Drugs interacting with organic anion transporter-1 affect uptake of Tc-99m-mercaptoacetyl-triglycine (MAG3) in the human kidney: Therapeutic drug interaction in Tc-99m-MAG3 diagnosis of renal function and possible application of Tc-99m-MAG3 for drug development

doi:10.1016/j.nucmedbio.2013.03.006

Nuclear Medicine and Biology

Volume 40, Issue 5, July 2013, Pages 643-650

https://doi.org/10.1016/j.nucmedbio.2013.03.006 Get rights and content

Abstract

Introduction

Renal uptake of Tc-99m-MG3 involves organic anion transporter (OAT). Treatment with drugs showing OAT affinity might interfere with renal uptake of Tc-99m-MAG3, leading to misinterpretation in Tc-99m-MAG3. This study was conducted to discuss a possible drug interference with Tc-99m-MAG3 diagnosis on OAT sites.

Methods

Renal uptake and plasma clearance of Tc-99m-MAG3 were analyzed in healthy volunteers under control and OAT1 and OAT3 related drug treatment conditions. An in vitro uptake study using OAT1 or OAT3 expressing cells was also conducted.

Results

Both PAH and probenecid treatment induced delays in Tc-99m-MAG3 clearance from blood, and reductions in the renal uptake clearance. As a result, the normalized effective renal plasma flow estimated from Tc-99m-MAG3 clearance was significantly underestimated, whereas the glomerular filtration rate estimated from plasma creatinine levels was unchanged. The transport activity of Tc-99m-MAG3 was higher in OAT1-expressing cells than in OAT3-expressing cells.

Conclusion

Drugs with OAT1 affinity affect the renal uptake of Tc-99m-MAG3 and blood clearance. This might cause misinterpretation of functional diagnosis of the kidney using Tc-99m-MAG3.

Introduction

Although much has been published on renal transporters and drug interactions [1], in vivo imaging using a radiopharmaceutical is an underdeveloped area [2]. Tc-99m-mercaptoacetyl-triglycine (Tc-99m-MAG3) was introduced in 1986 [3], and has become the radiopharmaceutical of choice in the evaluation of transplant kidneys, diagnosis of tubular necrosis, and scintigraphic study of tubular function. The image quality when using Tc-99m-MAG3 is superior to that with I-131-orthoiodohippurate (OIH) [4], and is adequate for monitoring renal function [5].

The urinary excretion of compounds is determined by glomerular filtration, tubular secretion and reabsorption from the urine. Glomerular filtration is determined by the unbound fraction in the plasma and GFR, whereas transporters play an indispensable role in the ability of the epithelial cells, forming proximal tubules, to remove the compounds from the blood. Complementary DNA (cDNA) encoding a p-aminohippurate transporter designated as Organic Anion Transporter-1 (OAT1)/SLC22A6 has been isolated [6]. OAT1 is expressed in the middle segment of the proximal tubule in the kidney, and acts as a multispecific transporter mediating the uptake of various drugs, such as diuretics, beta-lactam antibiotics, and antiviral agents [7], [8]. It has been demonstrated that Tc-99m-MAG3 is a substrate of OAT1 in cDNA-transfected cells, suggesting that OAT1 accounts for the kidney uptake of Tc-99m-MAG3 from blood [9]. In addition to OAT1, OAT3/SLC22A8, an OAT1 isoform, is also predominantly expressed in the basolateral membrane of kidney proximal tubules [10]. Because OAT3 shows overlapped substrate specificity with OAT1, it is also possible that OAT3 is involved in the renal uptake of Tc-99m-MAG3 together with OAT1. Thus, drug treatment might cause an alteration of the renal uptake and excretion pattern of Tc-99m-MAG3 by inhibiting the transporters, potentially causing misinterpretation of renal function diagnosis based on Tc-99m-MAG3 clearance.

In the present work, a Tc-99m-MAG3 study was performed in healthy volunteers under control and drug-treated conditions in a crossover fashion, and the effect of drug treatment was evaluated by ordinary diagnostic procedures as well as pharmacokinetic analysis. “Sodium p-aminohippurate injection (10%)” and “benecid tab 250mg (probenecid)” were selected as a relatively selective OAT1 substrate [6], [10], [11] and a potent OAT1 and OAT3 inhibitor [12], [13], [14], respectively. The former is approved as a drug for diagnosis of kidney function, and the latter approved for the treatment of hyperuricemia as well as prolongation of the effectiveness of penicillin antibiotics drug. Thus, a single dose of these drugs does not affect the physiological status of the kidney. Probenecid has been known to inhibit the tubular secretion of various anionic drugs at its clinical doses [8], [15]. Comparison of the unbound concentration in the plasma and inhibition constants of probenecid indicates that inhibition of the uptake process by OAT1 and OAT3 is in vivo relevant at its therapeutic dose [15].

Based on the results obtained, the possible interference of drug treatment in functional diagnosis of kidneys using Tc-99m-MAG3 and the possible contribution of OAT1 and/or OAT3 to the renal uptake of Tc-99m-MAG3 in human were discussed.

Section snippets

Materials

Tc-99m-MAG3 Injection was purchased from Fujifilm RI Pharma Co., Ltd. (Tokyo, Japan). Creatinine was purchased from Sigma Chemical Co. (St. Louis, MO), and PAH and probenecid were purchased from Wako Pure Chemicals (Osaka, Japan). All other chemicals used were commercially available and of analytical grade.

Subjects

This study was approved by the Institutional Review Board and informed consent was obtained. Twelve healthy male volunteers (age range 22–25 y; mean age 22.9± :1.1 y) were included in this

Clinical studies

Plasma creatinine levels were measured before and after the treatment. No significant change was found between pre- and post- PAH and probenecid treatment (pre-PAH:0.72 ± 0.09 mg/dL, post-PAH:0.72 ± 0.11 mg/dL, pre-provenecid:0.81 ± 0.12 mg/dL, post-:0.84 ± 0.12 mg/dL), indicating that kidney function was maintained during the study. The plasma PAH and probenecid concentrations during the study are shown in Table 1.

Time courses of blood Tc-99m-MAG3 concentration in control and drug-treated conditions are

Discussion

Proximal renal tubule secretion and glomerular filtration are important processes in renal drug excretion. Renal functions related to these processes can be evaluated as the effective renal plasma flow (ERPF) and glomerular filtration rate (GFR), respectively. Radioiodinated hippurate (OIH) has excellent properties as an ERPF agent, but Tc-99m-MAG3 is now widely used as an alternative to OIH [24] as ERPF for OIH can be estimated from those of Tc-99m-MAG3 by a simple calculation. The principle

Conclusion

The dependency of renal uptake of Tc-99m-MAG3 on OAT1 is considered to be a limitation for the measurement of nERPF, and it is important to consider the effect of prescribed drug(s). This characteristic can be useful as a biomarker for the evaluation of the drug interaction potential of new drug candidates against OAT1 in vivo.

Acknowledgment

This study was conducted partly as the NEDO MicroDose-PJ, sponsored by the New Energy and Industrial Technology Development Organization (NEDO), Japan.

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Drugs interacting with organic anion transporter-1 affect uptake of Tc-99m-mercaptoacetyl-triglycine (MAG3) in the human kidney: Therapeutic drug interaction in Tc-99m-MAG3 diagnosis of renal function and possible application of Tc-99m-MAG3 for drug development

Abstract

Introduction

Methods

Results

Conclusion

Introduction

Section snippets

Materials

Subjects

Clinical studies

Discussion

Conclusion

Acknowledgment

Pharmacol Ther

Semin Nucl Med

Pharmacol Ther

Eur J Pharmacol

Kidney Int

Kidney Int

J Biol Chem

Dynamic and static small-animal SPECT in rats for monitoring renal function after 177Lu-labeled Tyr3-octreotate radionuclide therapy

J Nucl Med

Synthesis and biological evaluation of technetium-99m MAG3 as a hippuran replacement

J Nucl Med

Reproducibility of single-sample clearance of 99mTc-mercaptoacetyltriglycine and 131I-orthoiodohippurate

J Nucl Med

Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney

Am J Physiol

Membrane transporters in drug development

Nat Rev Drug Discov