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Digoxinlike immunoreactive substances (DLIS) cross-react with antidigoxin antibodies and falsely elevante total digoxin levels. Cross-reactivity of DLIS with various immunoassays for digoxin has been extensively studied in the past. The digitoxin molecule differs from digoxin by having one extra hydroxyl group in the aglycone ring. Therefore, DLIS may also falsely elevate total digitoxin concentrations. However, in the past, limited studies have shown the presence of digitoxinlike immunoreactive substances (DTLIS) in cord blood and sera of neonates. We compared DLIS and DTLIS concentrations in sera of patients with uremia, liver disease, and hypoalbuminemia. We found measurable DLIS concentrations in 11 of 45 patients by the fluorescence polarization immunoassay (FPIA) for digoxin (range, 0.20-0.89 ng/ml digoxin equivalent). These patients did not receive any digoxin or digitoxin. Using the FPIA, we also found elevated DTLIS concentrations in 10 of these 45 patients (range, 2.88-21.24 ng/ml digitoxin equivalent). Given the narrow therapeutic range of digitoxin (15-30 ng/ml), this cross-reactivity is significant. Elevated concentrations of DTLIS in sera falsely elevated the measured concentrations of digitoxin (positive interference) when known amounts of digitoxin were added to such sera. Interestingly, we found a poor correlation between DLIS and DTLIS concentrations in sera of patients with liver disease and uremia (r = 0.58), with some patients having no measurable DLIS activity but measurable DTLIS activity and vice versa. Digoxin showed only 4-8% cross-reactivity against digitoxin antibody with a wide range of concentration. Some proposed DLIS compounds (nonesterified fatty acids, cholic acid, lysophospholipid, and DHEA-sulfate) did not show any cross-reactivity with the digitoxin assay at a concentrations much higher than the physiologic range. We conclude that DTLIS activity is present in patients with liver disease and uremia, and the correlation between DLIS activity and DTLIS activity is poor. Moreover, some proposed DLIS do not explain the DTLIS activity detected in serum.

Ketoconazole is an antifungal agent widely used in the management of patients with fungal infection, especially in patients with acute acquired immuno-deficiency syndrome (AIDS). Ketoconazole is 99% bound to serum albumin and may interact with valproic acid, an anticonvulsant with 90% to 95% binding to serum albumin. The interaction may be more significant in hypoalbuminemia, a common finding in patients with AIDS. However, valproic acid-ketoconazole interaction has not been reported. The authors prepared two serum pools from patients receiving valproic acid with normal serum albumin and another pool from patients with hypoalbuminemia. Another serum pool was prepared from uremic patients not receiving valproic acid. The aliquots of serum pool were supplemented with various concentrations of ketoconazole, representing therapeutic and slightly higher therapeutic concentrations. The concentrations of free valproic acid were determined in protein-free ultrafiltrates (prepared by centrifuging specimens at 25 degrees C with the Centrifree Micropartition System at 1500 g for 20 minutes) using fluorescence polarization immunoassay. In the serum pool with normal albumin concentration, the authors observed statistically significant displacement of valproic acid only at higher ketoconazole concentrations (10 and 20 micrograms/ml) whereas, in the serum pool with hypoalbuminemia, they observed statistically significant displacement of valproic acid by ketoconazole with lower and higher concentrations of ketoconazole. The magnitude of displacement was more significant at high valproic acid concentrations (95 and 150 mg/ml, respectively) probably because of the concentration-dependent binding of valproic acid to serum albumin. The authors observed no displacement of valproic acid by ketoconazole in the uremic serum pool. On the other hand, the free valproic acid concentrations were decreased in the presence of ketoconazole in the uremic serum pool.

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