THE UNIVERSITY OF NEW MEXICO COLLEGE OF PHARMACY ALBUQUERQUE, NEW MEXICO The University of New Mexico Correspondence Continuing Education Courses for Nuclear Pharmacists and Nuclear Medicine Professionals VOLUME 111, NUMBER 3 ● Radiopharmaceuticals for the Scintigraphic Assessment of Hepatobiliary Function by: Anne-Line Anderson, M.S, Co-sponsored by: mpi pharmacy services inc an ~mersham company ● The University of New Mexico College of Pharmacy is approved by the American Council on Pharrnaceulical Education as a provider of continuing pharmaceutical education. Program No. 180-039-93-006. 2.5 Contact Hours or .25 CEU’S M UI Editor Director of Ptimcy Continuing Education William B. Hladik III, M.S., R. Ph. College of Pharmacy University of New Mexico Production Spectiist Sharon I. Ramirez, Staff Assistant College of Pharmacy University of New Mexico While the advice and information in this publication are believed to bc true and accurate at press time, neither the author(s) nor the editor nor the publisher can accept any legal responsibility for tiny errors or omissions that may bc made. The publisher makes no warranty, express or implid, with respect to the mtiterial contained herein. Copyright 1994 University of New Mexico Phamcy Continuing Education Albuquerque, New Mexico RADIOPHARMA CEUTICALS FOR THE SCINTIGR.APHIC ASSESSMENT OF HEPATOBILL4RY FUNCTION STATEMENT OF OBJECTIVES The goal of this correspondence lesson is to increase the reader’s knowledge and understanding of current hepatobiliary radiopharmaceuticals. To that end, this course discusses hepatobiliary anatomy and finction, hepatocyte uptake, metabolism, and excretion of endogenous and exogenous compounds, and the pathway of bile excretion. In addition, gallstone formation, composition, and treatment is reviewed. The course presents information related to the development of current hepatobiliary radiopharmaceuticals, optimal characteristics of such agents, and the in vivo and in vitro properties of agents available for routine use in the U.S. This is followed by a discussion of the clinical use of hepatobiliary radiopharmaceuticals, including augmented cholescintigraphy, and a review of quantitative methods for the assessment of hepatocyte function. Upon successful completion of this mate~l, the retier shouti be able to: 1. Describe hepatobiliary anatomy and function. 2. Explain the major functions of the hepatocyte. 3. Describe the biliary uptake and excretion pathways for bile acids and organic anions. 4. List three major components of bile. 5. Explain the origin, conjugation, enterohepatic circulation and function of bile acids. ● 6. Describe the origin and excretion pathway of bilirubin and how it affects hepatocyte excretion of other organic anions. 7. Discuss the factors that affect gallbladder filling and emptying. 8. Explain the current understanding of the underlying causes for gallstone formation. 9. Explain methods used in the treatment of gallstone disease. 10. List the required chemical and pharmacologic characteristics of an ideal hepatobiliary radiopharmaceutical. 11. Discuss the development of current hepatobiliary radiopharmaceuticals. 12. Explain the role that analysis of structure-activity relationships has played in the development of improved cholescintigraphic agents. 13. List hepatobiliary radiopharmaceuticals currently available for routine use in the U.S. 14. Describe the preparation and radiochemical quality control of Tc-99m iminodiacetic acid (IDA) analogs. 15. Compare the in vivo characteristics in humans of routinely used Tc-99m IDA radiopharmaceuticals. 16. List the four organs that receive the highest absorbed radiation doses from Tc-99m iminodiacetic acid (IDA) radiopharmaceuticals. 17. Understand how drug therapy can interfere with the movement of cholescintigraphic agents through the hepatobiliary system. 18. List the principal applications for cholescintigraphy. 19, Describe how hepatobiliary imaging studies are performed. 20. Explain the three types of pharmacologic interventions used in augmented cholescintigraphy. 21. Discuss the various causes of cholecystitis. 22. Explain the two most common causes of neonatal jaundice and the role of cholescintigraphy in the ● differential diagnosis. 23. Discuss the current status of methods for quantitation of hepatocellular function. 24. Describe the hepatocyte uptake and handling of Tc-99m galactosyl-neogly coalbumin. 1 COURSE OUTLINE Ix. HEPATOBILIARY IMAGING I. INTRODUCTION A. Imaging Methods and Analysis 1. Patient Preparation II. HEPATOBILIARY ANATOMY AND 2. Imaging Technique and ● FUNCTION Analysis 111. HEPATOBILIARY PHYSIOLOGY B. Augmented Cholescintigraphy 1. Cholecystokinetic Agents A. Bile Acids 2. Morphine B. Lipids 3. Phenobarbital c. Organic Anions D. Organic Cations c. Cholecystitis E. Pathway of Bile Excretion D. Sphincter of Oddi Dysfunction F. Gallstones E. Biliary Obstruction F. Bile ~kage and Reflux IV. CHAR4CTERlSTICS OF O~IMAL G. Nanatal Jaundice ~PATOBILIARY RADIOPHAR- MACEUTICALS X. QUANTITATION OF HEPATIC FUNCTION v. DEVELOPMENT OF CURRENT A. Measurement of Hepatic Extraction ~PATOBILIARY RADIOPHAR- Fraction (HEF) Using Tc-99m IDA MACEUTICALS Analogs B. Quantitation of Hepatic Binding A. Historical Perspective Protein Rweptors B. Technetium-99m Pyridoxylidene Amino Acid Complexes c. Technetium-99m Acetanilido- iminodtacetates D. Relationship BetweerIBiodistribution RADIOPHARMACEUTICALS and Chemical Structure FOR THE SCJNTIGRAPHIC ASSESSMENT OF VI. COMMERCIALLY AVAILABLE HEPATOBILIARY FUNCTION HEPATOBILIARY RADIOPHARMACEUTICALS By: A. Agents Available in the U. S. Anne-Line Anderson, M.S. B. Radiochemical Quality Control Clinical Professor of Radiological Sciences Methods Department of Radiological Sciences c. In Vitro Stability ‘Division of Nucledr Medicine D. Pharmacoklnetics in Humans University of California, Irvine, Medical Center Orange, California VII. RADIATION DOSIMETRY VIII. PRECAUTIONS INTRODUCTION A. Drug Interference 1. Narcotic Analgesics He~atohiliary radiopharmaceuti cals are an 2. Nicotinic Acid . important adjunct in the differential diagnosis of acute 3. Total Parenteral Nutrition Due to the excellent (TPN) Therapy and chronic abdominal pain. 4. Miscellaneous Drugs physical and biological properties of current Tc-99m labeled radiopharmaceuticals, cholescintigraph y is B. Adverse Reactions considered to be both a noninvasive and very sensitive c. Use During Pregnancy and in Nursing test for evaluation of the functional Sbdtusof the cystic Mothers duct and the gallbladder. Hepatobiliary imaging can also be helpful in the differentiation between surgical 2 and medical jaundice, and it is an excellent method for blood by the hepatocytes, including bile acids and visualizing the pathway of bile following surgery or bilirubin. The alternate pathway of excretion is trauma. The greatwt impact has been on the secretion back into plasma and subsequent clearance diagnostic evaluation of suspected acute. cholecystitis by the kidneys. The biliary excretory system begins ● (l). More than 90% of cases of acute cholecystitis with the bile canalicular network, which drains into a result from cystic duct obstruction by gallstones, series of progressively larger ducts that eventually which cause stasis in the gallbladder followed by combine to form the common hepatic duct. This is chemically-induced inflammation and mucosal injury joined by the cystic duct from the gallbladder to form (2). Biliary tract disease caused by gallstones the common bile duct, which empties into the (cholelithiasis) is a major mdical and surgical duodenum through the sphincter of Oddi. Just prior problem in many parts of the world. It is estimated to entering the duodenum, the common biIe duct is that 20 million individuals in the United States have usually joined by the pancreatic duct. During fasting, gallstones. Although gallstones do not cause bile is diverted into the gallbladder where it is symptoms in the majority of individuals, gallstone- concentrated and stored. In response to a meal, the related disease afflicts up to two million Americans sphincter of Oddi relaxes, the gallbladder contracts, annual]y, leading to direct health care costs exceeding and concentrated bile empties into the duodenum. $2 billion per year. Cholelithimis is the most common single indication for abdominal surgery in the HEPATOBILIARY PHYSIOLOGY United States, with around 500,000 cholecystectomies performed annually (2). The epidemiology, symptoms, The first step in hepatobiliary excretion is up~dke diagnostic workup, and available treatment for across the hepatocyte membrane. Receptor binding cholecystitis and some other abnormalities of the sites on the sinusoidal plasma membrane of hepatohiliary system will he reviewed in the following hepatocytes are responsible for selective uptake of a sections. variety of endogenous and exogenous compounds. Specific carrier-mediated active transport systems HEPATOBILIARY ANATOMY AND FUNCTION appear to exist for various classes of compounds such as organic anions, bile acids, organic cations, and ● The 1iver is tie largest organ in the body, weighing neutral organic compounds (3,5), Distinct transpofi 1200-1600 g in normal adults. The hepatic mechanisms exist for inorganic ions as well; the parenchyma contains a complex network of blood transport of these ions in and out of hepatocytes is vessels and excretory ducts. The liver has dual blood regulated by various “pumps” that maintain conditions supply with about 80% coming from the G.I. tract via required