MRI Provides New Insights Into the Pharmacologic Mechanism of Bisacodyl: A Blueprint for Understanding Intestinal Drug Mechanisms

Abstract

Constipation remains a major healthcare problem affecting about 15% of adults, especially older adults, women, and individuals with chronic diseases such as diabetes, Parkinson's disease, and hypothyroidism. Impacting a substantial portion of nursing home residents, constipation diminishes their quality of life and sometimes leads to healthcare complications such as bowel obstructions. For the treatment of constipation, bisacodyl has been a highly used therapeutic agent, acting as a stimulant laxative where it is believed to increase intestinal motility and intestinal water content.

Magnetic resonance imaging (MRI) is a vital diagnostic tool widely used for detecting and characterizing a variety of pathological conditions such as neoplasms in the brain and breast, demyelination in neurological conditions, cardiomyopathies, and lesions in the liver and kidney. In the intestine, MRI can be used for studies of intestinal drug toxicities, drug effects on intestinal permeability and inflammation, and drugs used in the treatment of intestinal disorders such as Crohn's disease. In the elegant study of Aliyu et al. entitled: Magnetic Resonance Imaging Reveals Novel Insights Into the Dual Mode of Action of Bisacodyl: A Randomized, Placebo-controlled Trial in Constipation,¹ MRI was used to study the water content of the ascending colon after single and multiple doses of bisacodyl with the goals of understanding the pharmacologic mechanism of the drug and comparing the effects of a single dose with three daily doses of the drug. In this placebo-controlled crossover study involving patients with constipation, the investigators studied the pharmacologic effects of bisacodyl following single and multiple doses. The primary end point was the impact of the drug on ascending colon water content. Secondary end points included the effects of the drug on whole gut transit time (WGTT) and other related measures. The investigators observed that the predominant effect of a single dose of bisacodyl was on gastrointestinal motility, reducing WGTT and shortening the time to defecate. Interestingly, the study found that bisacodyl only affected ascending colon water content after 3 days of treatment, with no significant impact after a single dose. In addition, multiple doses of bisacodyl significantly affected the number of “mass movements,” frequency of bowel movements, and stool formation, indicating more benefits after prolonged use (Figure 1).

The study by Aliyu et al. demonstrates the power of MRI in clinical pharmacology beyond diagnostics.¹ While pharmacologic measurements can be made using a variety of methods, MRI offers numerous advantages. It is non-invasive, quantitative, and visual, allowing for precise dose response or concentration response characterization. In the Aliyu et al. study, the use of MRI produced a striking visual display of the pharmacologic mechanism of a commonly used laxative.¹ In particular, figure 5 in their article depicts three-dimensional volume renderings of the colon in one patient after they received multiple doses of bisacodyl. Clear, time-dependent effects of repeated doses of bisacodyl were observed on the volume of the ascending, transverse, and descending colon, as well as the rectosigmoid colon. A distinctive expansion (compared with placebo) of the descending colon was observed, along with an enlarged rectosigmoid colon at 450 minutes after dosing. The reader is presented with remarkable images of pharmacologic action through this one figure, complemented by many summary figures and tables that characterize and compare the effects of single and multiple dose bisacodyl with placebo on various quantitative MRI measurements.

MRI has also been used in clinical pharmacology to assess the effects of drugs used in the treatment of diseases of organs beyond the intestine. For example, a recent study used MRI to measure the effect of a new PNPLA3 antisense oligonucleotide on liver fat content in patients with hepatic steatosis.² Recently, Clinical Pharmacology and Therapeutics has published several studies centered on the use of transcranial magnetic stimulation for depressive disorders, another potentially powerful use of magnetic resonance, in this case in treatment rather than as an investigational tool.^3-5 Notably, a commentary published about a decade ago described the use of MRI as a CNS imaging biomarker to accelerate the development of medications for neurodegenerative diseases, which continues to represent an area of unmet need in health care.⁶ In fact, as noted in the manuscript, imaging may be used in all phases of drug development for CNS active drugs. For example, during early Phase I through late Phase III clinical trials, MRI may be used to assess target engagement, efficacy, and safety of drugs as well as disease progression. However, few studies in clinical pharmacology have employed MRI for assessing the mechanism of action of drugs. The current study by Aliyu et al. is novel and shows the enormous advantages of MRI that extend beyond pharmacologic characterization to elucidating pharmacologic mechanism.¹

For healthcare practitioners, particularly those working in nursing homes or with the elderly, constipation continues to represent a major problem and a time-consuming issue in patient care. Questions frequently arise, such as: How many days can a patient go without a bowel movement? How can the bowels be stimulated to provoke a bowel movement? How can the patient's diet be adjusted? Enemas are frequently used alongside a wide range of oral products, including bulk-forming agents, osmotic and stimulant laxatives, stool softeners, and lubricant laxatives. In addition, newer medications such as chloride channel activators, guanylate cyclase C agonists, mu-opioid receptor antagonists, and various probiotics are part of the therapeutic arsenal for treating constipation. However, healthcare practitioners often struggle with dosing issues of these compounds to effectively treat their patients.

By studying the mechanism of action of bisacodyl, Aliyu et al. show that the pharmacologic effects of the drug are time-dependents.¹ Their study highlights the role of precision dosing for the commonly used laxative, bisacodyl. In particular, the study encourages practitioners to prescribe multiple daily doses of bisacodyl (5 mg) to relieve constipation in their patients. Multiple doses of the drug have additional therapeutic effects that are not apparent after a single dose. Therefore, as noted by the authors, patients derive enhanced effects after three doses in comparison to one dose, and practitioners should continue dosing the patient to derive these effects.

In conclusion, Aliyu et al. demonstrate tremendous benefits through their elegant study of the use of MRI to understand the pharmacologic mechanisms of the stimulant laxative bisacodyl. This non-invasive method uncovered new dose-dependent pharmacologic mechanisms not previously thought to be associated with bisacodyl. In particular, a single dose of bisacodyl has a prokinetic effect, accelerating whole gut transit time and reducing the time to defecation. In contrast, three daily doses of bisacodyl increased the water content of the descending sigmoidal colon and the small intestine, as well as reduced the whole gut transit time and the time to defecation. For the field of clinical pharmacology, a laxative, even a commonly used one, may not be seen as a novel concept nor an innovative therapeutic modality. However, the application of contemporary technologies to enhance our understanding of pharmacologic mechanisms, even of older drugs, is crucial in both clinical practice and research in clinical pharmacology. This is especially true for technologies that are safe and provide quantitative measurements that can be made over time and with varying doses. MRI is one such technology, and as noted, the striking image rendered in a single patient with this imaging study after receiving multiple doses of bisacodyl (see figure 5 in their article) stimulates the imagination of the reader as it graphically depicts intestinal segments and volumes over time.

The study clearly represents a shift in our understanding of pharmacologic mechanisms of this drug and provides a blueprint for the use of MRI in assessing the pharmacologic mechanisms of novel prokinetics, secretagogues, and other agents under development for the treatment of constipation. Importantly, there are many intestinal diseases that extend beyond constipation, including inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancer. It is clear that MRI should be explored to examine the pharmacologic effects of new drugs for the treatment of intestinal disorders beyond constipation.

No funding was received for this work.

The author declared no competing interests for this work.