PET Imaging of the Gastrointestinal Absorption of Orally Administered Drugs in Conscious and Anesthetized Rats

Abstract

This study assessed the process of gastrointestinal drug absorption in vivo using PET. Methods: 18 F-FDG was used as a model probe and was orally administered to rats as a solution. PET scans were obtained of the whole body and abdominal region under conscious and anesthetized conditions. Blood samples were routinely taken from the femoral vein during scanning. The rate of gastric emptying and intestinal absorption of 18 F-FDG was estimated from the time profiles of radioactivity in the stomach and small intestine. In addition, nonradiolabeled 2-fluoro-2-deoxy-D-glucose (2-FDG) was used in an intestinal closed-loop experiment to compare the intestinal permeability of 2-FDG with that of D-glucose. Results: In conscious rats, gastrointestinal absorption of 18 F-FDG was rate-limited by the process of intestinal membrane permeation, because the permeability of 2-FDG through the intestinal membrane was low compared with that of D-glucose. In anesthetized rats, the gastric emptying rate of 18 F-FDG decreased dramatically whereas the intestinal absorption rate constant was not significantly different from that in conscious rats. As a result, the rate-limiting step of gastrointestinal absorption of 18 F-FDG was shifted to the gastric emptying process by anesthesia. Conclusion: PET technology is a powerful tool for in vivo analysis of the gastrointestinal absorption of orally administered drugs. Gast rointestinal absorption of orally administered drugs involves many processes that occur in parallel or sequentially, starting with the disintegration and dissolution of drugs in the gastrointestinal fluid and continuing to the transit of drugs in the gastrointestinal tract, permeation of drug molecules through the intestinal membrane, and metabolism in the intestine or liver. The rate and amount of drug absorption into systemic circulation are defined as total outputs of these processes. Except for first-pass metabolism, the rate and amount of drug absorption are expressed by the following equations, Absorption rate 5 P eff · S · C E q : 1where P eff is an effective permeability of drugs, S is a surface area of the intestinal membrane, and C is the luminal concentration of drugs. AUC expresses the area under the drug concentration-time curve in the gastrointestinal tract during the intestinal transit time, t. To calculate the fraction of drugs absorbed in each segment of the gastrointestinal tract, these parameters in equations should be assessed. The P eff of drugs can be estimated by in vitro or in situ experiments (1,2). At pharmaceutical companies, in vitro permeation assays with cultured cell systems such as Caco2 or Madin-Darby canine kidney cell monolayers are widely used to determine drug permeability (3,4). Luminal concentration is affected by various factors, including drug solubility, dissolution rate, and the volume of gastrointestinal fluid. Among these factors, drug solubility and dissolution profiles can be evaluated by in vitro experiments. Recently, the use of simulated intestinal fluid under fasting or fed ...

Investigation of Biodistribution and Speciation Changes of Orally Administered Dual Radiolabeled Complex, Bis(5-chloro-7-[¹³¹I]iodo-8-quinolinolato)[⁶⁵Zn]zinc

“…In recent years, it was reported that this technique is also useful for the assessment of the oral drug absorption process in vivo. [28][29][30] In the present study, the accumulation of I were not observed at 0-0.5 h, but were observed at 2-3, and 4-5 h after an administration. The ROI analysis shows that at least 11.7% of [Zn(Cq) 2 ] was dissociated in the body at 2-3 h after an administration (Table 2).…”

PET Imaging Analysis with 64Cu in Disulfiram Treatment for Aberrant Copper Biodistribution in Menkes Disease Mouse Model

“…With the development of dedicated small-animal PET scanners, it is possible to perform functional imaging in small animals at high spatial resolutions (26)(27)(28). Using a small-animal PET imaging system, we obtained the first evidence-to our knowledge-that disulfiram pretreatment efficiently corrects inappropriate copper biodistribution in living MD model mice.…”

“…Traditionally, the evaluation of absorption, distribution, metabolism, and excretion in the development of pharmaceuticals has involved autoradiography of the whole body and the detection of radioactivity associated with dissected tissues by use of radioactive 125 I-or 111 In-labeled pharmaceuticals (25). However, recently developed molecular imaging technologies allow the visualization and quantitative measurement of biologic processes in living systems (26)(27)(28). Radioisotope-based molecular imaging techniques, such as PET, have been used for the noninvasive detection of pharmacodynamics in the gut and for the determination of functional changes in the nervous system (26,27).…”

“…However, recently developed molecular imaging technologies allow the visualization and quantitative measurement of biologic processes in living systems (26)(27)(28). Radioisotope-based molecular imaging techniques, such as PET, have been used for the noninvasive detection of pharmacodynamics in the gut and for the determination of functional changes in the nervous system (26,27).…”

Exploration of Antiemetics for Osteoporosis Therapy-Induced Nausea and Vomiting Using PET Molecular Imaging Analysis to Gastrointestinal Pharmacokinetics

“…Although minimally-invasive methods can measure GI absorption, such as gamma-scintigraphy (9)(10)(11) and magnetic resonance imaging (12), these methods are insufficiently quantitative and lack of spatial or temporal resolution. We previously showed that the GI transit rate of drugs can be measured directly by that positron emission tomography (PET), a minimally invasive and highly sensitive method with good spatio-temporal resolution (13)(14)(15)(16). For example, 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) PET has been utilized in rats (13) and humans (14); PET with deoxy-[ 18 F]fluoropoly(ethylene glycol)s, having an average mass of 2 kDa, has been used in rats (15); and PET has been used to monitor the hepatic distribution of [ 11 C]telmisartan in rats (16).…”