the post-mitochondrial and cytosol fractions; but mainly allantoin in the liver homogenate fraction. The kinetic studies of TG metabolism by the subcellar fractions indicated that the formation of TGR served as a depot form of TG. The level of TGR decreased when the catabolism of TG became prominent. The oxidation of TG to GSO(,2)H mediated by the hepatic microsomes represented a new catabolic pathway of TG. This GSO(,2)H, under acidic conditions, readily decomposes to guanine and inorganic sulfate. In the presence of reduced glutathione in Tris buffer, pH 7.8 at 25(DEGREES), GSO(,2)H is adducted to glutathione chemically to form S-(2-amino-purin-6-yl) glutathione and conceivably, inorganic sulfate. Therefore, the formation of GSO(,2)H from TG might have implication in the desulfuration mechanism of TG. On the other hand, the unknown formed from TG by the action of the microsomal enzymes appeared to be a TG conjugate. However, it is neither a glutathione, a glucuronide, nor a ribose conjugate. Additionally, the deamination of TG by guanine deaminase (E.C.3.5.4.3) isolated from rat liver was also investigated. TG is a poorer substrate (Km = 4.8 x 10('-3)M) for guanine deaminase than that of guanine (Km = 4.7 x 10('-6)M) at pH 7.25, optimal pH for TG as a substrate. TG is also a competitive inhibitor of guanine for guanine deaminase, with a ki of 2.2 x 10('-4)M. ^