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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.

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.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
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

Certain factors are well known to alter renal drug clearance. These include age, body weight, disease states, and drug interactions. Only recently, the genetic contribution toward the variability of renal drug clearance has been reported.¹ In that report by Leabman and Giacomini,¹ the genetic factors were found to contribute highly (64%-94%) to the interindividual variation in renal clearances of various drugs such as metformin, amoxicillin, and ampicillin. Those reported data, however, were based on previously published literature with relatively small numbers of subjects, and some subjects were elderly volunteers, which may have confounded the magnitude of the genetic variability reported. In addition, the ethnicity of the study subjects was not specified.

In view of the scarcity of "clean" data on the genetic versus environmental contributions toward the variability in renal drug clearance, we carried out this study in a single ethnic population (Chinese subjects) involving young healthy subjects. The specific objective of the study was to investigate the intra- and interindividual variability in renal drug clearance of 4 drugs that are known to undergo extensive renal secretion via the 2 major renal transport systems, organic anion transporters (OATs) and organic cation transporters (OCTs).

	METHODS

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Drug Substrates
Two substrates of OATs (ampicillin and cephalexin) and 2 substrates of OCTs (famotidine and metformin) were selected in this study. Ampicillin and cephalexin are organic anions that are mainly excreted in the urine by renal tubular secretion and to a lesser extent by glomerular filtration. Famotidine and metformin are organic cations that undergo extensive secretion via transporter-mediated mechanisms.

Subjects
The study protocols were approved by Joint The Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee. Written informed consent was obtained from each subject before participating in the study.

The subjects were all nonsmokers and in good health based on their medical history, physical examination, electrocardiogram evaluation, and routine laboratory tests (blood chemistry, hematology, and urine analysis). The subjects were required not to take any prescription or nonprescription medication 2 weeks before and throughout the study. They were also instructed to abstain from grapefruit, grapefruit juice, herbal dietary supplements, and caffeine-containing beverages including coffee and green tea 3 days before the study and during the study period.

Study Protocols
To estimate the intra- and interindividual variability in renal clearances of the substrates selected, the repeated drug administration method proposed by Kalow et al^2,3 was used. An open label, 2-period, 2-sequence, and crossover design was used. The study procedure for each drug substrate was similar. Briefly, healthy male Chinese subjects (with sample size ranging from 12 to 28) were recruited and underwent 2 study sessions separated by a washout period of 1 to 2 weeks. During each session, the subjects received single oral doses of each drug from 2 bioequivalent formulations (as part of bioequivalence studies). Multiple blood samples were collected from each subject up to 8 to 24 hours after dosing and placed in lithium heparin tubes. All blood samples were centrifuged immediately, and the separated plasma samples were stored at –80°C until analysis. During each study session, urine samples were also collected at different intervals up to 8 to 24 hours after drug administration. The total volume of urine collected during each interval was measured and recorded. Ten milliliters of urine was retained and stored at –80°C until analysis. The demographic data of the study subjects as well as blood and urine sampling time of each drug are summarized in Table I.

Plasma and Urine Sample Analysis
The concentrations of the drug substrates (ampicillin, cephalexin, famotidine, and metformin) in plasma and urine were determined by high-performance liquid chromatographic (HPLC) methods. For all assays, the same HPLC system was used, which consisted of a Waters Alliance 2690 separation module, Millennium³² chromatography management system, and Waters 996 photodiode array detector (Waters, Milford, Mass).

Ampicillin
Determinations of ampicillin in plasma and urine were performed using a previously described HPLC method,⁴ with slight modifications as follows: ampicillin and its internal standard (cefazolin) were extracted from 0.5 mL of plasma by a 1-step deproteination using trichloracetic acid. The sample was then centrifuged, and the aqueous supernatant was injected into the HPLC system. The urine sample was diluted 20-fold with water, followed by direct injection into the HPLC. Detection of ampicillin and cefazolin was performed by ultraviolet (UV) spectrometry at the wavelength of 220 nm.

The intra- and interday coefficients of variation (CVs) of the assay were <2.4% and <3.7%, respectively. The accuracy of the assay ranged from 92.9% to 104.8%. The lower limit of quantification (LLOQ) of ampicillin was 0.25 µg/mL and 25 µg/mL in plasma and urine, respectively.

Cephalexin
The concentrations of cephalexin in plasma and urine were determined by an HPLC method as described by Kovach et al.⁵ The intra- and interday CVs of the assay were <5.1% and <10.2%, respectively. The accuracy of the assay ranged from 90.9% to 100.8%. The LLOQ for cephalexin was 60 ng/mL and 5 µg/mL in plasma and urine, respectively.

Famotidine
The plasma concentrations of famotidine were determined by a previously published HPLC method with slight modification.^6,7 Briefly, 30 µL of internal standard (IS; 10 µg/mL cimetidine solution) and 0.5 mL of 0.1N HCL were added to 0.5 mL of plasma. The mixture was then loaded onto an Oasis MCX cartridge, which was washed with 2 mL of 0.1N HCL, 2 mL of methanol, and then 2 mL of methanol-water (30:70). The basic fraction was eluted by 2 mL of 5% NH₄OH in methanol, and the eluant was subsequently evaporated to dryness. The residue was reconstituted with 150 µL of mobile phase, and 100 µL of aliquot was injected for HPLC analysis. The urine concentrations of famotidine were determined by direct injection of the urine sample into the HPLC after appropriate dilution with water. Detection was preformed by UV spectrometry at a wavelength of 266 nm for famotidine and 240 nm for cimetidine (IS).

The intra- and interday CVs of the assay were <8.3% and <10.5%, respectively. The accuracy of the assay ranged from 95.5% to 100.4%. The LLOQ for famotidine was 10 ng/mL and 50 ng/mL in plasma and urine, respectively.

Metformin
The concentrations of metformin in plasma and urine were determined by an HPLC method as described previously.⁸ The intra- and interday CVs of the assay were <4.1% and <7.1%, respectively. The accuracy of the assay ranged from 90.1% to 111.2%. The LLOQ for metformin was 25 ng/mL and 1 µg/mL in plasma and urine, respectively.

Pharmacokinetic Analyses
Pharmacokinetic analysis of the plasma concentration data was performed using the WinNolin program (version 2.1, Pharsight Corp). The area under the plasma concentration-time curve from time 0 to the last sampling time t (AUC_0-t) was calculated using the linear trapezoidal rule. The renal clearance (CL_R) was calculated according to the following:

where X_u,t is the cumulative amount of the drug excreted in the urine for time 0 to t.

Statistical Analyses
Analysis of variance (ANOVA) was performed on CL_R, with inclusion of the factors of subject, period, sequence, and treatment. The genetic component (r_GC) contributing to the variations in CL_R was estimated according to the equation^2,3

where _inter and _intra refer to the inter- and intraindividual variances obtained from ANOVA, respectively.

To evaluate the relationship between CL_R values of each substrate from 2 study sessions, Spearman's rank correlation analysis was performed. A P value of <.05 was considered statistically significant for all tests. All analyses were performed with the SPSS software (version 11.0, SPSS Inc).

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
There were no statistically significant period, sequence, or treatment effects on the renal clearance (CL_R) of each substrate from ANOVA analyses (all P > .05).

The CL_R value together with the inter- and intraindividual variability data for each substrate are shown in Table II. For all these drugs, the variance in CL_R observed between individuals (_inter) was significantly greater (all P < .05, F test) than that within individuals (_intra). The CL_R of ampicillin, cephalexin, famotidine, and metformin averaged 5.21 (2.87-11.20), 3.01 (1.50-3.82), 4.96 (2.84-8.17), and 9.44 (5.66-15.43) mL/min/kg, respectively. The r_GC values ranged from 0.75 to 0.93 for these 4 substrates, suggesting a strong genetic component contributing to the variations in the renal clearance of these drugs.

The CL_R values of the 2 OAT substrates, ampicillin and cephalexin, in individual subjects over 2 study sessions are shown in Figure 1A, whereas the CL_R values of the 2 OCT substrates, famotidine and metformin, are shown in Figure 1B. For all substrates, no statistically significant differences were observed in the CL_R values between session 1 and 2 (all P > .05, paired t test). The individual renal clearance values also correlated well between the 2 sessions, with Spearman's rank correlation coefficients (r_s) of 0.66 (P < .05), 0.80 (P < .01), 0.68 (P < .01), and 0.67 (P < .05) for ampicillin, cephalexin, famotidine, and metformin, respectively.

View larger version (36K): [in this window] [in a new window]   Figure 1. (A) Renal clearance of organic anion transporter substrates ampicillin and cephalexin in individual subjects over 2 study sessions. (B) Renal clearance of organic cation transporter substrates famotidine and metformin in individual subjects over 2 study sessions.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
In our study, the renal clearances of ampicillin, cephalexin, famotidine, and metformin were found to be 5.21, 3.01, 4.96, and 9.44 mL/min/kg, respectively. These values are generally in good agreement with those reported in the literature in non-Chinese subjects.^9-12 Considering that the creatinine clearance in the healthy subjects is 1.5 to 2.0 mL/min/kg,¹³ our results confirm the significant involvement of tubular secretion for these drug substrates.

In this study, we have observed high r_GC values (0.75-0.93) for renal clearances of all 4 drugs, indicating that at least 75% or more of the interindividual variability in renal clearance of these substances is due to the genetic factors. These data are consistent with the previous report in other ethnic populations.¹

The observed high r_GC values suggest that there is a strong genetic component contributing to the variations in renal drug clearance in Chinese subjects, presumably attributable to the transporters involved in the tubular secretion of these 4 drugs. The specific transporter for ampicillin and cephalexin has been identified to be organic anion transporter OAT1 at the basolaterol membrane site of the renal proximal tubule cells.^14,15 However, these drugs can also interact with the peptide transporters such as PEPT1 and PEPT2 at the luminal membrane site.^16,17 The specific transporter for metformin has been identified to be OCT2.^18,19 Although the renal transport mechanism of famotidine is unclear at present, based on data from interactions between famotidine and OCT2 substrates (ie, cimetidine) or inhibitors (ie, probenecid),^20,21 famotidine clearance also appears to be mediated via OCT2.

Recently, several alternative splicing variants and single nucleotide polymorphisms (SNPs) have been identified for OAT1, OCT2, and PEPT. Bahn et al^22,23 reported that among the 4 OAT1 isoforms, the major variants OAT1-1 (563 amino acid) and OAT1-2 (550 amino acid) were functionally similar, whereas the splice variants OAT1-3 and OAT1-4 (having a 132-bp deletion) did not exhibit transport activities when expressed in COS7 cells. For OCT2, 28 SNPs have been identified in ethnically diverse populations, and 4 SNPs have been shown to exhibit altered function in vitro.²⁴ Similarly, some rare variants in PEPT2 have also been shown to disrupt PEPT2 function.^25,26 Although the polymorphism of the above transporters in Chinese populations has not been reported, our observed high r_GC values for the 4 drugs' renal clearances in the Chinese subjects suggest that genetic polymorphisms of these transporters may exist, and this needs to be investigated.

In our study, we have observed lower r_GC values for ampicillin and famotidine than those for cephalexin and metformin. Both ampicillin and famotidine are known to undergo partial metabolism. Ampicillin is partially metabolized by hydrolysis of the ß-lactam ring, and 7% to 11% of a single oral dose is excreted in the urine as penicilloic acid.²⁷ About 2% to 8% of an oral dose of famotidine also undergoes metabolism in the liver to form its metabolite famotidine S-oxide.²⁸ Thus, these metabolic pathways may have contributed to the higher intrasubject relative to intersubject variation in renal clearance and hence lower r_GC values for ampicillin and famotidine.

All subjects who participated in our study were young and healthy nonsmokers. The interindividual variations of the major demographic factors such as age and body height ranged from 2.5% to 7.0% (variation in body weight was taken into account in CLcr). Thus, the potential influences on the overall interindividual variations of CLcr by these demographic factors should be small. Also, all study subjects did not use any concomitant medication during the study period. Such uniform basal environmental conditions allow minimization of the variations of the environmental contribution. This is reflected in the relatively small intraindividual CVs (7%-18%) observed in our subjects.

In our study, the renal clearance (CLcr) is calculated based on the plasma and urine data obtained up to 8 hours (for ampicillin and cephalexin) or 24 hours (for famotidine and metformin) following a single dose of each substrate. Since the elimination half-lives (t_1/2)of these drugs are relatively short (t_1/2 averaged 1.0, 1.4, 3.1, and 3.9 hours for ampicillin, cephalexin, famotidine, and metformin, respectively), such sampling time periods should be sufficient for the estimation of CLcr for these compounds.

In this study, we have included 2 bioequivalent formulations of each substrate as part of bioequivalence studies. The inclusion of 2 formulations may theoretically contribute to the variability in drug pharmacokinetics. However, the 2 formulations of each substrate are bioequivalent. In addition, the formulation effect, if it exists, normally influences the absorption and bioavailability of the drug. Since our main pharmacokinetic parameter measured is renal clearance, it is not expected to be influenced by any formulation effect. Nevertheless, further studies with larger sample sizes are needed to verify our findings.

Another potential shortcoming of our present study is the lack of glomerular filtration and reabsorption rate determinations concurrent with the renal clearance determination. A previous twin study has suggested that glomerular filtration is not significantly controlled by genetic factors.²⁹ Since all these 4 drugs are known to be extensively cleared via tubular secretion, the observed variation in renal clearances is likely to be a reflection of the variation in net tubular secretion.

	CONCLUSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
High r_GC values were obtained for the renal clearances of ampicillin, cephalexin, famotidine, and metformin, suggesting a potential significant genetic contribution by the renal OATs and OCTs in our Chinese subjects. These data imply the potential need for consideration of pharmacogenetics in the therapeutic management of patients receiving these drugs. However, 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.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 
This study was partially supported by a grant from the Innovation and Technology Commission of the Government of Hong Kong SAR (ITS/174/00). We would like to thank Evelyn Chau, Ping-chuen Ho, Sherry Lam, Carrie Wong, and Li-min Zhou for their valuable technical assistance in this investigation. None of the authors has any financial or personal relationships that could be perceived as influencing the research described. The study protocols were approved by Joint The Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee.

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TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSION ACKNOWLEDGEMENTS REFERENCES

 

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