Relationship of hepatic functional imaging to irinotecan pharmacokinetics and genetic parameters of drug elimination.
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PURPOSE: The marked variability of irinotecan (Ir) clearance warrants individualized dosing based on hepatic drug handling. The aims of this trial were to identify parameters from functional hepatic nuclear imaging (HNI) that correlate with (1) Ir pharmacology, and (2) single-nucleotide polymorphisms (SNPs) for the ABCB1 (P-glycoprotein) and UGT-1A1 genes, known to influence Ir handling. METHODS: Patients underwent genotyping for ABCB1 SNPs and UTUGT-1A1*28 carriage and HNI with 99mTc-DIDA (acetanilidoiminodiacetic acid)/99mTc-DISIDA (disofenin) and MIBI (99mTc-sestamibi) scans, probes for biliary transport proteins ABCC1 and -2, and ABCB1 function. HNI data were analyzed by noncompartmental and deconvolutional analysis to provide hepatic extraction and biliary excretion parameters. Patients received Ir, fluorouracil, and folinic acid using a weekly x2, every-3-weeks schedule. Plasma was taken for Ir and SN-38 analysis on day 1, cycle 1. RESULTS: Of the 21 patients accrued, Ir pharmacokinetics data were obtained from 16 patients. 99mTc-DIDA/DISIDA percent retention at 1 hour (1-hour RET) correlated to baseline serum bilirubin (P = .008). Both 99mTc-DIDA/DISIDA and MIBI 1-hour RET correlated with SN-38 area under the curve (AUC; P < .01). On multiple regression analysis, SN-38 AUC = -215 + 18.68 x bilirubin + 4.27 x MIBI 1-hour RET (P = .009, R2 = 44.2%). HNI parameters did not correlate with Ir toxicity or UGT1A1*28 carriage. MIBI excretion was prolonged in patients with the ABCB1 exon 26 TT variant allele relative to wild-type (P = .015). CONCLUSION: Functional imaging of hepatic uptake and excretory pathways may have potential to predict Ir pharmacokinetics. Evaluation of a larger cohort as well as polymorphisms in other biliary transporters and UGT1A1 alleles is warranted. (+info)
Comparative evaluation of intragastric bile acids and hepatobiliary scintigraphy in the diagnosis of duodenogastric reflux.
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75Se HCAT test in the detection of bile acid malabsorption in functional diarrhoea and its correlation with small bowel transit.
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The purpose of this study was to evaluate whether bile acid malabsorption assessed by the 75SeHCAT test, had a pathogenetic role in functional chronic diarrhoea and to ascertain whether the small bowel transit time (SBTT) could be correlated with the 75SeHCAT test results. The test was based on the counting of the abdominal retention of a 75-selenium labelled homotaurocholic acid. The 75SeHCAT test was carried out in a control group of 23 healthy adults and in 46 patients, 38 of whom were suffering from irritable bowel syndrome (IBS) of diarrhoeic form and eight patients who had undergone cholecystectomy and were suffering from chronic diarrhoea. Faecal bile acid loss was determined in nine patients, and in 14, serum bile acid increase after a standard meal was measured. In 17, SBTT was studied by hydrogen breath test after lactulose administration (21 g in 300 ml water). In 15 patients, choledochocaecal transit time was estimated by Tc99m-HIDA (111 MBq) cholescintigraphy. In 20 of 46 subjects, 75SeHCAT retention was below normal level, and in 19 cholestyramine administration relieved diarrhoea. 75SeHCAT results were related to faecal bile acid loss, while no correlation was found with serum bile acids and SBTT. The data suggest a possible wider use of the 75SeHCAT test in chronic diarrhoea to estimate bile acid malabsorption in irritable bowel syndrome, diarrhoeic form, and provide an effective treatment. In our patients small bowel transit velocity does not seem to be a pathogenetic factor of bile acid malabsorption. (+info)
Enterogastric reflux and gastric clearance of refluxate in normal subjects and in patients with and without bile vomiting following peptic ulcer surgery.
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A noninvasive scintigraphic technique was used to estimate enterogastric reflux and subsequent gastric evacuation of refluxate in 35 normal, healthy subjects and 55 patients previously treated by vagotomy or partial gastrectomy. Reflux was provoked by a milk drink and quantitated by counting 99Tcm-EHIDA activity within the gastric area during gamma camera imaging. Seven normal subjects (20%) showed reflux of 5-18% of initial activity (mean: 10%), with peak values occurring at 5-30 minutes (mean: 14 minutes) following the milk. Gastric evacuation of activity in these subjects was monoexponential (r = 0.993, T1/2 = 24.1 minutes). Reflux occurred more frequently than normal in patients with truncal vagotomy and drainage (22/28 patients) and partial gastrectomy (20/21 patients). All of 16 patients with Billroth II anastomoses exhibited reflux, which was excessive compared with refluxing normal subjects (mean: 25%; p less than 0.01) and occurred later into the study (mean: 34 minutes; p less than 0.01). Ten of 11 asymptomatic patients showed reflux of similar amounts of activity (mean: 21%) compared with 16 patients who complained of bile vomiting (mean: 22%). However, asymptomatic patients exhibited gastric evacuation of refluxate at a rate similar to that of refluxing normal subjects, while bile vomiters showed significant gastric retention of refluxate at 25-30 minutes following peak gastric activity (p less than 0.05). This result confirms that post-operative bile vomiting is essentially a problem of gastric emptying. (+info)
Relationship between gastric emptying of solids and gall bladder emptying in normal subjects.
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Very little is known about the normal temporal and quantitative relationships between gastric emptying and gall bladder emptying. Using a non-invasive double isotope technique these relationships were investigated in 22 normal healthy adults. 99Tcm EHIDA was used as the biliary tracer and 113Inm labelled bran as the gastric content tracer. Gastric emptying was monoexponential with a t1/2 of 45 +/- 3 minutes (mean +/- SEM). In 15 subjects the gall bladder emptied in relation to eating according to a double exponential function. In these subjects 15.0 +/- 1.6% of gall bladder contents emptied before gastric emptying began. They could be further divided into two clear cut types (p less than 0.001), according to the ejection fraction at 10 minutes and the t1/2 of the first exponential. Emptying of the gall bladder was faster and more of its contents were ejected in subjects with a type I response (n = 9) than in subjects with a type II response (n = 6). In the remaining seven subjects the gall bladder began to empty spontaneously, unrelated to eating. These observations suggest that gall bladder emptying: (a) may have a cephalic phase, (b) can be expressed as a double exponential function, (c) may occur unrelated to eating, (d) which occurs only in relation to eating would appear to be either fast (type I) or slow (type II). (+info)
Radiation-dose calculation for five Tc-99m IDA hepatobiliary agents.
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The radiation absorbed doses from five commercially available hepatobiliary agents--Tc-99m-tagged analogs of IDA (EIDA, PIPIDA, HIDA, PBIDA, DISIDA) have been calculated from biokinetic data in 41 normal subjects. Serial gamma images, with blood and urine samples, were obtained to calculate cumulated radioactivity in the source organs: blood, kidney, bladder, liver, gallbladder, and intestines. The critical organ was the gallbladder, with an absorbed-dose range of 690 to 780 mrad/mCl. Absorbed doses for other target organs were: upper large intestine 320 to 370 mrad/mCi, lower large intestine 210 to 240, small intestine 170 to 200, liver 65 (DISIDA) to 130 (PBIDA), ovaries 63 to 72, and urinary bladder wall 23 (PBIDA) to 36 (EIDA). The radiation absorbed dose was largely independent of changes in chemical structure except in (a) the liver, where absorbed dose varied by a factor of two in proportion to the rate of excretion of the IDA agent from the liver, and (b) the urinary bladder, where absorbed dose varied by a factor of 1.6 because of differences in rate of excretion. When the stimulus for gallbladder emptying is changed from whole-meal ingestion to cholecystokinin injection, the absorbed dose to the gallbladder increases to approximately 1 rad/mCi; if no gallbladder emptying is assumed, its absorbed dose increases to approximately 1.9 rad/mCi. In the absence of contraindication, the gallbladder absorbed dose may thus be decreased by inducing gallbladder emptying at the end of the imaging study. (+info)
Interdigestive biliary output in man: relationship to fluctuations in plasma motilin and effect of atropine.
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The fasting output of bile into the bowel was investigated in nine healthy volunteers by hepatobiliary scanning. Subjects were studied twice, on each occasion for 2.5 hours. A significant flow of radioactivity from the gall bladder to the duodenum was observed on one or two occasions during each experiment. A 32 +/- 4% mean decrease in counts over the gall bladder was recorded, indicating partial emptying of this organ in the interdigestive state. The output of bile into the bowel was found to be related to fluctuations in fasting plasma motilin levels in that a significant motilin increment (18 +/- 4 pmol/l, p less than 0.005) paralleled the appearance of radioactivity in the duodenum. The onset of gall-bladder emptying regularly preceded the peak in plasma motilin (mean: 25 +/- 2 minutes). Atropine, intravenously, 0.6 mg followed by 0.3 mg, nearly abolished both fasting biliary output and plasma motilin fluctuations. Thus, bile output appears to occur frequently in fasting humans, but our data do not allow any conclusions as to the possible causal relationship between fasting gall-bladder emptying and release of motilin. Cholinergic influences appear to be of importance in the regulation of interdigestive biliary output in man. (+info)