Clin Endosc > Volume 55(5); 2022 > Article
Jeong: Tacrolimus for prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis: a potential new target of old drug?
Tacrolimus is a macrocyclic lactone antibiotic that was first isolated in 1984 from the soil microorganism Streptomyces tsukubaensis in Japan.1 This agent, which acts as a calcineurin inhibitor, has been the cornerstone immunosuppressive agent used to prevent graft rejection in organ transplant recipients for a long time.2
Acute pancreatitis, which is the most common complication of endoscopic retrograde cholangiopancreatography (ERCP) performed for the endoscopic management of biliary complications, frequently occurs after liver transplantation and can induce a systemic inflammatory response along with a painful local inflammatory reaction of the pancreas.3 Post-ERCP pancreatitis (PEP) can occur in up to 10% of cases, and most cases are not severe. However, some patients progress to severe pancreatitis, which can cause serious morbidity and complications and require long-term hospitalization and outpatient treatment.3 Therefore, effective preventive drugs or interventional strategies for PEP, such as rectal indomethacin, an 8-hour protocol of aggressive lactated Ringer’s solution, and pancreatic duct stenting, have been developed.4
It has recently been revealed that one of the key mechanisms of the inflammatory cascade leading to PEP is zymogen activation occurring early through the calcium-activated phosphatase calcineurin in acinar cells.5 After that, a calcineurin inhibitor, tacrolimus, has been suggested based on several previous preclinical and clinical studies.6-8
Rao et al.9 reported the results of a prospective pilot study that compared the PEP rate of the tacrolimus group and control group based on this recent emerging evidence. In this study, the authors reported that the incidence of PEP was reduced by nearly 50% in the tacrolimus group compared with that in the control group (8.3% vs. 15.7%). They suggested that tacrolimus might prevent the occurrence of PEP. Considering the main mechanism of PEP development, tacrolimus, which inhibits calcineurin, may theoretically be a suitable pharmacological measure. However, before accepting the positive results of the PEP-prevention effect of tacrolimus as evidenced in this study, the issues of this study must be pointed out. First, this study was a small-scale, uncontrolled pilot study; there was a selection bias, and there was no analysis of PEP risk factors for the subjects. It is difficult to accept the results of this study as having a high level of evidence. In addition, even though this study was implemented in the average-risk PEP cohort, the PEP rate of both the control and tacrolimus groups was higher than that of the previous studies. One reason could be that the definition of difficult biliary cannulation (DBC) in this study was used in previous relevant studies. This definition differs from the new DBC definition that has been strengthened in the recently published European Society of Gastrointestinal Endoscopy guidelines about papillary cannulation.10 Applying the older definition of DBC while implementing ERCP to the subjects of this study may raise ethical concerns because it has already been shown that the chance of PEP incidence increases as the number of papilla attempts increases in previous studies.
Nevertheless, the results of this preliminary prospective study suggest that PEP has the potential to become a new target for tacrolimus, which has been used to prevent transplant rejection in organ transplant patients for over three decades. In addition, the results of the study are worth considering in the implementation of subsequent relevant studies that demonstrate the PEP preventive effect of tacrolimus and establish an appropriate therapeutic dosage that can have a preventive effect not only in patients at high risk of PEP but also in the average risk of the PEP cohort.

NOTES

Conflicts of Interest
The author has no potential conflicts of interest.
Funding
None.

REFERENCES

1. Winkler M, Christians U. A risk-benefit assessment of tacrolimus in transplantation. Drug Saf 1995;12:348–357.
crossref pmid
2. Plosker GL, Foster RH. Tacrolimus: a further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs 2000;59:323–389.
crossref pmid
3. Thiruvengadam NR, Forde KA, Chandrasekhara V, et al. Tacrolimus and indomethacin are safe and effective at reducing pancreatitis after endoscopic retrograde cholangiopancreatography in patients who have undergone liver transplantation. Clin Gastroenterol Hepatol 2020;18:1224–1232.
crossref pmid
4. Thiruvengadam NR, Kochman ML. Emerging therapies to prevent post-ERCP pancreatitis. Curr Gastroenterol Rep 2020;22:59.
crossref pmid pdf
5. Jin S, Orabi AI, Le T, et al. Exposure to radiocontrast agents induces pancreatic inflammation by activation of nuclear factor-κB, calcium signaling, and calcineurin. Gastroenterology 2015;149:753–764.
crossref pmid pmc
6. Orabi AI, Wen L, Javed TA, et al. Targeted inhibition of pancreatic acinar cell calcineurin is a novel strategy to prevent post-ERCP pancreatitis. Cell Mol Gastroenterol Hepatol 2017;3:119–128.
crossref pmid pmc
7. Oh HC, Easler JJ, El Hajj II, et al. Effect of calcineurin inhibitor on post-endoscopic retrograde cholangiopancreatography pancreatitis in patients with liver transplantation: a propensity-matched cohort study. Korean J Intern Med 2020;35:1364–1370.
crossref pmid pmc pdf
8. Wang R, Wang W, Ma K, et al. Variation in tacrolimus trough concentrations in liver transplant patients undergoing endoscopic retrograde cholangiopancreatography: a retrospective, observational study. Front Pharmacol 2020;11:1252.
crossref pmid pmc
9. Rao HB, Vincent PK, Nair P, et al. Preventive effect of tacrolimus on patients with post-endoscopic retrograde cholangiopancreatography pancreatitis. Clin Endosc 2022;55:665–673.
crossref pmid
10. Testoni PA, Mariani A, Aabakken L, et al. Papillary cannulation and sphincterotomy techniques at ERCP: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy 2016;48:657–683.
crossref pmid
TOOLS
PDF Links  PDF Links
PubReader  PubReader
ePub Link  ePub Link
XML Download  XML Download
Full text via DOI  Full text via DOI
Download Citation  Download Citation
CrossRef TDM  CrossRef TDM
  Print
Share:      
METRICS
0
Crossref
0
Scopus
619
View
124
Download
Related articles
Role of vitamin C and rectal indomethacin in preventing and alleviating post-endoscopic retrograde cholangiopancreatography pancreatitis: a clinical study   
Preventive effect of tacrolimus on patients with post-endoscopic retrograde cholangiopancreatography pancreatitis  2022 September;55(5)
An unwonted complication of endoscopic retrograde cholangiopancreatography  2022 May;55(3)
Portal cavernography during endoscopic retrograde cholangiopancreatography: from bilhemia to hemobilia  
Validation of a Novel Endoscopic Retrograde Cholangiopancreatography Cannulation Simulator  2020 May;53(3)
Editorial Office
Korean Society of Gastrointestinal Endoscopy
#817, 156 Yanghwa-ro (LG Palace, Donggyo-dong), Mapo-gu, Seoul, 04050, Korea
TEL: +82-2-335-1552   FAX: +82-2-335-2690    E-mail: CE@gie.or.kr
Copyright © Korean Society of Gastrointestinal Endoscopy.                 Developed in M2PI
Close layer