Variable Furosemide Absorption and Poor Predictability of Response in Elderly Patients

Authors

  • Michael D. Murray Pharm.D., M.P.H.,

    Corresponding author
    1. Clinical Pharmacology Division, Department of Medicine, Indiana University School of Medicine, and the Pharmacy Practice Department, Purdue University School of Pharmacy, Indianapolis, Indiana.
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  • Kathy M. Haag R.N.,

    1. Clinical Pharmacology Division, Department of Medicine, Indiana University School of Medicine, and the Pharmacy Practice Department, Purdue University School of Pharmacy, Indianapolis, Indiana.
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  • Paula K. b́lack R.N.,

    1. Clinical Pharmacology Division, Department of Medicine, Indiana University School of Medicine, and the Pharmacy Practice Department, Purdue University School of Pharmacy, Indianapolis, Indiana.
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  • Stephen D. Hall Ph.D.,

    1. Clinical Pharmacology Division, Department of Medicine, Indiana University School of Medicine, and the Pharmacy Practice Department, Purdue University School of Pharmacy, Indianapolis, Indiana.
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  • D. Craig Brater M.D.

    1. Clinical Pharmacology Division, Department of Medicine, Indiana University School of Medicine, and the Pharmacy Practice Department, Purdue University School of Pharmacy, Indianapolis, Indiana.
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Clinical Pharmacology Division, Department of Medicine, Wishard Memorial Hospital, 1001 West Tenth Street, OPW 320, Indianapolis, IN 46202.

Abstract

Study Objectives. To determine the between- and within-patient variability of furosemide bioavailability and natriuretic response, and whether four marketed products differ in bioavailability and response.

Design. Open-label, crossover study.

Setting. General clinical research center at an academic medical center.

Patients. Convenience sample of 17 patients age 65 ± 6 years receiving diuretics for the treatment of hypertension or congestive heart failure.

Intervention. Each patient received each of five furosemide products (one intravenous and four oral tablet formulations) twice in random order for a total of 10 treatments.

Measurements and Main Results. Measurements included absolute bioavailability using cumulative amounts of urinary furosemide collected over 8 hours after oral versus intravenous dosing, and cumulative amounts of urinary sodium. Extensive between- and within-patient variability in all measured values rendered any differences among the products neither clinically nor statistically significant. Mean (± SD) bioavailability was 49 ± 17% (range 12–112%) and coefficients of variation with different products were from 25–43%. Coefficients of variation for urinary furosemide excretion and urinary sodium excretion were also large, 25–42% and 23–51%, respectively. Multivariate analyses that incorporated between- and within-patient effects failed to reveal differences among the products for bioavailability (F=1.04, p=0.403), urinary furosemide excretion (F=1.09, p=0.371), or urinary sodium excretion (F=0.97, p=0.448). Correlation coefficients were 0.81–0.85 for the rates of sodium and furosemide excretion, and half-maximum response using a sigmoid Emax model did not differ among products.

Conclusion. Although furosemide concentration in urinary and natriuretic responses showed good correlation, variability in bioavailability considerably affects the drug's excretion into urine. Variability in absorption both among patients and within an individual patient is great and overwhelms any differences in bioavailability among approved furosemide products. Switching from one formulation to another will not likely result in any predictable change in patient response.

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