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Variability in Renal Clearance of Substrates for Renal Transporters in Chinese Subjects

From the School of Pharmacy (Dr Yin, Dr Chow) and the Department of Medicine and Therapeutics (Dr Tomlinson), Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.

The authors evaluated the inter- and intraindividual variability in the renal clearance of substrates of organic anion transporters (OAT) or organic cation transporters (OCT) using repeated drug application procedures. Two OAT substrates (ampicillin and cephalexin) and 2 OCT substrates (famotidine and metformin) were selected. Each drug was administered orally twice to healthy subjects, with sample sizes ranging from 12 to 28 (using bioequivalent formulations of each drug). The inter-(_inter) and intrasubject (_intra) variances in renal clearance were estimated based on analysis of variance, and the genetic contribution (r_GC) was calculated as (_{inter – intra})/_inter. The renal clearances of ampicillin, cephalexin, famotidine, and metformin averaged 5.21 (range, 2.87-11.20), 3.01 (range, 1.50-3.82), 4.96 (range, 2.84-8.17), and 9.44 (range, 5.66-15.43) mL/min/kg, with mean intraindividual coefficients of variation of 17.7%, 7.3%, 13.5%, and 9.0% and r_GC values of 0.75, 0.89, 0.81, and 0.93, respectively. These high r_GC values suggest a potential significant genetic contribution by the renal OATs and OCTs in Chinese subjects. Further studies in a larger population are needed to confirm the importance of these results as well as to identify specific genetic variants in these transporters responsible for such variability.

Key Words: Genetic variability • renal clearance • renal transporters

Address for reprints: Ophelia Q. P. Yin, PhD, School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong.