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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS
Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom (A.S.W., S.L., C.D.A.B.); and DMPK, AstraZeneca LP, Wilmington, Delaware (Y.W.)
Received May 16, 2007; accepted June 20, 2007.
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Abstract |
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).
In clinical trials to determine the pharmacokinetics of rosuvastatin, renal clearance in healthy male volunteers accounted for 28% of the total plasma clearance, with 90% of the renal clearance thought to result from tubular secretion (Martin et al., 2003). Renal clearance and, in particular, tubular secretion, has been reported for several other statins including lovastatin (
10%), simvastatin (13%), and pravastatin (40%). In contrast, renal clearance plays only a minor role (2%) in the clearance of atorvastatin (Vickers et al., 1990; Hatanaka, 2000; White, 2002).
Tubular secretion of xenobiotics is a key function of the proximal tubule and is mediated by a range of carrier-mediated transport mechanisms located at both the basolateral and apical membranes of proximal tubule cells (for review, see Wright and Dantzler, 2004). In rats and humans, Oat1/OAT1 and Oat3/OAT3, localized to the basolateral membrane of proximal tubules, have been shown to play a central role in the renal uptake of a wide range of anionic xenobiotics (Sekine et al., 1997; Sweet et al., 1997; Hosoyamada et al., 1999; Race et al., 1999; Hasegawa et al., 2002). Indeed, recently, pravastatin has been reported to be a substrate for both rat Oat3 expressed in renal LLC-PK1 cells (Hasegawa et al., 2002) and for human OAT3 stably expressed in mouse proximal tubule cells (Takeda et al., 2004).
In this study, we investigated whether rosuvastatin is a substrate for either hOAT1 or rOat3/hOAT3 expressed in oocytes and determined the importance of rOat1/rOat3 to the uptake of rosuvastatin in rat renal cortical slices. The relative affinities of a range of statins (atorvastatin; pravastatin; simvastatin, and rosuvastatin) to inhibit either hOAT1-mediated PAH uptake or hOAT3-mediated estrone-3-sulfate uptake were then determined. The main findings of the study are that rosuvastatin is a high-affinity substrate for hOAT3 (Km 7.4 ± 2.5 µM) but is not a substrate for hOAT1. All statins inhibited hOAT3-mediated estrone-3-sulfate uptake with a rank order of potency of atorvastatin > rosuvastatin > simvastatin > pravastatin. Of the statins tested, only simvastatin competitively inhibited hOAT1-mediated PAH uptake (IC50 = 41.5 µM). The role of hOAT3, but not hOAT1, in the basolateral uptake of rosuvastatin is further strengthened by the demonstration that, in rat kidney slices, rosuvastatin was transported with an apparent Km of 10.7 ± 1.2 µM and the uptake of rosuvastatin was abolished in the presence of selective substrates of rOat3/hOAT3 (benzylpenicillin and estrone-3-sulfate).
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Materials and Methods |
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50 to 100 oocytes were rinsed three times in Ca2+-free ORII buffer (82.5 mM NaCl, 2 mM KCl, 1 mM MgCl2, and 10 mM HEPES, pH 7.5) and then were placed in a collagenase solution (2.5 mg/ml collagenase A in Ca2+-free ORII) at 20°C for 1 to 2 h to remove the follicular layer. Healthy oocytes were then selected and maintained at 18°C in modified Barth's solution [88 mM NaCl, 1 mM KCl, 0.82 mM MgSO4, 0.41 mM CaCl2, 0.33 mM Ca(NO3)2,10 mM HEPES, and 2.4 mM NaHCO3, pH 7.5, with 0.02 mg/ml gentamicin] overnight.
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OATs Are Na+-Independent Transporters. To measure transport activity, groups of 10 oocytes were washed three times in Na+-free uptake solution (100 mM choline Cl, 2 mM KCl, 1 mM CaCl2, 1 mM MgCl2, and 10 mM HEPES, pH 7.4). Uptake of radiolabeled substrates was initiated by adding 200 µl of the appropriate Na+-free uptake solution (as detailed in each figure legend) containing either [3H]PAH (5 µCi/ml), [3H]estrone-3-sulfate (5 µCi/ml), or [3H]rosuvastatin (5 µCi/ml). Oocytes were incubated for 40 or 60 min at 20°C. Uptake of substrates into oocytes was linear over 60 min (linear regression analysis of the time course of uptake gave r2 >0.98 for each substrate). Uptake was terminated by the removal of the uptake solution and the addition of 2.5 ml of ice-cold uptake buffer. The oocytes were then washed an additional two times with 2.5 ml of ice-cold uptake buffer, transferred to individual scintillation vials, and dissolved overnight in 200 µl of 2% SDS. The radioactivity was determined by scintillation counting (Beckman LS 6500 Multipurpose Liquid Scintillation System; Beckman Coulter, Buckinghamshire, UK) after the addition of 1 ml of scintillation cocktail (OptiPhase HiSafe; Fisher Chemicals, Leicester, UK).
Rat Renal Slices. Rat renal cortical slices were prepared from the kidneys of male Sprague-Dawley rats (180–250 g). The kidneys were removed and placed immediately into oxygenated ice-cold modified Cross-Taggart buffer (95 mM NaCl, 80 mM mannitol, 5 mM KCl, 0.74 mM CaCl2, 9.5 mM Na2HPO4, and 20 mM HEPES, pH 7.4). Slices of kidney cortex (200 µm thick, 5–20 mg in weight) were cut using a Stadie-Riggs microslicer.
To measure tracer uptake, three kidney slices per tube were incubated in 2 ml of oxygenated Cross-Taggart buffer containing either (0.5 µCi/ml): [3H]PAH, [3H]rosuvastatin, [3H]estrone-3-sulfate, or [3H]benzylpenicillin and the appropriate additions (as detailed in individual figure legends) for 60 min at 20°C. Over this period uptake was linear (r2 >0.96). After incubation the slices were washed three times in ice-cold Cross-Taggart buffer, blotted, and weighed. The tissue was then dissolved in 0.5 ml of 1 M NaOH and neutralized with 0.5 ml of 1 M HCl and the radioactivity associated with a sample was assayed by liquid scintillation spectroscopy.
Statistics. Data are presented as means ± S.E.M. Means were compared using one-way analysis of variance with Dunnett's multiple comparison post-test. Differences in the mean values were considered to be significant when p 
0.05. Nonlinear regression analysis of the data was performed using GraphPad Prism 3.0 software (GraphPad Software Inc., San Diego, CA).
Chemicals. [N-methyl-3H]Rosuvastatin (specific activity, 79 Ci/mmol) was a gift from AstraZeneca (Alderley Park, Cheshire, UK). [phenyl-4(n)-3H]Benzylpenicillin (specific activity, 20 Ci/mmol) was purchased from GE Healthcare (Buckinghamshire, UK). [6,7-3H(N)] Estrone-3-sulfate (specific activity, 46 Ci/mmol) and p-[glycyl-2-3H]aminohippurate (specific activity, 4.5 Ci/mmol) were from PerkinElmer Life and Analytical Sciences (Buckinghamshire, UK).
Rosuvastatin (Ca2+ salt), pravastatin (Na+ salt), simvastatin (Na+ salt), and atorvastatin (Ca2+ salt) were gifts from AstraZeneca. Estrone-3-sulfate, PAH, benzylpenicillin, and gentamicin were from Sigma-Aldrich (Poole, Dorset, UK). Collagenase A was from Roche Diagnostics (West Sussex, UK). All other chemicals were from Sigma-Aldrich or VWR International (Durham, UK) and were of the highest quality available.
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Results |
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; Hosoyamada et al., 1999; Bleasby et al., 2005). At a PAH concentration close to the Km for hOAT1 (5 µM), hOAT1-mediated [3H]PAH uptake was almost abolished by cis-inhibition with 50 µM cold PAH (p < 0.01) and significantly reduced in the presence of 50 µM simvastatin (p < 0.05). In contrast to the effects of simvastatin upon hOAT1-mediated PAH uptake, the presence of 50 µM atorvastatin, pravastatin, or rosuvastatin (p > 0.05) in the uptake buffer had no significant impact upon hOAT1-mediated PAH uptake (Fig. 1B).
Figure 2A shows the concentration-dependent uptake of [3H]estrone-3-sulfate by hOAT3. Non linear regression analysis of the data revealed a Km of 21.2 ± 1.5 µM for the interaction of estrone-3-sulfate with hOAT3, in line with previously published values (Cha et al., 2001). In cis-inhibition studies (Fig. 2B), hOAT3-mediated [3H]estrone-3-sulfate uptake (5 µM) was abolished in the presence of estrone-3-sulfate (50 µM) and significantly inhibited by 50 µM atorvastatin, pravastatin, simvastatin, or rosuvastatin (p < 0.01).
Concentration Dependence of cis-Inhibition of PAH and Estrone-3-Sulfate Uptake by Statins. To further understand the interactions of statins with hOAT1 and hOAT3, the concentration dependence of cis-inhibition of hOAT1-mediated PAH uptake or hOAT3-mediated estrone-3-sulfate uptake was investigated over a range of statin concentrations. Consistent with the data presented in Fig. 1B, only simvastatin displayed a concentration-dependent inhibition of hOAT1-mediated PAH uptake with an apparent IC50 of 41.5 ± 1.3 µM (Fig. 3). Atorvastatin, pravastatin, or rosuvastatin had no effect on PAH uptake over the concentration range tested (0–1 mM).
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Rosuvastatin Is a Substrate for hOAT3 but Not hOAT1. The data summarized in Figs. 3 and 4 demonstrate that rosuvastatin can cis-inhibit hOAT3-mediated estrone-3-sulfate uptake but not hOAT1-mediated PAH uptake. To demonstrate that rosuvastatin is also a substrate for hOAT3 but not hOAT1, the uptake of radiolabeled [3H]rosuvastatin was determined in oocytes expressing either hOAT1 or hOAT3 (Fig. 5A). Consistent with the results of the cis-inhibition studies and in contrast with the marked hOAT1-mediated uptake of PAH, there was no significant uptake of [3H]rosuvastatin into hOAT1-injected oocytes over that found in H2O-injected control oocytes (0.30 ± 0.02 versus 0.24 ± 0.02 pmol/oocyte/60 min, n = 10, p > 0.05). However, the uptake of [3H]rosuvastatin in hOAT3-expressing oocytes was approximately 20-fold higher than that in the control oocytes (4.28 ± 0.24 versus 0.24 ± 0.02 pmol/oocyte/60 min, n = 10, p < 0.01). There was also a significant hOAT3-mediated uptake of PAH compared with the control (2.23 ± 0.14 versus 0.59 ± 0.06 pmol/oocyte/60 min, n = 10, p < 0.01). To determine the apparent affinity of rosuvastatin for hOAT3, uptake of [3H]rosuvastatin was tested over a range of rosuvastatin concentrations (1–100 µM). Analysis of the resultant concentration curve gave an apparent Km of 7.4 ± 2.5 µM (Fig. 5B).
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65% (IC50 = 358.5 ± 90.0 µM), suggesting that rOat3 mediates 65% of the total PAH uptake into rat renal slices (Fig. 6B). Consistent with rosuvastatin being a substrate for hOAT3, the uptake of PAH into rat cortex slices was inhibited by rosuvastatin with an apparent IC50 of 20.1 ± 4.6 µM but with a maximum inhibition of PAH uptake of 55% (Fig. 6C). Equally, rosuvastatin almost completely abolished the uptake of the selective rOat3 substrate benzylpenicillin, with an apparent IC50 of 17.7 ± 2.6 µM (Fig. 6D). In the final series of experiments the uptake of [3H]rosuvastatin into rat renal cortical slices was measured. Figure 7A shows the uptake of [3H]rosuvastatin into kidney slices over a range of rosuvastatin concentrations. The calculated Km value was 10.7 ± 1.2 µM. To estimate the importance of rOat3 to rosuvastatin uptake in rat renal slices the impacts of selective substrates of rOat3 were assessed for their ability to inhibit rosuvastatin uptake. In these experiments the initial rate of rosuvastatin uptake (5 µM) into rat renal slices was 12.5 ± 0.5 pmol/mg of protein/5 min, and rosuvastatin uptake was almost completely abolished (80–85% inhibition) in the presence of either 50 µM estrone-3-sulfate or 50 µM benzylpenicillin (Fig. 7B). To confirm that rat Oat3 handles rosuvastatin in a manner similar to that of human OAT3 (Fig. 5B) the uptake of [3H]rosuvastatin over a range of rosuvastatin concentrations was measured in oocytes expressing rOat3 (Fig. 8). The calculated Km was 4.7 ± 0.7 µM for rat Oat3 compared with 7.4 ± 2.5 µM for human OAT3.
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Discussion |
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; Sekine et al., 2006). The present study was designed to investigate the possible role of rOat1/hOAT1 and rOat3/hOAT3 in the basolateral uptake of a range of statins including rosuvastatin.
To test the role of hOAT1 in the uptake of statins, the ability of statins to inhibit hOAT1-mediated uptake of PAH was assessed using Xenopus oocytes. Of the statins tested, only simvastatin had an inhibitory effect upon hOAT1-mediated PAH uptake with an apparent IC50 of 41.5 ± 1.3 µM (Fig. 3). The lack of interaction of rosuvastatin with hOAT1 was confirmed by the demonstration that [3H]rosuvastatin uptake into oocytes expressing hOAT1 was not significantly greater than uptake into H2O-injected oocytes (Fig. 5A).
In contrast, all statins caused a concentration-dependent inhibition of hOAT3-mediated estrone-3-sulfate uptake with a rank order of potency of atorvastatin (13.1 ± 1.8 µM) > rosuvastatin (25.7 ± 1.4 µM) > simvastatin (48.1 ± 1.1 µM) > pravastatin (96.9 ± 1.5 µM) (Fig. 4). Additional experiments also demonstrated that rosuvastatin is a substrate, as well as an inhibitor, of hOAT3 with an apparent Km of 7.4 ± 2.5 µM (Fig. 5B).
There have been relatively few studies of the renal handling of statins at a molecular level. Of these, Hasegawa et al. (2002), using transfected LLC-PK1 cells, demonstrated that pravastatin was a substrate for rOat3 (slc22a8) but not rOat1 (slc22a6). Likewise, Takeda et al. (2004) reported that pravastatin is a substrate for hOAT3 (SLC22A8) expressed in mouse kidney cells and demonstrated that both simvastatin and fluvastatin can inhibit hOAT3-mediated estrone-3-sulfate uptake. They also reported that simvastatin and pravastatin inhibited hOAT1-mediated PAH uptake with inhibitory constants of 73 and 408 µM, respectively. In the present study, although we found a similar simvastatin-mediated inhibition of hOAT1 (IC50 = 41.5 µM), we saw no inhibition of hOAT1-mediated PAH uptake at pravastatin concentrations up to 1 mM (Fig. 3). It would be interesting to see whether simvastatin not only inhibits hOAT1-mediated transport but is itself a substrate for hOAT1, particularly, as, given the close structural relationship between simvastatin and pravastatin (Reinoso et al., 2001), this may provide important information into the structure-affinity relationship of hOAT1 and its substrates.
To estimate the importance of hOAT3 to the overall renal uptake of rosuvastatin in an intact system, we investigated rosuvastatin transport in rat renal slices. Rat renal slices have been used extensively to study the uptake of drug molecules and have proved invaluable in defining the mechanisms of drug uptake at the basolateral membrane (van Montfoort et al., 2003; Dantzler, 2006). Because there may be species differences in the handling of compounds by rat and human isoforms of OAT1 and OAT3, we first demonstrated that rosuvastatin uptake mediated by rOat3 and hOAT3 expressed in oocytes had similar kinetics. The apparent Km values were 4.7 ± 0.7 µM (Fig. 8) and 7.4 ± 2.5 µM (Fig. 5B) for rat Oat3 and human OAT3, respectively. Neither human OAT1 nor rat Oat1 expressed in oocytes transported rosuvastatin. In rat renal slices, we demonstrated that [3H]PAH uptake could be almost abolished by the addition of increasing concentrations of PAH (IC50 = 119 µM), consistent with inhibition of both rOat1- and rOat3-mediated [3H]PAH uptake (Fig. 6A). In contrast, benzylpenicillin was found to produce only a maximal inhibition of [3H]PAH uptake of 65.2 ± 7.8% with an IC50 of 358.5 ± 90.0 µM. As benzylpenicillin is a relatively selective rOat3 inhibitor (Deguchi et al., 2004), these findings suggest that rOat3 is responsible for 65% of the total PAH uptake into rat renal slices. Rosuvastatin showed a similar inhibitory profile compared with benzylpenicillin, with a maximum inhibition of [3H]PAH uptake of 55 ± 6.2% not significantly different from that observed with benzylpenicillin. The apparent IC50 for rosuvastatin inhibition of [3H]PAH uptake was 20.1 ± 4.6 µM. Further indirect evidence that rosuvastatin and benzylpenicillin share the same uptake pathway in rat kidney (rOat3) is the observation that benzylpenicillin uptake into rat slices was completely abolished by rosuvastatin with an IC50 of 17.7 ± 2.6 µM (Fig. 6D). Direct measurement of rosuvastatin uptake into rat renal slices gave an apparent Km of 10.7 ± 1.2 µM (Fig. 7A), very close to the Km value of 4.7 ± 0.7 µM for rOat3-mediated rosuvastatin uptake measured in oocytes (Fig. 8). Taken together these data strongly support the hypothesis that in a manner similar to that of pravastatin (Hasegawa et al., 2002), rosuvastatin uptake across the basolateral membrane of rat kidney slices is mediated by rOat3; however, given the overlapping substrate specificities of renal transporters, we cannot rule out the potential contribution of other transporters such as oatp4c1 or mrp1 to statin uptake across the basolateral membrane of rat tubules.
Although it is difficult to translate in vitro measurements of the kinetic parameters of a single transporter to the impact of this transporter upon the in vivo clearance of a drug molecule, it is important to note that there is a large difference between the peak plasma concentration (Cmax) of rosuvastatin (40–65 nM) (Schneck et al., 2004; Lee et al., 2005) and the estimated Km value for uptake of rosuvastatin by either hOAT3 (Km 7.4 ± 2.5 µM) or rOAT3 (Km 10.7 ± 1.2 µM in rat slices and 4.7 ± 0.7 µM in oocytes). In fact, if protein binding (88% of total) is taken into account, the estimated free concentration of rosuvastatin in humans at Cmax is in the order of 4.8 to 7.8 nM. Likewise, Cmax values in the nanomolar range have also been reported for other statins (Shitara and Sugiyama, 2006). With free rosuvastatin concentrations in the nanomolar range and a Km in the micromolar range, we predict that the rank order of affinities of statins for OAT3 will be maintained but that in the absence of significant passive diffusion, the overall rate of uptake of rosuvastatin across the basolateral membrane of renal tubule cells will be primarily governed by the number of transporters expressed along the length of the tubule.
In summary, we have demonstrated that rosuvastatin is a substrate for human OAT3 but not OAT1. We have also shown that rosuvastatin is a substrate for rat Oat3 and, moreover, demonstrated that rOat3-mediated transport can account for the majority of rosuvastatin uptake across the basolateral membrane of rat renal slices. From these data, we suggest that hOAT3 may play a central role in the renal uptake of rosuvastatin in humans.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: OAT/Oat, organic anion transporter; h, human; r, rat; PAH, para-aminohippurate.
Address correspondence to: Dr. Colin D. A. Brown, Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. E-mail: c.d.a.brown{at}ncl.ac.uk
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