Levothyroxine is a biopharmaceutical classification system class IV drug with low-solubility and low-permeability, which makes this drug very susceptible to changes in the gastrointestinal tract, such as changes in pH and motility [19]. In this study, it was found that morning exercise increases the absorption of LT4 tablets and the ratio of this significant change in absorption kinetics correlates with the daily dose of LT4: greater the daily dose, greater the percentage decrease in TSH level. The possible mechanisms which might explain this outcome need to be divided into 2 separate sections, i.e., gastric and intestinal changes.
Delayed gastric emptying, most commonly due to gastroparesis, has been previously reported to correlate with the reduction of LT4 absorption, causing a decrease in maximum drug concentration and an increase in time taken to reach maximum concentration [6–8]. From another point of view, it can be stated that an increase in gastric motility could improve oral LT4 absorption. A study reported by Gkotsina et al. demonstrated that pharmacokinetic parameters of LT4 absorption was improved after performance of sleeve gastrectomy [20]. The authors indicated a reduction in binding of LT4 to the proteins secreted from the stomach as a potential contributor to that outcome of the study. Regarding the effect of exercise on gastric motility, Oettle et al. found that GI transit time was significantly accelerated by moderate exercise and in another study, gastric emptying was shown significantly faster in the low-intensity exercise group than the moderate-intensity exercise group [11, 12]. Similarly, a study reported that the half time for gastric emptying was shorter in subjects during exercise and was possibly contributed to a relative dominance in parasympathetic tone [21]. It was also theorized that increased intra-abdominal pressure caused increased gastric emptying during exercise [22]. In agreement with the literature, the patients had significantly lower TSH levels after a 30-day low-intensity exercise programme in our study, which was possibly due to the increased gastric motility, thus resulting in a less exposure of LT4 to gastric proteins.
The relationship between intestinal motility and LT4 absorption has not been studied, to date. In addition to that, the reported data on the effect of exercise on intestinal motility is inconsistent, despite the generally accepted hypothesis that exercise shortens the transit through the gastrointestinal tract and is considered one of the practical methods for the management of chronic constipation [9, 10, 23, 24]. Therefore, it is quite difficult to discuss the outcome of this study using the literature data. A few animal studies and a study included 7 healthy men, reported that intestinal motility is required for intestinal magnesium and glucose absorption [25–27]. In contrast, a rat study showed that increased intestinal tone and motility were associated with a decrease in intestinal water absorption [28].
A recent animal study demonstrated that eight weeks of voluntary running exercise had no significant effect on the motility of GI tract, but caused an increase in the number of caveolae in the smooth muscles and the number of Bifidobacteria in the microbiome [29]. In parallel, a review concluded that no evidence that exercise independently benefits patients with chronic constipation, unless the patients have sedentary lifestyles [23]. In our study, one of the inclusion criteria was having a sedentary lifestyle. Various studies reported that the mouth-to-cecum transit and total colonic transit times were significantly decreased during and after 12-week period of exercise, respectively [30, 31]. In agreement with these studies, it can be presumed that intestinal motility was increased in our patients with sedentary lifestyles due to 6-week morning exercise in our study and it caused an increase in LT4 absorption.
The main limitation of the present study was the absence of a professional trainer who controls the consistency in daily exercise and walking pace of the patients. The patients were asked to have a walk for 45 minutes at a comfortable speed; thus, their walking pace may show a variation from patient to patient. Moreover, the consistency in daily exercise of our patients were noted according to self-report. Future prospective studies with a larger sample size and a professional surveillance, evaluating parameters which indicate gastric and intestinal motility, are required to enlighten the mechanism of how exercise affects oral LT4 absorption.
In conclusion, to the best of our knowledge, this is the first study which demonstrates the significant positive effect of morning exercise on the absorption of LT4 tablets. In addition to that, it was also found that as the daily dose of LT4 increases, the percentage decrease of TSH level becomes greater. The possible mechanisms which could cause this increase in the drug absorption are the potential positive influence of exercise on both gastric and intestinal motility; thus, resulting in a less exposure of LT4 to gastric proteins and an increased absorption of LT4 from intestinal tissue due to augmented intestinal movements triggered by exercise in patients with sedentary lifestyles.