Radiopharmacokinetics of Radioiodine in the Parotid Glands After the Administration of Lemon Juice

Abstract

Background:

The ability of sialagogues to increase or decrease radiation induced-sialoadenitis and/or xerostomia after therapeutic administration of ¹³¹I is controversial. To evaluate this we measured the radiopharmacokinetics of ¹²³I in the parotid glands (PGs) after its administration of lemon juice (LJ).

Methods:

A retrospective review was performed on all patients who had a salivary gland scan performed before ¹³¹I therapy between July 2008 and April 2009 at the Washington Hospital Center. Two hours after ¹²³I was given orally, dynamic scintigraphy was initiated. Five milliliters of LJ was given 5 minutes later. Then, the patient was imaged for 1 hour (phase 1) at which point the sequence was repeated (phase 2). Twenty-three patients were studied. For each PG, the presence or absence of uptake was assessed, and based on background corrected counts, the mean, range, and standard deviation were determined for multiple radiopharmacokinetic parameters such as (i) percent radioiodine washout, (ii) time from LJ administration to re-accumulation of radioiodine to pre-LJ activity, and (iii) percent reduction in radiation absorbed dose to the PGs if LJ had been re-administered at the time the radioiodine activity re-accumulated to the pre-LJ activity.

Results:

The mean ± one standard deviation and range for percent washout were 84% ± 18% (35%–100%) and 83% ± 21% (37%–100%) in phase 1 and 2, respectively. The times from LJ to re-accumulation of the radioiodine to the pre-LJ activity were 21 ± 10 minutes (4–45 minutes) and 40 ± 14 minutes (12–62 minutes) for phase 1 and 2, respectively. The estimated percent reduction in radiation absorbed dose to the PGs following the first and second administration of LJ was 37% ± 14% (13%–93%) and 47% ± 16% (21%–97%), respectively.

Conclusions:

The washout of radioiodine from the PGs is rapid but transient. Early repeat administration may result in continued and cumulative reduction of radiation absorbed dose in the PGs.

Introduction

¹³¹ I is used in the therapy of differentiated thyroid cancer, and one of the most common side effects of ¹³¹I therapy is sialoadenitis (1 –3). Sialagogues such as lemon candies, lemon juice (LJ), sour candies, and sugarless chewing gum are often administered with the intent of minimizing the residence time of radioiodine within the salivary glands, thereby reducing the radiation absorbed dose to the salivary glands and helping to reduce the frequency and severity of sialoadenitis and xerostomia. However, Nakada et al. (4) reported data suggesting that the use of sialagogues should be avoided during the first 24-hour period after ¹³¹I therapy. Their conclusion, however, is controversial (5 –7).

The objective of this study was to characterize the radiopharmacokinetics of radioiodine in the parotid glands (PGs) after LJ.

Methods

A retrospective review was performed on all patients who had a clinical salivary gland scan performed before ¹³¹I therapy for differentiated thyroid cancer between July 2008 and April 2009 at the Washington Hospital Center. Patients fasted for 4 hours before the start of the scan. Two hours after the oral administration of a capsule of 15–37 MBq (0.4–1 mCi) of ¹²³I, a dynamic imaging sequence was initiated on a Siemens gamma camera using the protocol outlined in Table 1. Without moving the patient, 5 mL of Real Lemon Juice^® (LJ) was given orally 5 minutes after the start of the acquisition. The patient was then imaged for another 60 minutes (phase 1). At 65 minutes after the initiation of the images, the patient was given a second bolus of 5 mL of LJ orally with imaging continuing for an additional 60 minutes (phase 2). Regions of interest were placed over each observed PG along with a background region (see Fig. 1). Background corrected time activity curves were obtained for each PG in each phase. Decay correction was not performed. For each PG and each phase, the mean, range, standard deviation, and confidence intervals were determined for (i) maximum percent washout relative to pre-LJ ¹²³I activity, (ii) time from administration of LJ to nadir of washout of ¹²³I, (iii) time from nadir to re-accumulation of ¹²³I activity to pre-LJ ¹²³I activity, (iv) time from administration of LJ to re-accumulation of ¹²³I to pre-LJ ¹²³I activity, and (v) ratio of ¹²³I activity at 1 hour relative to pre-LJ ¹²³I activity (see Fig. 2).

FIG. 1.

The regions of interest positioned over each parotid gland and the background regions placed superior to the respective parotid gland.

FIG. 2.

This figure demonstrates the time points used for the calculation of the radiopharmacokinetic parameters. (A) Peak activity (counts/min) when lemon juice (LJ) was administered and typically just before washout after administration of LJ. (B) Nadir (counts/min) after LJ administration. (C) Point where activity returned to activity equal to activity at point (A). Note: activity may not return to activity equal to activity at point (A) within the 1 hour of imaging. (D) Maximum activity (counts/min) during the 1 hour of imaging, which may occur earlier than 1 hour and may not equal the activity at point (A). (E) time after start of imaging (min) to point (A). (F) Time after start of imaging (min) to point (B). (G) time after start of imaging (min) to point (C). (H) Time after start of imaging (min) to point (D). Percent washout out relative to pre-LJ ¹²³I activity = (A – B)/A. Time from administration of LJ to nadir of washout of ¹²³I = F – E. Time from nadir to re-accumulation of ¹²³I equal to pre-LJ ¹²³I = G – F activity. Maximum % re-accumulation relative to pre-LJ activity = (100 × D – A)/A during the first hour.

Table 1.

Protocol for Acquisition of Images

Position: supine with the head in the Waters' position

Camera: dual detector E-Cam

Energy peak: 159 keV for ¹²³I

Window: 20% centered on the photo peak

Collimator: low-energy, high-resolution

Acquisition sequence: 125 images for 1 min each

Digital acquisition: 64 × 64 computer matrix

The relative reduction in radiation absorbed dose to the PGs secondary to the administration of sialagogues was estimated based on two assumptions (see Fig. 3). First, we assumed that if the LJ had not been administered, the radioiodine activity in the PGs would have remained at the same value as the value on the 5 minute image (baseline value), and, second, sialagogues would have been given again at a time interval equal to that required for the ¹²³I in the PG to re-accumulate to the baseline value. It is important to note that we cannot calculate actual radiation absorbed dose. Rather we are estimating the percent reduction of radiation absorbed dose based on the above two assumptions. The submandibular glands were not evaluated for this study. This retrospective study was approved by the MedStar Institutional Review Board.

FIG. 3.

This figure shows the areas used to estimate the percent change in radiation absorbed dose to the parotid glands from the radioiodine after the administration of the LJ. The dark gray area represents the area under a typical time activity curve (TAC), with the latter representing the total counts from the radioactivity in the salivary glands during one phase. The hatched area reflects the total counts of radioactivity in the salivary glands based on the assumption that the radioiodine remained constant from the administration of LJ [point (A) in Fig. 2] to the time that the radioiodine had re-accumulated back to the amount of radioiodine before the administration of the initial LJ [point (C) in Fig. 2]. The light gray area represents the percent reduction of radiation absorbed dose as a result of the administration of LJ (hatched area minus the dark gray area within the hatched area). Area A = Area under the TAC reflecting the radioactivity exposing the salivary glands when LJ had been administered. Area B = Total area under the TAC reflecting the radioactivity exposing the salivary glands based on the assumption that the radioactivity remained constant between points A–C in Figure 2. Area C = The relative reduction of radiation absorbed dose as a result of use of LJ. The estimated % change in radiation absorbed dose to the parotid gland was calculated as % reduction in radiation absorbed dose = ([Area B – Area A]/[Area B]) × 100.

Results

A total of 29 patients had salivary gland scans available for review. The demographics of the patients are shown in Table 2. Six patients had no visible radioiodine activity in the PGs, of which two had no prior ¹³¹I treatments and four had one prior ¹³¹I treatment. These patients were not evaluated further. Thus, there were 23 patients who had evaluable radioiodine uptake. Sixteen, five, and two patients had no prior ¹³¹I therapy, one prior therapy, and two or more prior ¹³¹I therapies, respectively. In these 23 patients, 46 PGs were evaluated.

Table 2.

Patient Demographics

Histology
Papillary	19
Follicular	5
Papillary–follicular	5
Age (mean)	49
Age (range)	23–74
Women	16
Men	13

The data for the ¹²³I radiopharmacokinetics in phase 1 and phase 2 are shown in Table 3. The mean decreases in radioactivity after LJ for phase 1 and phase 2 were 84% and 83%, respectively. The mean intervals from the administration of LJ to the return of the activity to that present before LJ administration was 21 minutes in phase 1 and 40 minutes in phase 2 (p < 0.0001). A typical time–activity curve for patients with PG uptake, washout, and re-accumulation is shown in Figure 4. Tables 4 and 5 demonstrate the parameters and p-values comparing right versus left individual PGs in phase 1 and 2, respectively. There were no significant differences in any parameter between the right and left PGs in both phase 1 and phase 2. Tables 6 and 7 present comparisons of the data for patients who had no prior ¹³¹I therapy and those who had at least one such therapy. At a p-value of <0.05, no statistical difference was noted regarding any parameter in both phase 1 and phase 2. In patients who were prepared with recombinant human thyrotropin injections, thyroid hormone withdrawal, or on thyroid hormone suppression, no statistical difference in any of the parameters was noted at the p < 0.05 level. Because the number of patients was low, a nonparametric method (Kruskal–Wallis one-way analysis of variance) was used to evaluate the differences.

FIG. 4.

A typical background-corrected TAC demonstrating the response to the oral administration of LJ. The numbers on the X-axis are minutes, and the numbers on the Y-axis are counts/minute. The notations are the same as described in Figure 2. Note the prompt response to LJ with subsequent re-accumulation and the similar response following the second administration of LJ at ∼65 minutes into the acquisition.

Table 3.

Data for Combined Right and Left Parotid Gland Radioactivity: Phase 1 Versus Phase 2

	Phase 1				Phase 2
	Mean	Range	Standard deviation	95% confidence interval	Mean	Range	Standard deviation	95% confidence interval	p-Value for difference between phases
Percent washout relative to baseline	84%	35%–100%	18%	78%–89%	83%	37%–100%	21%	76%–89%	0.6646
Time from administration of lemon juice to nadir of washout of radioiodine	4 min	2–8 min	1.5 min	3.5–4.4 min	4.4 min	2–12 min	2.1 min	3.8–5.0 min	0.1399
Time from nadir to re-accumulation of radioiodine to baseline	17 min	1–39 min	10 min	14–20 min	36 min	9–56 min	14 min	29–43 min	<0.0001
Time from administration of lemon juice to re-accumulation of radioiodine to baseline	21 min	4–45 min	10 min	18–24 min	40 min	12–62 min	14 min	32–47 min	<0.0001
Maximum ratio of radioiodine relative to baseline during each phase	2.2	0.58–8.0	1.3	1.8–2.6	1.0	0.13–3.5	0.61	0.83–1.2	<0.0001
Percent reduction in radiation absorbed dose to the parotid glands	37%	13%–93%	14%	33%–41%	47%	21%–97%	16%	42%–52%	<0.0001

p-Values were calculated using a matched-pairs t significance test. For each observation, the differences between phase 1 and phase 2 were calculated and tested against the null hypothesis that the difference is zero. The boldface entries are significant at the 0.05 level or lower.

Table 4.

Data for Individual Right and Left Parotid Gland Radioactivity: Phase 1

	Phase 1 right				Phase 1 left
	Mean	Range	Standard deviation	95% confidence interval	Mean	Range	Standard deviation	95% confidence interval	p-Value for difference between right/left
Percent washout relative to baseline	85%	35%–100%	18%	77%–92%	83%	37%–100%	19%	75%–91%	0.6953
Time from administration of lemon juice to nadir of washout of radioiodine	3.8 min	2–8 min	1.7 min	3.1–4.6 min	4.1 min	2–7 min	1.3 min	3.6–4.7 min	0.4653
Time from nadir to re-accumulation of radioiodine to baseline	17 min	1–39 min	9.4 min	13–21 min	17 min	1–38 min	11 min	13–22 min	0.7839
Time from administration of lemon juice to re-accumulation of radioiodine to baseline	21 min	4–41 min	9.1 min	17–25 min	22 min	4–45 min	11 min	17–26 min	0.6713
Maximum ratio of radioiodine relative to baseline during each phase	2.5	1.1–8.0	1.7	1.8–3.2	2.0	0.58–3.7	0.89	1.6–2.4	0.0363
Percent reduction in radiation absorbed dose to the parotid glands	39%	20%–67%	11%	34%–44%	35%	13%–93%	17%	28%–42%	0.1981

p-Values were calculated using a matched-pairs t significance test. For each observation, the differences between right and left were calculated and tested against the null hypothesis that the difference is zero. The boldface entries are significant at the 0.05 level or lower.

Table 5.

Data for Individual Right and Left Parotid Gland Radioactivity: Phase 2

	Phase 2 right				Phase 2 left
	Mean	Range	Standard deviation	95% confidence interval	Mean	Range	Standard deviation	95% confidence interval	p-Value for difference between right/left
Percent washout relative to baseline	90%	37%–100%	17%	82%–97%	75%	41%–100%	23%	65%–85%	0.0115
Time from administration of lemon juice to nadir of washout of radioiodine	3.6 min	2–7 min	1.3 min	3–4.2 min	5.2 min	2–12 min	2.5 min	4.2–6.3 min	0.0130
Time from nadir to re-accumulation of radioiodine to baseline	31 min	9–47 min	14 min	19–42 min	40 min	20–56 min	12 min	31–50 min	0.0895
Time from administration of lemon juice to re-accumulation of radioiodine to baseline	34 min	12–51 min	14 min	22–45 min	45 min	25–62 min	13 min	35–55 min	0.0550
Maximum ratio of radioiodine relative to baseline during each phase	1.0	0.13–3.5	0.72	0.73–1.4	0.97	0.30–2.2	0.49	0.76–1.2	0.6198
Percent reduction in radiation absorbed dose to the parotid glands	49%	21%–97%	17%	41%–56%	45%	25%–95%	15%	39%–52%	0.0385

Table 6.

Data for Combined Right and Left Parotid Gland Radioactivity in Patients Who Had No Prior Therapy Versus at Least One Prior ¹³¹ I Therapy: Phase 1

	16 patients No therapy				7 patients At least one therapy
	Mean	Range	Standard deviation	95% confidence interval	Mean	Range	Standard deviation	95% confidence interval	p-Value for difference between no vs. at least one therapy
Percent washout relative to baseline	80%	35%–100%	20%	73%–87%	93%	72%–100%	10%	88%–99%	0.0283
Time from administration of lemon juice to nadir of washout of radioiodine	4.1 min	2–8 min	1.5 min	3.5–4.6 min	3.8 min	2–7 min	1.5 min	2.9–4.6 min	0.5769
Time from nadir to re-accumulation of radioiodine to baseline	17 min	1–38 min	10 min	13–20 min	19 min	6–39 min	9 min	13–24 min	0.4551
Time from administration of lemon juice to re-accumulation of radioiodine to baseline	21 min	4–45 min	11 min	17–25 min	22 min	8–41 min	8.6 min	17–27 min	0.5294
Maximum ratio of radioiodine relative to baseline during each phase	2.3	0.58–8.0	1.5	1.8–2.9	2.1	0.86–4.3	0.76	1.7–2.5	0.5938
Percent reduction in radiation absorbed dose to the parotid glands	37%	13%–93%	16%	31%–42%	38%	21%–54%	10%	32%–43%	0.3500

p-Values were obtained from the Wilcoxon signed-rank test based on the null hypothesis that there is no difference between the two groups. A nonparametric test was used because of the small sample size in the “Prior Therapy” group. The boldface entries are significant at the 0.05 level or lower.

Table 7.

Data for Combined Right and Left Parotid Gland Radioactivity in Patients Who Had No Prior Therapy Versus at Least One Prior ¹³¹ I Therapy: Phase 2

	16 patients No therapy				7 patients At least one therapy
	Mean	Range	Standard deviation	95% confidence interval	Mean	Range	Standard deviation	95% confidence interval	p-Value for difference between no vs. at least one therapy
Percent washout relative to baseline	81%	37%–100%	22%	73%–89%	87%	42%–100%	19%	75%–98%	0.6650
Time from administration of lemon juice to nadir of washout of radioiodine	4.4 min	2–9 min	1.9 min	3.7–5.1 min	4.4 min	2–12 min	2.5 min	3.0–5.9 min	0.8942
Time from nadir to re-accumulation of radioiodine to baseline	29 min	9–47 min	12 min	20–37 min	46 min	34–56 min	9.5 min	37–54 min	0.0265
Time from administration of lemon juice to re-accumulation of radioiodine to baseline	32 min	12–51 min	12 min	24–41 min	50 min	38–62 min	9.8 min	41–59 min	0.0218
Maximum ratio of radioiodine relative to baseline during each phase	1.0	0.13–3.5	0.66	0.77–1.2	1	0.48–2.2	0.49	0.72–1.3	0.8124
Percent reduction in radiation absorbed dose to the parotid glands	46%	21%–97%	18%	40%–53%	49%	38%–66%	8%	44%–53%	0.1217

p-Values were obtained from the Wilcoxon signed-rank test based on the null hypothesis that there is no difference between the two groups. The boldface entries are significant at the 0.05 level or lower.

Discussion

This study examined the radiopharmacokinetics of radioiodine in the PGs from 2 to 3 hours (phase 1) and from 3 to 4 hours (phase 2) after administration of ¹²³I. At the start of both phases patients received LJ. After LJ was administered, the radioiodine in the PGs rapidly declined in ∼4 minutes followed by re-accumulation of the radioiodine to the same amount of radioactivity that was present when the initial LJ was administered. This period of re-accumulation was ∼20–40 minutes. The radiopharmacokinetics of radioiodine in phase 1 and 2 were similar.

Although the actual radiation absorbed dose to the PGs cannot be calculated and although the study was not controlled by administering placebo in place of LJ, an estimate of the percent reduction in radiation absorbed dose to the PGs can be calculated with two assumptions, namely, repeat LJ was administered at the time the radioiodine re-accumulated back to the same amount of radioactivity that was present when the initial LJ was administered, and if the initial LJ had not been administered, no further radioiodine would have accumulated. On the basis of these assumptions, the percent reduction in radiation absorbed dose during this period would be as much as 37%–47%, and these estimates may be conservative because it is possible that the radioiodine would have continued to accumulate if the initial LJ has not been administered.

The time from either administration of LJ or the nadir after administration of LJ to the re-accumulation of radioiodine to baseline in phase 2 was longer than the comparable time in phase 1 (<0.0001). Although this may in part be a result of a higher uptake of radioiodine in the salivary glands at the start of phase 2 relative to phase 1, the mean percent reduction in radiation absorbed dose to the PGs was also greater in phase 2 than in phase 1 (<0.0001). This was true regardless of whether the data for the right and left PGs were pooled or the comparisons were made for the right or left PG individually.

It is not clear if prior treatment with ¹³¹I affected the results since there were a relatively small number of patients who could be compared. Similarly, attempts to determine if preparation of the patient with prior recombinant human thyrotropin administration differed from preparation with thyroid hormone withdrawal did not yield significant differences, again possibly the result of the small number of patients.

On the basis of the results of this study, we disagree with the recommendation of Nakada et al.'s that sialagogues be withheld for the first 24-hour period after ¹³¹I therapy (4). While withholding sialagogues for the first 24-hour period after ¹³¹I therapy may be better than a schedule of administering sialagogues every 2–3 hours when the patient is awake, our data suggest that more frequent administration of sialagogues will significantly reduce the radiation absorbed dose to the PGs. In addition, our results would support Silberstein's approach of a continuous administration of sialagogues while the patient is awake and then intermittently after retiring (6). Of note, however, the low incidence of ¹³¹I induced sialoadenitis reported by Silberstein could in part or in toto be the result of the prophylactic administration of dexamethasone to all his patients. Nevertheless, our results support the argument for more frequent administration of sialagogues.

Liu et al. (8) concluded that “the salivary stimulation with vitamin C [the same active stimulant of salivary glands as in LJ] at any time after ¹³¹I administration has only a limited effect on salivary absorbed dose in thyroid cancer patients.” They had four groups of patients who were administered 100 vitamin C orally at 1, 5, 13, and 25 hours after ¹³¹I, and the patients received additional vitamin C every 4 hours thereafter for the next 6 days, excluding the hours between 2 and 6 a.m. On the basis of the results of our study in which we noted re-accumulation of radioiodine 20–40 minutes after administration of LJ, it is likely that an interval of 4 hours between administration of vitamin C is too long to have a meaningful effect on the exposure of the PG to radioiodine.

The present study has its positive attributes and limitations. One positive attribute is that this study used radioiodine rather than ^99mTechnetium pertechnetate (^99mTc04). While the pharmacokinetics of ^99mTc04 in the salivary glands may be similar to radioiodine, they may not be identical (9 –11). Second, the assessment of the radiopharmacokinetics of iodine in the PGs were performed during a time period after the oral administration of radioiodine when the concentration of radioiodine in the blood is typically near its peak level (12). Third, it was shown that the effects of LJ did not diminish after a second dose.

The study has several limitations. It only evaluated a 2-hour period starting 2 hours after the administration of ¹³¹I. The effect of sialagogues for a more prolonged period of several more hours or even several days is not known. Also, only one dose and one sialagogue were evaluated. Different doses of the LJ used or different sialagogues might produce different results. Third, assumptions were required to estimate the potential reduction in radiation absorbed doses. However, we consider our assumptions to be conservative since the formula used was based on PG radioactivity reaching a plateau, not continuing to rise, after the time the initial LJ was administered. It is very likely that had LJ not been administered, radioactivity would have continued to rise. In addition, if an earlier time for the administration of the LJ had been selected or if the sialagogues had been given continuously, the estimated percent reduction of radiation absorbed dose could be even greater. Another limitation of the study is that it was not placebo (in place of LJ) controlled. Finally, this study only focused on the PGs, and thus this study did not evaluate the submandibular or sublingual salivary glands.

On the basis of the data presented in this study, we recommend that sialagogues not be withheld for the first 24-hours period after administration of a therapeutic dose of ¹³¹I, but that sialagogues should be administered far more frequently than every 2–3 hours such as every 15–30 minutes or even continuously and that the sialagogues should not only be administered when the patient is awake but also intermittently throughout the night and possibly the next day. While this may result in a poor night sleep for the patient, we believe this will result in a significant reduction of the radiation absorbed dose to the patient's salivary glands. The exploration and use of a longer acting sialagogue might also be valuable especially while the patient is as sleep. In regard to when sialagogues should be initiated, this study does not address that, but this study indicates that sialagogues initiated at least 2 hours after the administration of a therapeutic dose of ¹³¹I can reduce the radiation absorbed dose to the PGs. Further study is warrant to assess the radiopharmacokinetics in the first 2 hours.

Footnotes

Acknowledgment

This study was under written in part by generous donations from grateful patients.

Disclosure Statement

The authors declare that no competing financial interests exist.

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