Histamine Receptor 1 and 2 Antagonists Alter Biodistribution of Radioiodine

DISCUSSION

The organs and tissues selected for analysis in this project were chosen for specific reasons. Selected organs/tissues include the thyroid itself and organs that typically receive a relatively high absorbed dose of radiation during ¹³¹I treatment for hyperthyroidism or thyroid cancer, including the salivary tissue and stomach. Whole blood, which is an indicator of whole-body burden of radioiodine and an indirect indicator of bone marrow exposure, was also assayed. Radioiodine uptake by the liver was also measured because of data that support that hepatic metabolism of thyroid hormone may be regulated by H2 receptors (6). Although the bladder wall also receives a relatively high dose of exposure (from urinary excretion), urine activity was not assayed because of the volatile nature of ¹³¹I in the urine and difficulty with an accurate collection in small rodents. Whether the drugs tested could affect urinary excretion of ¹³¹I was not tested but is thought to be unlikely given the lack of variability in blood levels of radioiodine between the control rats and the drug-treated cohorts.

Compared with controls, treatment with the H1 receptor blocker promethazine resulted in an increase in radioiodine uptake by the thyroid, both at 1 d after ¹³¹I administration (1.3-fold increase) and at 8 d after ¹³¹I administration (1.5-fold increase). This result suggests that the use of H1 blockers could confound the results of diagnostic tests of radioiodine uptake and uptake determinations that are made for the purpose of calculating an appropriate dose for treatment of hyperthyroidism. If the radioactive iodine uptake and therapeutic administration of ¹³¹I are done under different conditions of exposure to H1 blockers, then dosimetric decisions based on the radioactive iodine uptake determinations could be inaccurate. There is no information provided by this study to indicate that any of the drugs tested result in alterations in uptake of ¹³¹I by well-differentiated thyroid cancer. Famotidine (H2 blocker) and esomeprazole (PPI) do not affect radioiodine uptake by the thyroid at either 1 or 8 d after ¹³¹I administration.

Sialadenitis and a dry mouth (xerostomia) caused by radiation damage to salivary tissue is one of the more common and bothersome side effects of ¹³¹I therapy. There are also some data that support an increase in secondary primary salivary gland malignancies in thyroid cancer patients treated both with low (ablative) and high doses of ¹³¹I (12,13). Measures to mitigate radiation damage to the salivary tissue are typically aggressively used with ¹³¹I treatment, including the use of salivation-inducing maneuvers, such as sucking on sour candy, chewing gum, and good oral hydration. Despite these maneuvers, there is significant variability in the magnitude of uptake of radioiodine observed in the salivary tissue on clinical radioiodine scans, either with ¹²³I, or on posttherapy ¹³¹I scans after treatment of thyroid cancer. The causes of variability in magnitude of uptake of radioiodine by salivary tissue are not well understood. However, concomitant use of either H1 or H2 blockers, which are commonly taken as over-the-counter drugs, could contribute to higher levels of uptake of ¹³¹I in some patients. With H1 and H2 blocker treatment, there is a 1.37- and 1.40-fold increase, respectively, over control levels in radioiodine uptake by the salivary gland 1 d after administration of ¹³¹I. Treatment with H1 and H2 blockers results in more substantial elevations in uptake of radioiodine by salivary tissue 8 d after ¹³¹I administration (4.5- and 5.57-fold increase over control levels), suggesting that both increased uptake and delayed clearance of radioiodine by salivary tissue may result from nonspecific histamine receptor blockade. That H1 and H2 blockers could contribute to the complication of sialadenitis, dry mouth, and salivary gland malignancies with radioactive iodine treatment is a theoretic risk but one that is relatively easily prevented, by avoidance of these drugs in patients who will receive ¹³¹I for therapeutic purposes.

Compared with control levels, radioiodine uptake by the stomach was significantly increased by promethazine treatment both at 1 d (1.47-fold increase) and at 8 d (2.46-fold increase) after the administration of ¹³¹I. The gastric wall receives a relatively high absorbed dose of radiation with ¹³¹I treatment, which has raised theoretic concerns for radiation-induced gastritis and late atrophic gastritis as complications of radioiodine treatment. A recent report cites an increased risk of second primary tumors, including those of the stomach, in thyroid cancer survivors, although it is not clear whether this is due to radioiodine treatment (14). A possible trend in induction of gastric cancers from radioactive iodine associated with treatment of benign thyroid diseases has also been reported, although this remains to be conclusively confirmed (15). It is therefore possible that irradiation of the gastric wall from ¹³¹I may increase the risk of gastric cancer. Treatment of rats with famotidine or esomeprazole did not result in any change in gastric uptake of radioiodine.

The liver may be an important organ in the microsomal deiodination of T4 to T3 and in the modulation of systemic effects of thyroid hormone (16). There is also evidence that histamine may play a role in the regulation of hepatic metabolism of thyroid hormone (6). There is a slight but significant decrease in radioiodine uptake by the liver at 1 d after ¹³¹I administration in both famotidine- (1.67-fold decrease) and promethazine- (1.41-fold decrease) treated rats. However, compared with control levels, there is a marked increase in uptake of ¹³¹I by the liver 8 d after ¹³¹I administration in rats treated with daily famotidine (11.21-fold increase) and promethazine (9.28-fold increase). The basis for these observations is unclear but supports an active role in the processing of thyroid hormone by the liver, which can be significantly altered by both H1 and H2 blockers. There is no significant difference in uptake of radioiodine by the liver between control rats and those treated with esomeprazole at either 1 or 8 d after ¹³¹I administration.

There are some limitations with regard to this study. To ensure that all rats received an equivalent amount of radioiodine systemically, ¹³¹I was administered by intraperitoneal injection. This route of administration should reproduce the vascular drainage pathway resulting from oral administration of radioiodine (mesenteric veins to portal vein). The intraperitoneal route of administration has been used in several rodent studies examining the biodistribution and therapeutic effects of radioiodine (17–19). Although there is no theoretic mechanistic basis to suggest that H1 or H2 blockers or PPIs could alter enteric absorption of ¹³¹I, this was not specifically assessed and the future confirmation of the effects of these medications with an oral route of radioiodine administration may be appropriate. In addition, further studies to confirm that effects in humans similar to those we have demonstrated in this preclinical rodent model are observed may also be warranted.

Despite these limitations, there is sufficient preclinical experimental evidence provided herein to support that elective use of H1 blockers be discontinued before diagnostic measurements of radioiodine uptake by the thyroid. Both H1 and H2 blockers should be withheld before, and at least 1 wk after, ¹³¹I administration for therapeutic purposes. In this study, esomeprazole did not alter the biodistribution of radioiodine. However, there is a single brief report describing increased uptake of radioiodine by the stomach in patients taking omeprazole, another PPI, compared with patients not taking the drug (10). The interval necessary for discontinuation of the drugs before ¹³¹I administration would vary as a function of the specific pharmacokinetic profile of the formulation, which can generally be obtained from the available drug package insert. In general, it is necessary to wait 4–5 elimination half-lives after cessation of a drug before pharmacologic activity is no longer present. However, it is important to realize that elimination half-lives can be altered by liver and kidney disease and are generally longer when a drug is taken chronically, rather than sporadically.