Abstract
Purpose
Dose modification in renal impairment has traditionally been based on changes in estimated glomerular filtration rate (eGFR; estimated by creatinine clearance). However, many drugs are eliminated by tubular anionic and cationic transport where changes in eGFR may not necessarily reflect changes in tubular function. This study investigated the relationship between GFR and renal tubular function with reference to drug handling by using accepted drug probes.
Methods
Three drug probes, 51Cr-EDTA, fluconazole, and pindolol, were administered to patients who had varying degrees of renal impairment. Blood sampling, assays, and a pharmacokinetic analysis were performed for all drug probes and endogenous urate. Measured GFR (51Cr-EDTA clearance; mGFR) was compared to tubular anionic transport (urate clearance), tubular reabsorption (fluconazole clearance), and tubular cationic transport (S-pindolol clearance).
Results
A moderately strong association was demonstrated between the measured isotopic GFR and creatinine clearance (R2 = 0.78). A moderate positive correlation was found between mGFR and proximal tubular anion transport and reabsorption (R2 = 0.40–0.44, p < 0.0001). In contrast, cationic secretion correlated poorly with mGFR (R2 = 0.11, p = 0.036).
Conclusions
Given that drug dosing schedules utilise eGFR values as the basis for modifying drug dosing, our results would suggest that a recommendation of a dose reduction according to eGFR alone should be treated with caution.
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Acknowledgments
This study was funded by a Laurenson Grant awarded from the Otago Medical Research Foundation. Dr Putt was the recipient of an Otago University Emily Johnston Scholarship. Mr Ashley Duncan, Department of Human Nutrition, University of Otago, kindly undertook the pindolol and fluconazole assays as well as the routine biochemical assays. This work was presented in abstract form at the World Congress of Nephrology, Hong Kong 2013.
Conflict of interest
The authors have no financial conflicts of interest.
Author contributions
Dr Putt planned and conducted the study, analysed the GFR, and was the primary author of the manuscript. Professor Walker was the primary investigator and co-wrote the manuscript. Professor Duffull conducted the NONMEM analysis and assisted with manuscript preparation. Dr Schollum was involved in the planning of the study along with the other authors.
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Putt, T.L., Duffull, S.B., Schollum, J.B.W. et al. GFR may not accurately predict aspects of proximal tubule drug handling. Eur J Clin Pharmacol 70, 1221–1226 (2014). https://doi.org/10.1007/s00228-014-1733-7
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DOI: https://doi.org/10.1007/s00228-014-1733-7