Whole-body distribution and radiation dosimetry of [11C]telmisartan as a biomarker for hepatic organic anion transporting polypeptide (OATP) 1B3

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Abstract

Introduction

Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist used as an antihypertensive drug, is specifically taken up by the liver through the OATP1B3. PET imaging with [11C]telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as its transport property by OATP1B3. The purpose of the study was to determine the biodistribution and radiation dosimetry of [11C]telmisartan in humans.

Methods

Biodistribution of [11C]telmisartan was measured in three rats and six healthy male human volunteers. In the rat study, a dynamic emission scan was performed for 90 min. In the human study, dynamic whole-body PET images were acquired after intravenous injection of [11C]telmisartan. ROIs were defined for source organs on the PET images to measure time-course of [11C]telmisartan uptake as percentage injected dose and the number of disintegration for each organ. Radiation dosimetry was calculated with OLINDA/EXM.

Results

In the rat study, most radioactivity was rapidly taken up by the liver and part of it was excreted into the biliary tract and intestine. Extrapolating from the rat data, the effective dose for the adult human being was estimated to be 3.65±0.01 microSv/MBq (n=3). In the human study, most of the tracer was taken up by the liver as well, although not as rapidly as in the rat. The activity in the gall bladder and intestine increased gradually. The effective dose for the adult human being was 4.24±0.09 microSv/MBq (n=6).

Conclusions

[11C]Telmisartan is a safe PET tracer with a dosimetry profile comparable to other common 11C PET tracers.

Introduction

Telmisartan, an antihypertensive drug marketed as Micardis, inhibits vasoconstriction and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues. From the standpoint of pharmacokinetics, telmisartan is taken up by the liver, conjugated with glucuronic acid and subsequently excreted into bile as telmisartan glucuronide [1], [2].

The pharmacokinetics of orally administered telmisartan is known to be nonlinear over the dose of 40 mg, with greater than proportional increases of plasma concentrations with increasing dose. According to the phase I clinical trial of telmisartan [3], following oral administration of 20 mg, 40 mg and 80 mg tablet on Japanese healthy adults, peak concentration (Cmax) of telmisartan was 33.84±17.32 (n=31), 78.52±32.72 (n=29) and 365.81±253.08 ng/ml (n=30), and the area under the plasma concentration-time curve (AUC0–24h) was 424.65±232.25 (n=31), 807.41±334.76 (n=29) and 2304.54±1522.85 ng⁎h/ml (n=30), respectively.

Telmisartan is specifically taken up by hepatocytes through organic anion transporting polypeptide (OATP) 1B3 [1]. OATP1B3 is expressed on the sinusoidal membrane of the hepatocytes, and is thought to be involved in the transport of a wide variety of drugs together with OATP1B1. Thus, OATP1B3 governs the hepatic clearance of telmisartan and saturation of OATP1B3-mediated uptake at high dose was considered to be one of the possible mechanisms for the non-linear pharmacokinetics of telmisartan. However, it was almost impossible to directly measure the transport of drugs from blood circulation to liver on humans because of difficulty in the measurement of tissue concentration of drugs.

PET is a powerful non-invasive technique in which drugs labeled with positron emitters are injected and the distribution and time course of radioactivity are imaged. The high sensitivity and exceptional spatial–temporal resolution of PET make it a particularly useful tool for estimating the in vivo function of drug transports in various tissues over time following intravenous administration of a radiolabeled drug. Very recently, Takashima et al. have demonstrated that [11C]15R-TIC could be useful for the evaluation of transporter-mediated hepatic uptake and biliary excretion [4]. The preliminary data in a rat study using a small animal PET scanner as well as radiometric HPLC showed that administered radioactivity of [11C]telmisartan was promptly taken up by the liver and its acylglucuronide was excreted into the bile, and that accumulation of radioactivity in the other organs was very low after intravenous administration of [11C]telmisartan to the rats [5].

Therefore, PET imaging with [11C]telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as the transport function by hepatic OATP1B3 in humans. The changes in the transport function of OATP1B3 caused by drug–drug interaction, genetic polymorphisms and liver diseases may affect the hepatic clearance of OATP1B3 substrates, resulting in the changes in the plasma concentration and its pharmacological effect. For example, Kiyotani et al. demonstrated that genetic polymorphism of SLCO1B3 (rs11045585), which encodes OATP1B3, increased the risk of docetaxel-induced neutropenia possibly due to the decreased plasma concentration of docetaxel [6].

Because [11C]telmisartan has never been administered in humans, the purpose of the present study was to confirm its safety and determine the biodistribution and radiation exposure by [11C]telmisartan in healthy volunteers. Considering the species difference, dosimetry was estimated from the rat data before the first human subject was injected with [11C]telmisartan, based on which practicability of estimating human dosimetry from rat data was also discussed. The liver kinetic analysis is presented in another paper.

Section snippets

Radiopharmaceutical preparation

[11C]Telmisartan was synthesized by 11C-methylation of N-desmethyl telmisartan with [11C]CH3I followed by HPLC separation, and radiochemical purity of >97% was obtained [7]. Fig. 1 shows structure formula for [11C]telmisartan.

Rat study

Male Sprague–Dawley (SD) rats weighing 240±3 g (n=3) were purchased from Japan SLC Inc. (Shizuoka, Japan). All experimental protocols were approved by the Ethics Committee on Animal Care and Use of the Center for Molecular Imaging Science in RIKEN, and were performed in

Rat study

The radioactivity was rapidly taken up by the liver and the urinary bladder was not visualized in the PET image after intravenous administration of [11C]telmisartan. Table 1 shows organ dose and effective dose for a 73 kg human being estimated from the rat data using OLINDA/EXM by use of MIRD method. The effective dose of [11C]telmisartan was estimated to be 3.65±0.01 microSv/MBq (n=3) using tissue weighting factor based on ICRP 1990. Radiation dose of liver was highest and was estimated to be

Discussion

The purpose of this study was to evaluate the clinical safety and the whole-body biodistribution after the intravenous bolus administration of [11C]telmisartan in healthy adult volunteers and the associated internal radiation dosimetry. In this study, the tracer was found to be safe and well tolerated.

The effective dose of [11C]telmisartan in our human subjects was estimated to be approximately 16% higher than that in rat study — that is, 4.24±0.09 microSv/MBq (n=6) versus 3.65±0.01 microSv/MBq

Conclusion

[11C]Telmisartan is a safe PET tracer for humans, and the effective dose is 4.24±0.9 microSv/MBq (n=6), which is within the range of other common 11C PET imaging tracers. With 100 or 150 MBq injected radioactivity, the radiation exposure will be 0.424 mSv or 0.636 mSv, respectively. This would allow repeated PET scans on the same subject per year under different conditions. These data warrant further clinical study using [11C]telmisartan.

Acknowledgments

We would like to thank Hiroyuki Nishida, Hidehito Nagai, Hitoshi Iimori and Yoshinobu Kajiwara for their assistance with this study. This study is a part of “Research Project for Establishment of Evolutional Drug Development with the Use of Microdose Clinical Trial”, sponsored by the New Energy and Industrial Technology Development Organization (NEDO).

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