Ann Nucl Med DOI 10.1007/s12149-014-0909-7
ORIGINAL ARTICLE
Comparison of radioactive iodide uptake in the rat thyroid between oral and intravenous bolus administration Hiroyuki Kurosawa • Kazuhisa Sakurai • Hideaki Hasegawa Keisuke Uchida • Hiroyuki Kasahara • Takao Minamizawa • Masatoyo Nakajo • Masayuki Nakajo
•
Received: 3 July 2014 / Accepted: 7 August 2014 Ó The Japanese Society of Nuclear Medicine 2014
Abstract Objective Radioiodide is commonly used to diagnose and treat hyperthyroidism and thyroid carcinoma. However, we could not find any experimental data that strictly compared the biodistribution and thyroid uptake of radioactive iodide between the oral and intravenous (iv) routes with time. This prompted us to compare 123I biodistribution and thyroid uptake to clarify the differences between oral and iv bolus administration in rats. Methods The rats were divided into two groups, A and B (n = 5, each). In the first imaging experiment, Na123I solution (35 MBq/200 lL) was administered as a bolus to the rats orally in group A and intravenously in group B. Two weeks later, the second imaging experiment was performed as a crossover experiment. 123I biodistribution was evaluated visually and quantitatively with a gamma camera at 10 min, 3, 6, 12, 24, and 48 h after 123I administration. Thyroid uptake was compared between oral and iv groups. Correlation of 123I thyroid uptake and whole-body excretion was evaluated. The area under the curve (AUC) of thyroid uptake was also calculated.
H. Kurosawa K. Sakurai H. Hasegawa K. Uchida H. Kasahara T. Minamizawa Research Department, FUJIFILM RI Pharma Co., Ltd., 453-1 Shimo-okura, Matsuo-machi, Sammu, Chiba 289-1592, Japan H. Kurosawa (&) Product Management and Marketing Department, FUJIFILM RI Pharma Co., Ltd., 14-1 Kyobashi 2-chome, Chuo-ku, Tokyo 104-0031, Japan e-mail: [email protected] Masatoyo Nakajo Masayuki Nakajo Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
Results 123I biodistribution differed visually during 6 h between the two groups. 123I thyroid uptake was significantly higher in the iv group at 10 min (P \ 0.05) and in the oral group at 6 or more hour time points (P \ 0.005–P \ 0.0001) and peaked at 12 h in both groups (oral: 24.4 ± 2.8 %ID, iv: 15.2 ± 2.8 %ID). 123I thyroid uptake showed significant inverse correlations with whole-body excretion from 6 h (r = -0.799, P \ 0.0001), and thereafter [12 h (r = -0.957, P \ 0.0001), 24 h (r = -0.905, P \ 0.0001) and 48 h (r = -0.893, P \ 0.0001)], respectively. 123I whole-body excretion was significantly higher in the iv group at each time point (P \ 0.0001). The AUC of 123I thyroid uptake was 1.6 times higher in the oral group than the iv group. Conclusions These results suggest that radioiodide accumulates in the rat thyroid more effectively by oral than iv administration probably due to slower and lower 123I clearance from the body in the oral administration when administered in a bolus fashion. Keywords Radioiodine Rat Thyroid uptake Oral or intravenous administration Sodium iodide symporter (NIS)
Introduction After Enrico Fermi produced the first radioiodine, 128I, in 1934, active experimentation in the United States and France delineated the crucial role of iodine in thyroid metabolism and disease. 130I and 131I were first employed to treat thyrotoxicosis by 1941 and thyroid cancer in 1943. After World War II, 131I became widely available for diagnostic testing and therapy and 123I also became available for diagnosis of thyroid diseases after about 1982 [1]. 131 I has been widely used in the radiotherapy of Graves’
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disease and postoperative thyroid cancer and 131I or 123I has been also widely used in the diagnostic imaging of thyroid diseases. Although these radiopharmaceuticals have been administered orally to the patients in liquid or capsules, they can also be administered intravenously. In vivo biodistribution of radioactive iodide in the living body was extensively studied in the 1950s and 1960s. However, they differed in the administration route; intravenous (iv) [2, 3], intraperitoneal [4], subcutaneous [5] or oral [6] route. Although it was more recently reported that thyroid uptake and outcome of hyperthyroid cats did not differ between iv and subcutaneous administration routes [7] and there was no significant difference in influence on dose or outcome in Graves’ disease and unifocal autonomy between oral and iv administration routes [8], we could not find any experimental data strictly comparing the biodistribution and thyroid uptake of radioactive iodide between oral and iv routes with time. In addition, we consider that the administration route of radioiodine has the potential to influence the results of preclinical animal and clinical studies using radioactive iodide such as diagnosis and therapy of thyroid and nonthyroid cancers using sodium iodide symporter (NIS) gene delivery [9–11]. Motivated by this lack of comparative data, we examined the differences in biodistribution and thyroid uptake of 123I using a rat model, between oral and iv administration routes.
Materials and methods
switched to low iodine feed (CLEA Japan, Inc.) and distilled water. The low iodine diet was continued for the duration until completion of the second imaging experiment with the exception of enforced fasting on the day preceding Na123I administration. Group division The serum Free T3 and Free T4 concentrations were measured in all 15 rats on the day preceding the start of the low iodine diet. The mean levels of Free T3 and Free T4 were 3.9 ± 0.4 pg/mL and 2.6 ± 0.2 ng/dL, respectively. The coefficient of variation of serum Free T3 and Free T4 levels between individual rats was 0.10 and 0.08, respectively. The difference between individual levels was judged not to be significant. Based on these observations, the 15 rats were assigned, by body weight, using stratified randomization to one of the two groups A and B without consideration of serum Free T3 and Free T4 levels. Body weight measurement for the random group assignment was performed for all 15 rats on the morning of the first imaging experiment (280.5 ± 9.4 g). Five rats with large outliers from the average body weight were excepted and thus 10 rats, 5 in each group, were used for the experiments (276.1 ± 5.0 g). The 5 group A rats were administered Na123I orally in the first experiment and intravenously in the second experiment, and the 5 group B rats were conversely administered Na123I intravenously in the first experiment and orally in the second experiment.
Study design
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As 131I and 123I differ only in neutron number, the biodistribution of both radiotracers is held to be the same. In this study, we chose 123I because the emitted 159 keV gamma photons produce high resolution images in gamma camera imaging. The rats were fed low iodine food for 2 weeks and subsequently divided into two groups: A and B. In the first imaging experiment, group A rats received Na123I orally and group B rats received Na123I via iv injection. After cessation of Na123I administration for 2 weeks, the second imaging experiment was conducted as a crossover experiment which switched oral and intravenous administration between the two groups.
The imaging experiment was conducted 2 weeks after the rats received a low iodine diet. Na123I prepared by FUJIFILM RI Pharma Co., Ltd. (Chiba, Japan) was used for the experiments (the solvent was a mixed solution of diluted ammonia solution: 1 mol/L sodium hydroxide solution = 23:1). Na123I was diluted with 1:1 mixed solutions of saline and 0.3 M phosphate buffer (pH 7.0), and adjusted to a dose of 175 MBq/mL. The dose/volume for each rat was 35 MBq/200 lL and was delivered using a syringe for both oral and iv administration in a bolus fashion. The order of oral and iv administration was alternated between the two groups, A and B, to reduce the possibility of any systemic artifacts in the experiment. Before Na123I administration, the rats were anesthetized with pentobarbital sodium intraperitoneal injection. Oral Na123I was delivered directly into the stomach via the esophagus using a syringe and iv Na123I was injected into the femoral vein with a 26G needle connected to a syringe. The planar imaging was performed, over 3 min at each imaging time, using a PRISM2000 (Shimadzu Corporation, Kyoto, Japan) equipped with a low energy ultrahigh resolution parallel
Laboratory animals All animal experiments were conducted in compliance with the Guidelines for the Care and Use of Research Animals established by our institute. Fifteen 10-week old male Wistar rats were purchased from Japan SLC, Inc. All rats were acclimatized for 1 week with a free-feeding diet of standard feed (CLEA Japan, Inc.) and tap water. Then, the diet was
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I imaging experiment
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collimator (matrix: 256, MAG: 2.6). The gamma ray energy photo peak was adjusted at 159 keV with the window of ±10 %. The image acquisition was performed, under anesthesia by pentobarbital sodium, at 10 min, 3, 6, 12, 24, and 48 h. The rats in both groups received a twoweek drug holiday after the first imaging experiment before commencing the second imaging experiment. The low iodine diet was continued during the drug holiday. In the second imaging experiment, the procedure was reversed to that of the first imaging experiment; the group A rats received Na123I intravenously and the group B rats received Na123I orally. Two rats were excluded from the analysis: Extravascular leakage of Na123I was noted in one rat of group A. One rat of group B died due to the anesthetic during the imaging experiment. Therefore, the data of 9 rats in each group were finally analyzed. Image analysis The serial images obtained in each experiment were visually evaluated. For the quantitative evaluation, irregular regions of interest (ROIs) were drawn over the thyroid, stomach, urinary bladder, and whole body to obtain the count. The thyroid or stomach uptake ratio was calculated by the following formula: Thyroid or stomach uptake ratio at each time point ð%IDÞ ¼ thyroid or stomach uptake count at each time point ð*1Þ 100=administered dose count ð*2Þ
(*1) The thyroid or stomach ROI count at each time point which was decay corrected to the initial administered time. (*2) The 10 min whole-body count which was decay corrected to the administered time. The whole-body excretion ratio was calculated at each time point as follows: Whole body excretion ratio ð%IDÞ ¼ ðadministered dose count ð*1Þ count remained in the whole body ð*2ÞÞ 100=administered dose count (*1) The 10 min whole-body count which was decay corrected to the administered time. (*2) The whole-body count from which the bladder ROI count was subtracted based on the assumption that the urinary bladder activity was not reabsorbed and was extra-body activity. Each count was decay corrected to the administered time. Statistical analysis Data are expressed as mean ± standard deviation (SD). Two-sided Student’s t test was performed to compare mean
values between the oral and iv groups. Pearson’s linear regression model was used to correlate the thyroid uptake ratio and the whole-body excretion ratio at each time point. Area under the curve (AUC) was calculated by the program of GraphPad Prism ver.5.04.
Results Visual assessment Serial changes in the 123I biodistribution of the first imaging experiment from 10 min to 48 h were shown in Figs. 1 and 2. Figure 1 shows the images after oral administration and Fig. 2 shows those after iv administration. The 123I images acquired 10 min after oral administration visualized the thyroid faintly and the esophagus and the stomach clearly and did not visualize the urinary bladder. Bowel activity was also noted in a rat. On the other hand, the 123I images acquired 10 min after iv administration visualized the thyroid, stomach, and urinary bladder intensely and the heart and kidneys moderately. Thus, the major differences in biodistribution between the two groups at this time point were observed in the thyroid which was more intense in the iv group, the stomach which was more intense in the oral group and the urinary bladder which was more intense in the iv group. At 3 and 6 h after administration, the thyroid, stomach, and urinary bladder were visualized in both the oral and iv groups. At these time points, the stomach appeared more intense in the oral group. At 12 h after administration, the thyroid was visualized in all rats, but the stomach was only faintly visualized in the oral group and almost invisible in the iv group. There were some rats whose urinary bladders were visualized. At 24 and 48 h after administration, only the thyroid was visualized. Serial changes in the 123I biodistribution of the second imaging experiment were similar to those of the first imaging experiment. Quantitative assessment Serial
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I thyroid uptake
The serial thyroid uptake ratios are shown in Table 1 and Fig. 3. The thyroid uptake ratio peaked at 12 h in both the oral and iv groups and gradually decreased thereafter in both groups. Although at 10 min, the thyroid uptake ratio was significantly higher in the iv group (2.0 ± 0.7 %ID) than in the oral group (1.1 ± 0.6 %ID) (P \ 0.05), it was the almost same at 3 h and reversely and significantly higher in
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Ann Nucl Med Fig. 1 Serial whole-body planar images are shown at 10 min, 3, 6, 12, 24, and 48 h after oral administration of Na123I to 5 group A rats in the first imaging experiment. The arrowhead, solid arrow, and dashed arrow indicate the thyroid, stomach, and urinary bladder, respectively
Fig. 2 Serial whole-body planar images are shown at 10 min, 3, 6, 12, 24, and 48 h after intravenous administration of Na123I to 5 group B rats in the first imaging experiment. The arrowhead, solid arrow, and dashed arrow indicate the thyroid, stomach, and urinary bladder, respectively
the oral group than in the iv group 6 or more h after administration. With the thyroid uptake (%ID) specified as the therapeutic index, the AUC of oral administration was approximately 1.6 times that of iv administration (oral administration 761.2 ± 86.8 %ID h versus iv administration 475.0 ± 87.9 %ID h, P \ 0.0001).
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Serial
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I thyroid uptake and whole-body excretion
At all imaging time points, 123I whole-body excretion was clearly higher in the iv group than in the oral group (Table 2; Fig. 4). Relationships between individual rat 123I thyroid uptake ratios and whole-body excretion ratios at
Ann Nucl Med Table 1 Serial Group
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I rat thyroid uptake ratios (%ID) Imaging time point 10 min
3h
6h
12 h
24 h
48 h
Oral
1.1 ± 0.6
11.4 ± 2.4
18.3 ± 2.8
24.4 ± 2.8
19.4 ± 2.4
11.4 ± 2.1
IV
2.0 ± 0.7
9.9 ± 2.3
13.4 ± 2.6
15.2 ± 2.8
11.2 ± 2.4
6.8 ± 1.9
P value
\0.05
NS
\0.005
\0.0001
\0.0001
\0.0005
n = 9 for each group Oral oral administration, IV intravenous administration, NS not significant (P = 0.2113)
examined in all oral and iv rats (n = 18), a significant inverse correlation appeared from 6 h (r = -0.799, P \ 0.0001), and was significant thereafter [12 h (r = -0.957, P \ 0.0001), 24 h (r = -0.905, P \ 0.0001), and 48 h (r = -0.893, P \ 0.0001)], respectively.
123I
thyroid uptake ratio (
ID)
30
25
20
Serial 15
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I activity in the stomach in oral and iv groups
The stomach activity was significantly higher in the oral group than in the iv group at all imaging points (Table 3; Fig. 6). In both groups, the highest uptake was observed at 10 min. The activity decreased rapidly, exponentially in the oral group and gradually in the iv group from 10 min to 12 h.
10
5
0 0
10
20
30
40
50
Hour
Discussion
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Fig. 3 Time-activity curves of I thyroid uptake ratios are shown for both groups (each; n = 9). Data represent mean ± SD. Open circle oral administration group and closed circle intravenous administration group
each imaging point were shown in Fig. 5. The oral group (n = 9) showed gradual increases in both 123I thyroid uptake and whole-body excretion ratios from 10 min to 12 h and an inverse correlation between them appeared at 3 h and was significant at 12 h (r = -0.765, P \ 0.05) and 48 h (r = -0.716, P \ 0.05), respectively, while the iv group showed the inverse correlations from the beginning, 10 min, to end, 48 h and were significant at 10 min (r = -0.856, P \ 0.005), 6 h (r = -0.792, P \ 0.05), 12 h (r = -0.867, P \ 0.005), and 48 h (r = -0.700, P \ 0.05).When the correlations between 123I thyroid uptake ratios and whole-body excretion ratios were Table 2 Serial 123I rat wholebody excretion ratio (%ID)
Group
Differences in visual 123I biodistribution between the oral and iv rat groups The major difference in 123I biodistribution appeared at 10 min. In the oral group, the esophagus and stomach were intensely visualized. The thyroid visualized faintly, but the urinary bladder was not visualized. On the other hand, in the iv group, the thyroid, stomach, kidneys, and bladder were clearly visualized and the cardiac pool was also visualized at 10 min. Thyroid visualization in both the groups occurs by the same mechanism, namely uptake by the thyroid of the blood 123I via the NIS which is a transmembrane protein mediating iodide transport into the follicular cells of the thyroid gland [12]. However, the mechanisms differ in the gastric visualization between the two groups. The stomach
Imaging time point 10 min
3h
6h
12 h
24 h
48 h
Oral
1.5 ± 0.6
18.5 ± 6.2
30.1 ± 5.3
34.2 ± 6.8
44.0 ± 5.6
59.2 ± 3.8
n = 9 for each group
IV
17.9 ± 3.8
47.4 ± 10.4
56.0 ± 6.8
59.9 ± 6.6
66.1 ± 5.0
74.1 ± 4.2
Oral oral administration, IV intravenous administration
P value
\0.0001
\0.0001
\0.0001
\0.0001
\0.0001
\0.0001
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is visualized mainly due to the oral administration of Na123I in the oral group and via the NIS in the iv group [12]. The bladder was visualized in the iv group, but not in the oral group. Bladder visualization at 10 min in the iv
123I
whole body excretion ratio (%ID)
80 70 60 50 40 30 20 10 0 0
10
20
30
40
50
Hour Fig. 4 Time-activity curves of 123I whole-body excretion ratios are shown for both groups (each; n = 9). Data represent mean ± SD. Open circle oral administration group and closed circle intravenous administration group
a
d
10 min
12 h
b
e
Fig. 5 Relationships are shown between individual rat 123I thyroid uptake and whole-body excretion ratios at 10 min (a), 3 h (b), 6 h (c), 12 h (d), 24 h (e), and 48 h (f). Open circle oral administration group and closed circle intravenous administration group. The solid, dashed,
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group is considered due to the much higher blood concentration of 123I which is highest immediately after iv injection of Na123I and its earlier clearance from the blood into the urine through the kidneys during this period. This is validated by the renal and cardiac blood pool visualization. Nonvisualization of the bladder, cardiac blood pool, and kidneys at 10 min in the oral group suggests that 123I enters the bloodstream more gradually and at a much lower concentration in comparison with the iv administration by its absorption from the small intestine in which 123I is mainly mediated by NIS into the blood [13]. Serial changes in visualization differed among the thyroid and stomach. Although the thyroid was visualized from 10 min to 48 h in both groups, the stomach was noted from 10 min to 12 h images in the oral group and from 10 min to 6 h images in the iv group. This difference may be due to the difference in handling of 123I after entering the cells via NIS; the thyroid cells use 123I for iodide organification and thyroid hormone synthesis and retain 123I longer. On the other hand, the gastric cells secrete 123I into the gastric juice without such retention mechanisms seen in the thyroid gland [12]. Serial fluctuated changes in urinary bladder activity relate with voiding of urine. The rat salivary glands were not visualized in any serial images probably for lack or weakness of NIS expression [12].
3h
24 h
c
f
6h
48 h
and thin dashed lines indicate the regression lines of the oral administration group, intravenous administration group, and whole group, respectively
Ann Nucl Med Table 3 Serial activity (%ID)
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I rat stomach
Group
Imaging time point 10 min
n = 9 for each group Oral oral administration, IV intravenous administration
3h
stomach uptake (%ID) 123I
24 h
48 h
Oral
35.9 ± 4.5
11.9 ± 4.9
5.5 ± 3.5
1.6 ± 0.4
1.3 ± 0.3
1.1 ± 0.2
4.8 ± 0.7
3.7 ± 1.4
1.7 ± 0.7
0.8 ± 0.3
0.8 ± 0.3
0.7 ± 0.2
P value
\0.0001
\0.005
\0.01
\0.0005
\0.01
\0.001
40 35 30 25 20 15 10 5 0 10
12 h
IV
45
0
6h
20
30
40
50
Hour Fig. 6 Time-activity curves of rat 123I stomach uptake are shown for both groups (each; n = 9). Data represent mean ± SD. Open circle the oral administration group and closed circle the intravenous administration group. The time points were 10 min, 3, 6, 12, 24, and 48 h, respectively
Quantitative differences in 123I thyroid and stomach uptake and whole-body excretion between the oral and iv rat groups We initially anticipated that the thyroid uptake would be higher by the iv route than the oral route, because we thought that the administered weight of 123I was a very tiny amount (492.9 pg) and the rat was in an iodine deficient state to allow the thyroid to take up 123I instantaneously. However, this anticipation proved correct only during the first 10 min. At 10 min, the thyroid uptake (2.0 ± 0.7 %ID) via the iv route was 1.8 times as high as that (1.1 ± 0.6 %ID) via the oral route. However, at 3 h, the difference in thyroid uptake between the two groups disappeared and from 6 to 48 h, 123I thyroid uptake was significantly higher in the oral group. The main reason for these differences is thought to be the differences in serial 123 I blood concentrations and clearances from the wholebody with time. When administered orally, 123I is absorbed by the small intestine through the stomach and enters the blood stream gradually and is taken up by the thyroid via NIS for synthesis of thyroid hormones [11, 12], whereas when administered intravenously, 123I enters the blood
stream directly without the intestinal absorption process. Although we did not measure 123I blood concentrations, during the initial 10 min they were estimated to be much higher by the iv route because the 10 min images clearly visualized the cardiac blood pool in the iv group, but not in the oral group. Thus, it is reasonable to assume that during the initial 10 min, the extremely high 123I blood concentrations compared to the oral group resulted in the higher thyroid uptake. However, as the 123I blood concentration is higher, its excretion from the kidneys is also higher. This is validated by the 10 min whole-body excretion ratio (iv vs. oral; 17.9 vs. 1.5 %ID). As the earlier literature [14] suggested, almost all 123I was excreted from the body through blood to urine via the kidneys. In the iv group, the highest 123 I blood concentration was achieved immediately after iv injection and might decrease rapidly due to excretion into urine, while the 123I blood concentration gradually increased in the oral group due to absorption from the small intestine into the blood, with 123I then excreted into the urine in a concentration-dependent manner. At 3 h, the thyroid uptake was almost the same in the oral and iv groups, suggesting that during this period, the amount of 123 I reaching the thyroid through the blood was almost the same in the two groups as a whole. From 6 to 12 h, the thyroid uptake increased in both groups and became significantly higher in the oral group, suggesting that during this period, the amount of 123I reaching the thyroid through the blood was significantly higher in the oral group. After the peak of 12 h, the thyroid uptake decreased due to the same excretion mechanisms from the thyroid while keeping a significant difference at the peak between the two groups. The individual rat whole-body excretion inversely correlated with the thyroid uptake throughout the imaging sequence in the iv group, suggesting that the thyroid uptake in this group is mainly influenced by excretion of 123I into urine. On the other hand, no such inverse correlation was observed during 6 h in the oral group, suggesting that a different mechanism underlies thyroid uptake in the oral group during this period, that is, the absorption process of 123 I from the small intestine. However, at 12 h and thereafter, the individual thyroid uptake was inversely correlated with the whole-body excretion regardless of the administration route, suggesting that the thyroid uptake was mainly controlled by the whole-body excretion in the two groups.
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I stomach activity was highest at 10 min in both groups and different from 123I thyroid uptake which peaked at 12 h. The reasons for the different time activity relationships were already discussed in the section on the visual assessment. When visualization of NIS-transfected tumors in the rat by 123I is considered, it can be visualized as early as 10 min after a bolus iv injection, because the stomach may have NIS alone. Thyroperoxidase (TPO) catalyzes iodination of proteins and subsequently causes iodide retention within thyroid cells. When NIS and TPOtransfected tumors are considered [9, 15, 16], the thyroid 123 I time activity curve is of use as a reference. The present study showed that thyroid 123I uptake is more enhanced in the oral group than the iv group when administered in a bolus fashion mainly due to the difference in 123I excretion into urine between the two groups, and supports the current clinical practice of oral administration of the radioiodide. When the diagnosis and therapy of the NIS-transfected tumors are introduced in clinical practice in future, the administration route may become one of the important factors as suggested by the present study. The results in this study were when Na123I was administered in a bolus fashion for both oral and iv routes and at the initial 10 min, thyroid uptake was significantly higher with the iv route than oral route, but vice versa during the entire course, and thyroid uptake directly and inversely correlated with 123I urine excretion, suggesting that when a given amount of 123I is administered intravenously, thyroid uptake would be higher by a slow infusion of a diluted solution with a lower 123I concentration than a bolus injection of a small volume solution with a higher 123I concentration, although the validity of this hypothesis remains to be clarified in a future experimental study. Other possible routes to administer radioiodine are subcutaneous and intraperitoneal routes. Thus, comparisons will be required among oral, iv, subcutaneous and intraperitoneal routes to enhance the uptake of radioiodine in NIS or NIS and TPO-mediated gene diagnosis and therapy. The major difference in the extra-thyroidal biodistribution of radioiodine is the salivary gland between rat and human [14]. In fact, the salivary gland did not visualize in our rat study. Clinically, the use of lemon drops in the first few days may help to decrease the incidence and severity of radiation sialadenitis due to radiation exposure from 131I [17]. The present rat study suggests that nausea and gastralgia from acute radiation gastritis may be prevented by ample fluid intake during the initial several hours after oral radioiodine administration and radiation cystitis can be prevented by frequent urination in both the oral and iv groups.
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Conflict of interest Hiroyuki Kurosawa, Kazuhisa Sakurai, Hideaki Hasegawa, Keisuke Uchida, Hiroyuki Kasahara, Takao Minamizawa are employees of FUJIFILM RI Pharma Co., Ltd. The remaining authors have no conflicts of interest to declare.
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ORIGINAL ARTICLE
Comparison of radioactive iodide uptake in the rat thyroid between oral and intravenous bolus administration Hiroyuki Kurosawa • Kazuhisa Sakurai • Hideaki Hasegawa Keisuke Uchida • Hiroyuki Kasahara • Takao Minamizawa • Masatoyo Nakajo • Masayuki Nakajo
•
Received: 3 July 2014 / Accepted: 7 August 2014 Ó The Japanese Society of Nuclear Medicine 2014
Abstract Objective Radioiodide is commonly used to diagnose and treat hyperthyroidism and thyroid carcinoma. However, we could not find any experimental data that strictly compared the biodistribution and thyroid uptake of radioactive iodide between the oral and intravenous (iv) routes with time. This prompted us to compare 123I biodistribution and thyroid uptake to clarify the differences between oral and iv bolus administration in rats. Methods The rats were divided into two groups, A and B (n = 5, each). In the first imaging experiment, Na123I solution (35 MBq/200 lL) was administered as a bolus to the rats orally in group A and intravenously in group B. Two weeks later, the second imaging experiment was performed as a crossover experiment. 123I biodistribution was evaluated visually and quantitatively with a gamma camera at 10 min, 3, 6, 12, 24, and 48 h after 123I administration. Thyroid uptake was compared between oral and iv groups. Correlation of 123I thyroid uptake and whole-body excretion was evaluated. The area under the curve (AUC) of thyroid uptake was also calculated.
H. Kurosawa K. Sakurai H. Hasegawa K. Uchida H. Kasahara T. Minamizawa Research Department, FUJIFILM RI Pharma Co., Ltd., 453-1 Shimo-okura, Matsuo-machi, Sammu, Chiba 289-1592, Japan H. Kurosawa (&) Product Management and Marketing Department, FUJIFILM RI Pharma Co., Ltd., 14-1 Kyobashi 2-chome, Chuo-ku, Tokyo 104-0031, Japan e-mail: [email protected] Masatoyo Nakajo Masayuki Nakajo Department of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
Results 123I biodistribution differed visually during 6 h between the two groups. 123I thyroid uptake was significantly higher in the iv group at 10 min (P \ 0.05) and in the oral group at 6 or more hour time points (P \ 0.005–P \ 0.0001) and peaked at 12 h in both groups (oral: 24.4 ± 2.8 %ID, iv: 15.2 ± 2.8 %ID). 123I thyroid uptake showed significant inverse correlations with whole-body excretion from 6 h (r = -0.799, P \ 0.0001), and thereafter [12 h (r = -0.957, P \ 0.0001), 24 h (r = -0.905, P \ 0.0001) and 48 h (r = -0.893, P \ 0.0001)], respectively. 123I whole-body excretion was significantly higher in the iv group at each time point (P \ 0.0001). The AUC of 123I thyroid uptake was 1.6 times higher in the oral group than the iv group. Conclusions These results suggest that radioiodide accumulates in the rat thyroid more effectively by oral than iv administration probably due to slower and lower 123I clearance from the body in the oral administration when administered in a bolus fashion. Keywords Radioiodine Rat Thyroid uptake Oral or intravenous administration Sodium iodide symporter (NIS)
Introduction After Enrico Fermi produced the first radioiodine, 128I, in 1934, active experimentation in the United States and France delineated the crucial role of iodine in thyroid metabolism and disease. 130I and 131I were first employed to treat thyrotoxicosis by 1941 and thyroid cancer in 1943. After World War II, 131I became widely available for diagnostic testing and therapy and 123I also became available for diagnosis of thyroid diseases after about 1982 [1]. 131 I has been widely used in the radiotherapy of Graves’
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disease and postoperative thyroid cancer and 131I or 123I has been also widely used in the diagnostic imaging of thyroid diseases. Although these radiopharmaceuticals have been administered orally to the patients in liquid or capsules, they can also be administered intravenously. In vivo biodistribution of radioactive iodide in the living body was extensively studied in the 1950s and 1960s. However, they differed in the administration route; intravenous (iv) [2, 3], intraperitoneal [4], subcutaneous [5] or oral [6] route. Although it was more recently reported that thyroid uptake and outcome of hyperthyroid cats did not differ between iv and subcutaneous administration routes [7] and there was no significant difference in influence on dose or outcome in Graves’ disease and unifocal autonomy between oral and iv administration routes [8], we could not find any experimental data strictly comparing the biodistribution and thyroid uptake of radioactive iodide between oral and iv routes with time. In addition, we consider that the administration route of radioiodine has the potential to influence the results of preclinical animal and clinical studies using radioactive iodide such as diagnosis and therapy of thyroid and nonthyroid cancers using sodium iodide symporter (NIS) gene delivery [9–11]. Motivated by this lack of comparative data, we examined the differences in biodistribution and thyroid uptake of 123I using a rat model, between oral and iv administration routes.
Materials and methods
switched to low iodine feed (CLEA Japan, Inc.) and distilled water. The low iodine diet was continued for the duration until completion of the second imaging experiment with the exception of enforced fasting on the day preceding Na123I administration. Group division The serum Free T3 and Free T4 concentrations were measured in all 15 rats on the day preceding the start of the low iodine diet. The mean levels of Free T3 and Free T4 were 3.9 ± 0.4 pg/mL and 2.6 ± 0.2 ng/dL, respectively. The coefficient of variation of serum Free T3 and Free T4 levels between individual rats was 0.10 and 0.08, respectively. The difference between individual levels was judged not to be significant. Based on these observations, the 15 rats were assigned, by body weight, using stratified randomization to one of the two groups A and B without consideration of serum Free T3 and Free T4 levels. Body weight measurement for the random group assignment was performed for all 15 rats on the morning of the first imaging experiment (280.5 ± 9.4 g). Five rats with large outliers from the average body weight were excepted and thus 10 rats, 5 in each group, were used for the experiments (276.1 ± 5.0 g). The 5 group A rats were administered Na123I orally in the first experiment and intravenously in the second experiment, and the 5 group B rats were conversely administered Na123I intravenously in the first experiment and orally in the second experiment.
Study design
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As 131I and 123I differ only in neutron number, the biodistribution of both radiotracers is held to be the same. In this study, we chose 123I because the emitted 159 keV gamma photons produce high resolution images in gamma camera imaging. The rats were fed low iodine food for 2 weeks and subsequently divided into two groups: A and B. In the first imaging experiment, group A rats received Na123I orally and group B rats received Na123I via iv injection. After cessation of Na123I administration for 2 weeks, the second imaging experiment was conducted as a crossover experiment which switched oral and intravenous administration between the two groups.
The imaging experiment was conducted 2 weeks after the rats received a low iodine diet. Na123I prepared by FUJIFILM RI Pharma Co., Ltd. (Chiba, Japan) was used for the experiments (the solvent was a mixed solution of diluted ammonia solution: 1 mol/L sodium hydroxide solution = 23:1). Na123I was diluted with 1:1 mixed solutions of saline and 0.3 M phosphate buffer (pH 7.0), and adjusted to a dose of 175 MBq/mL. The dose/volume for each rat was 35 MBq/200 lL and was delivered using a syringe for both oral and iv administration in a bolus fashion. The order of oral and iv administration was alternated between the two groups, A and B, to reduce the possibility of any systemic artifacts in the experiment. Before Na123I administration, the rats were anesthetized with pentobarbital sodium intraperitoneal injection. Oral Na123I was delivered directly into the stomach via the esophagus using a syringe and iv Na123I was injected into the femoral vein with a 26G needle connected to a syringe. The planar imaging was performed, over 3 min at each imaging time, using a PRISM2000 (Shimadzu Corporation, Kyoto, Japan) equipped with a low energy ultrahigh resolution parallel
Laboratory animals All animal experiments were conducted in compliance with the Guidelines for the Care and Use of Research Animals established by our institute. Fifteen 10-week old male Wistar rats were purchased from Japan SLC, Inc. All rats were acclimatized for 1 week with a free-feeding diet of standard feed (CLEA Japan, Inc.) and tap water. Then, the diet was
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I imaging experiment
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collimator (matrix: 256, MAG: 2.6). The gamma ray energy photo peak was adjusted at 159 keV with the window of ±10 %. The image acquisition was performed, under anesthesia by pentobarbital sodium, at 10 min, 3, 6, 12, 24, and 48 h. The rats in both groups received a twoweek drug holiday after the first imaging experiment before commencing the second imaging experiment. The low iodine diet was continued during the drug holiday. In the second imaging experiment, the procedure was reversed to that of the first imaging experiment; the group A rats received Na123I intravenously and the group B rats received Na123I orally. Two rats were excluded from the analysis: Extravascular leakage of Na123I was noted in one rat of group A. One rat of group B died due to the anesthetic during the imaging experiment. Therefore, the data of 9 rats in each group were finally analyzed. Image analysis The serial images obtained in each experiment were visually evaluated. For the quantitative evaluation, irregular regions of interest (ROIs) were drawn over the thyroid, stomach, urinary bladder, and whole body to obtain the count. The thyroid or stomach uptake ratio was calculated by the following formula: Thyroid or stomach uptake ratio at each time point ð%IDÞ ¼ thyroid or stomach uptake count at each time point ð*1Þ 100=administered dose count ð*2Þ
(*1) The thyroid or stomach ROI count at each time point which was decay corrected to the initial administered time. (*2) The 10 min whole-body count which was decay corrected to the administered time. The whole-body excretion ratio was calculated at each time point as follows: Whole body excretion ratio ð%IDÞ ¼ ðadministered dose count ð*1Þ count remained in the whole body ð*2ÞÞ 100=administered dose count (*1) The 10 min whole-body count which was decay corrected to the administered time. (*2) The whole-body count from which the bladder ROI count was subtracted based on the assumption that the urinary bladder activity was not reabsorbed and was extra-body activity. Each count was decay corrected to the administered time. Statistical analysis Data are expressed as mean ± standard deviation (SD). Two-sided Student’s t test was performed to compare mean
values between the oral and iv groups. Pearson’s linear regression model was used to correlate the thyroid uptake ratio and the whole-body excretion ratio at each time point. Area under the curve (AUC) was calculated by the program of GraphPad Prism ver.5.04.
Results Visual assessment Serial changes in the 123I biodistribution of the first imaging experiment from 10 min to 48 h were shown in Figs. 1 and 2. Figure 1 shows the images after oral administration and Fig. 2 shows those after iv administration. The 123I images acquired 10 min after oral administration visualized the thyroid faintly and the esophagus and the stomach clearly and did not visualize the urinary bladder. Bowel activity was also noted in a rat. On the other hand, the 123I images acquired 10 min after iv administration visualized the thyroid, stomach, and urinary bladder intensely and the heart and kidneys moderately. Thus, the major differences in biodistribution between the two groups at this time point were observed in the thyroid which was more intense in the iv group, the stomach which was more intense in the oral group and the urinary bladder which was more intense in the iv group. At 3 and 6 h after administration, the thyroid, stomach, and urinary bladder were visualized in both the oral and iv groups. At these time points, the stomach appeared more intense in the oral group. At 12 h after administration, the thyroid was visualized in all rats, but the stomach was only faintly visualized in the oral group and almost invisible in the iv group. There were some rats whose urinary bladders were visualized. At 24 and 48 h after administration, only the thyroid was visualized. Serial changes in the 123I biodistribution of the second imaging experiment were similar to those of the first imaging experiment. Quantitative assessment Serial
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I thyroid uptake
The serial thyroid uptake ratios are shown in Table 1 and Fig. 3. The thyroid uptake ratio peaked at 12 h in both the oral and iv groups and gradually decreased thereafter in both groups. Although at 10 min, the thyroid uptake ratio was significantly higher in the iv group (2.0 ± 0.7 %ID) than in the oral group (1.1 ± 0.6 %ID) (P \ 0.05), it was the almost same at 3 h and reversely and significantly higher in
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Ann Nucl Med Fig. 1 Serial whole-body planar images are shown at 10 min, 3, 6, 12, 24, and 48 h after oral administration of Na123I to 5 group A rats in the first imaging experiment. The arrowhead, solid arrow, and dashed arrow indicate the thyroid, stomach, and urinary bladder, respectively
Fig. 2 Serial whole-body planar images are shown at 10 min, 3, 6, 12, 24, and 48 h after intravenous administration of Na123I to 5 group B rats in the first imaging experiment. The arrowhead, solid arrow, and dashed arrow indicate the thyroid, stomach, and urinary bladder, respectively
the oral group than in the iv group 6 or more h after administration. With the thyroid uptake (%ID) specified as the therapeutic index, the AUC of oral administration was approximately 1.6 times that of iv administration (oral administration 761.2 ± 86.8 %ID h versus iv administration 475.0 ± 87.9 %ID h, P \ 0.0001).
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Serial
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I thyroid uptake and whole-body excretion
At all imaging time points, 123I whole-body excretion was clearly higher in the iv group than in the oral group (Table 2; Fig. 4). Relationships between individual rat 123I thyroid uptake ratios and whole-body excretion ratios at
Ann Nucl Med Table 1 Serial Group
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I rat thyroid uptake ratios (%ID) Imaging time point 10 min
3h
6h
12 h
24 h
48 h
Oral
1.1 ± 0.6
11.4 ± 2.4
18.3 ± 2.8
24.4 ± 2.8
19.4 ± 2.4
11.4 ± 2.1
IV
2.0 ± 0.7
9.9 ± 2.3
13.4 ± 2.6
15.2 ± 2.8
11.2 ± 2.4
6.8 ± 1.9
P value
\0.05
NS
\0.005
\0.0001
\0.0001
\0.0005
n = 9 for each group Oral oral administration, IV intravenous administration, NS not significant (P = 0.2113)
examined in all oral and iv rats (n = 18), a significant inverse correlation appeared from 6 h (r = -0.799, P \ 0.0001), and was significant thereafter [12 h (r = -0.957, P \ 0.0001), 24 h (r = -0.905, P \ 0.0001), and 48 h (r = -0.893, P \ 0.0001)], respectively.
123I
thyroid uptake ratio (
ID)
30
25
20
Serial 15
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I activity in the stomach in oral and iv groups
The stomach activity was significantly higher in the oral group than in the iv group at all imaging points (Table 3; Fig. 6). In both groups, the highest uptake was observed at 10 min. The activity decreased rapidly, exponentially in the oral group and gradually in the iv group from 10 min to 12 h.
10
5
0 0
10
20
30
40
50
Hour
Discussion
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Fig. 3 Time-activity curves of I thyroid uptake ratios are shown for both groups (each; n = 9). Data represent mean ± SD. Open circle oral administration group and closed circle intravenous administration group
each imaging point were shown in Fig. 5. The oral group (n = 9) showed gradual increases in both 123I thyroid uptake and whole-body excretion ratios from 10 min to 12 h and an inverse correlation between them appeared at 3 h and was significant at 12 h (r = -0.765, P \ 0.05) and 48 h (r = -0.716, P \ 0.05), respectively, while the iv group showed the inverse correlations from the beginning, 10 min, to end, 48 h and were significant at 10 min (r = -0.856, P \ 0.005), 6 h (r = -0.792, P \ 0.05), 12 h (r = -0.867, P \ 0.005), and 48 h (r = -0.700, P \ 0.05).When the correlations between 123I thyroid uptake ratios and whole-body excretion ratios were Table 2 Serial 123I rat wholebody excretion ratio (%ID)
Group
Differences in visual 123I biodistribution between the oral and iv rat groups The major difference in 123I biodistribution appeared at 10 min. In the oral group, the esophagus and stomach were intensely visualized. The thyroid visualized faintly, but the urinary bladder was not visualized. On the other hand, in the iv group, the thyroid, stomach, kidneys, and bladder were clearly visualized and the cardiac pool was also visualized at 10 min. Thyroid visualization in both the groups occurs by the same mechanism, namely uptake by the thyroid of the blood 123I via the NIS which is a transmembrane protein mediating iodide transport into the follicular cells of the thyroid gland [12]. However, the mechanisms differ in the gastric visualization between the two groups. The stomach
Imaging time point 10 min
3h
6h
12 h
24 h
48 h
Oral
1.5 ± 0.6
18.5 ± 6.2
30.1 ± 5.3
34.2 ± 6.8
44.0 ± 5.6
59.2 ± 3.8
n = 9 for each group
IV
17.9 ± 3.8
47.4 ± 10.4
56.0 ± 6.8
59.9 ± 6.6
66.1 ± 5.0
74.1 ± 4.2
Oral oral administration, IV intravenous administration
P value
\0.0001
\0.0001
\0.0001
\0.0001
\0.0001
\0.0001
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is visualized mainly due to the oral administration of Na123I in the oral group and via the NIS in the iv group [12]. The bladder was visualized in the iv group, but not in the oral group. Bladder visualization at 10 min in the iv
123I
whole body excretion ratio (%ID)
80 70 60 50 40 30 20 10 0 0
10
20
30
40
50
Hour Fig. 4 Time-activity curves of 123I whole-body excretion ratios are shown for both groups (each; n = 9). Data represent mean ± SD. Open circle oral administration group and closed circle intravenous administration group
a
d
10 min
12 h
b
e
Fig. 5 Relationships are shown between individual rat 123I thyroid uptake and whole-body excretion ratios at 10 min (a), 3 h (b), 6 h (c), 12 h (d), 24 h (e), and 48 h (f). Open circle oral administration group and closed circle intravenous administration group. The solid, dashed,
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group is considered due to the much higher blood concentration of 123I which is highest immediately after iv injection of Na123I and its earlier clearance from the blood into the urine through the kidneys during this period. This is validated by the renal and cardiac blood pool visualization. Nonvisualization of the bladder, cardiac blood pool, and kidneys at 10 min in the oral group suggests that 123I enters the bloodstream more gradually and at a much lower concentration in comparison with the iv administration by its absorption from the small intestine in which 123I is mainly mediated by NIS into the blood [13]. Serial changes in visualization differed among the thyroid and stomach. Although the thyroid was visualized from 10 min to 48 h in both groups, the stomach was noted from 10 min to 12 h images in the oral group and from 10 min to 6 h images in the iv group. This difference may be due to the difference in handling of 123I after entering the cells via NIS; the thyroid cells use 123I for iodide organification and thyroid hormone synthesis and retain 123I longer. On the other hand, the gastric cells secrete 123I into the gastric juice without such retention mechanisms seen in the thyroid gland [12]. Serial fluctuated changes in urinary bladder activity relate with voiding of urine. The rat salivary glands were not visualized in any serial images probably for lack or weakness of NIS expression [12].
3h
24 h
c
f
6h
48 h
and thin dashed lines indicate the regression lines of the oral administration group, intravenous administration group, and whole group, respectively
Ann Nucl Med Table 3 Serial activity (%ID)
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I rat stomach
Group
Imaging time point 10 min
n = 9 for each group Oral oral administration, IV intravenous administration
3h
stomach uptake (%ID) 123I
24 h
48 h
Oral
35.9 ± 4.5
11.9 ± 4.9
5.5 ± 3.5
1.6 ± 0.4
1.3 ± 0.3
1.1 ± 0.2
4.8 ± 0.7
3.7 ± 1.4
1.7 ± 0.7
0.8 ± 0.3
0.8 ± 0.3
0.7 ± 0.2
P value
\0.0001
\0.005
\0.01
\0.0005
\0.01
\0.001
40 35 30 25 20 15 10 5 0 10
12 h
IV
45
0
6h
20
30
40
50
Hour Fig. 6 Time-activity curves of rat 123I stomach uptake are shown for both groups (each; n = 9). Data represent mean ± SD. Open circle the oral administration group and closed circle the intravenous administration group. The time points were 10 min, 3, 6, 12, 24, and 48 h, respectively
Quantitative differences in 123I thyroid and stomach uptake and whole-body excretion between the oral and iv rat groups We initially anticipated that the thyroid uptake would be higher by the iv route than the oral route, because we thought that the administered weight of 123I was a very tiny amount (492.9 pg) and the rat was in an iodine deficient state to allow the thyroid to take up 123I instantaneously. However, this anticipation proved correct only during the first 10 min. At 10 min, the thyroid uptake (2.0 ± 0.7 %ID) via the iv route was 1.8 times as high as that (1.1 ± 0.6 %ID) via the oral route. However, at 3 h, the difference in thyroid uptake between the two groups disappeared and from 6 to 48 h, 123I thyroid uptake was significantly higher in the oral group. The main reason for these differences is thought to be the differences in serial 123 I blood concentrations and clearances from the wholebody with time. When administered orally, 123I is absorbed by the small intestine through the stomach and enters the blood stream gradually and is taken up by the thyroid via NIS for synthesis of thyroid hormones [11, 12], whereas when administered intravenously, 123I enters the blood
stream directly without the intestinal absorption process. Although we did not measure 123I blood concentrations, during the initial 10 min they were estimated to be much higher by the iv route because the 10 min images clearly visualized the cardiac blood pool in the iv group, but not in the oral group. Thus, it is reasonable to assume that during the initial 10 min, the extremely high 123I blood concentrations compared to the oral group resulted in the higher thyroid uptake. However, as the 123I blood concentration is higher, its excretion from the kidneys is also higher. This is validated by the 10 min whole-body excretion ratio (iv vs. oral; 17.9 vs. 1.5 %ID). As the earlier literature [14] suggested, almost all 123I was excreted from the body through blood to urine via the kidneys. In the iv group, the highest 123 I blood concentration was achieved immediately after iv injection and might decrease rapidly due to excretion into urine, while the 123I blood concentration gradually increased in the oral group due to absorption from the small intestine into the blood, with 123I then excreted into the urine in a concentration-dependent manner. At 3 h, the thyroid uptake was almost the same in the oral and iv groups, suggesting that during this period, the amount of 123 I reaching the thyroid through the blood was almost the same in the two groups as a whole. From 6 to 12 h, the thyroid uptake increased in both groups and became significantly higher in the oral group, suggesting that during this period, the amount of 123I reaching the thyroid through the blood was significantly higher in the oral group. After the peak of 12 h, the thyroid uptake decreased due to the same excretion mechanisms from the thyroid while keeping a significant difference at the peak between the two groups. The individual rat whole-body excretion inversely correlated with the thyroid uptake throughout the imaging sequence in the iv group, suggesting that the thyroid uptake in this group is mainly influenced by excretion of 123I into urine. On the other hand, no such inverse correlation was observed during 6 h in the oral group, suggesting that a different mechanism underlies thyroid uptake in the oral group during this period, that is, the absorption process of 123 I from the small intestine. However, at 12 h and thereafter, the individual thyroid uptake was inversely correlated with the whole-body excretion regardless of the administration route, suggesting that the thyroid uptake was mainly controlled by the whole-body excretion in the two groups.
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I stomach activity was highest at 10 min in both groups and different from 123I thyroid uptake which peaked at 12 h. The reasons for the different time activity relationships were already discussed in the section on the visual assessment. When visualization of NIS-transfected tumors in the rat by 123I is considered, it can be visualized as early as 10 min after a bolus iv injection, because the stomach may have NIS alone. Thyroperoxidase (TPO) catalyzes iodination of proteins and subsequently causes iodide retention within thyroid cells. When NIS and TPOtransfected tumors are considered [9, 15, 16], the thyroid 123 I time activity curve is of use as a reference. The present study showed that thyroid 123I uptake is more enhanced in the oral group than the iv group when administered in a bolus fashion mainly due to the difference in 123I excretion into urine between the two groups, and supports the current clinical practice of oral administration of the radioiodide. When the diagnosis and therapy of the NIS-transfected tumors are introduced in clinical practice in future, the administration route may become one of the important factors as suggested by the present study. The results in this study were when Na123I was administered in a bolus fashion for both oral and iv routes and at the initial 10 min, thyroid uptake was significantly higher with the iv route than oral route, but vice versa during the entire course, and thyroid uptake directly and inversely correlated with 123I urine excretion, suggesting that when a given amount of 123I is administered intravenously, thyroid uptake would be higher by a slow infusion of a diluted solution with a lower 123I concentration than a bolus injection of a small volume solution with a higher 123I concentration, although the validity of this hypothesis remains to be clarified in a future experimental study. Other possible routes to administer radioiodine are subcutaneous and intraperitoneal routes. Thus, comparisons will be required among oral, iv, subcutaneous and intraperitoneal routes to enhance the uptake of radioiodine in NIS or NIS and TPO-mediated gene diagnosis and therapy. The major difference in the extra-thyroidal biodistribution of radioiodine is the salivary gland between rat and human [14]. In fact, the salivary gland did not visualize in our rat study. Clinically, the use of lemon drops in the first few days may help to decrease the incidence and severity of radiation sialadenitis due to radiation exposure from 131I [17]. The present rat study suggests that nausea and gastralgia from acute radiation gastritis may be prevented by ample fluid intake during the initial several hours after oral radioiodine administration and radiation cystitis can be prevented by frequent urination in both the oral and iv groups.
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Conflict of interest Hiroyuki Kurosawa, Kazuhisa Sakurai, Hideaki Hasegawa, Keisuke Uchida, Hiroyuki Kasahara, Takao Minamizawa are employees of FUJIFILM RI Pharma Co., Ltd. The remaining authors have no conflicts of interest to declare.
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