Robert M. Beihn

Disposition of radiolabelled suppositories in humans

The disposition of Witepsol H 15 suppositories radiolabelled with [99m Tc] technetium hydroxymethyldiphosphonate was studied after rectal administration in volunteers. The migration of the radiolabel was monitored continuously by external scintigraphy. The resulting scintiphotos were superimposed on lower GI radiographs to determine the extent of spreading of the dosage form in the rectum. The dosage form migrated approximately 5−7 cm into the rectum in nearly all of the studies and was, in general, confined to the lower and middle regions of the rectum. Since the venous supply to the lower rectum leads primarily to the inferior vena cava, the data presented here indicate that the metabolism of drugs sensitive to the ‘first‐pass’ effect may be partially avoided by their rectal administration.

Correlation of Ibuprofen Bioavailability with Gastrointestinal Transit by Scintigraphic Monitoring of 171Er-Labeled Sustained-Release Tablets

External gamma scintigraphy was used to monitor the gastrointestinal (GI) transit of radiolabeled sustained-release tablets containing 800 mg ibuprofen in eight fasted healthy volunteers. Ibuprofen serum concentrations were determined from blood samples drawn sequentially over a 24-hr period. Serum concentrations and related parameters were correlated to the position of the dosage form in the GI tract from the scintiphotos. The sustained-release tablets were radiolabeled intact utilizing a neutron activation procedure, by incorporating 0.18% of 170Er2O3 (enriched to >96% 170Er) into the bulk formulation. After manufacture of the final dosage forms, the tablets were irradiated in a neutron flux (4.4 × 1013 n/cm2 · sec) for 2 min, converting the stable 170Er to radioactive 171Er (t1/2 = 7.5 hr). Each tablet contained 50 µCi of 171Er at the time of administration. The scintigraphy studies suggested that the greatest proportion of ibuprofen was absorbed from this dosage form while the tablet was in the large bowel. The dosage forms eroded slowly in the small bowel and appeared to lose their integrity in the large bowel. In vitro studies showed only minimal effects of the neutron irradiation procedure on the dosage form performance.

The effect of food on gastrointestinal (GI) transit of sustained-release ibuprofen tablets as evaluated by gamma scintigraphy

The GI transit of radiolabeled sustained-release ibuprofen 800-mg tablets in eight healthy, fed volunteers was monitored using external gamma scintigraphy. Ibuprofen serum concentrations were determined from blood samples drawn over 36 hr following dosing. Sustained-release ibuprofen tablets containing 0.18% of 170Er2O3 (>96% 170Er) in the bulk formulation were manufactured under pilot-scale conditions and were radiolabeled utilizing a neutron activation procedure which converted stable 170Er to radioactive 171Er (t1/2 = 7.5 hr). At the time of dosing, each tablet contained 50 µCi of 171Er. Dosage form position was reported at various time intervals. In five subjects the sustained-release tablet remained in the stomach and eroded slowly over 7–12 hr, resulting in gradual increases in small bowel radioactivity. In the remaining three subjects, the intact tablet was ejected from the stomach and a gastric residence time of approximately 4 hr was measured. This is in marked contrast to a previous study conducted in fasted volunteers in which gastric retention time ranged from 10 to 60 min. Differences in GI transit between fed and fasted volunteers had little effect on ibuprofen bioavailability. AUC and Tmax were unaltered and Cmax was increased by 24%, which is in agreement with results from a previous, crossover-design food effect study.

An in Vitro/in Vivo Correlation for the Disintegration and Onset of Drug Release from Enteric-Coated Pellets

An empirical mass-transfer model for enteric-coating dissolution that uses in vitro dissolution data to characterize the pH-dependent solubility properties of the polymer film and a mass-transfer coefficient determined from in vivo dissolution or disintegration studies is developed. Once the in vivo mass- transfer coefficient has been evaluated, it can be used in conjunction with in vitro dissolution data from other formulations to predict the in vivo time to disintegration and onset of drug release. Results of in vitro dissolution experiments using the USP basket dissolution apparatus and in vivo disintegration experiments using gamma scintigraphy with four enteric-coated pellet formulations are presented. The good agreement among the in vivo mass-transfer coefficients that were determined supports the validity of the model.

Detection of upper abdominal abscesses by radionuclide imaging.

An improved means of detecting upper abdominal abscesses using the dual radionuclide subtraction technique was applied to 51 patients. 67Gallium citrate was used in the localization of the lesion and 99Tc-labeled human albumin microspheres and 99Tc sulfur colloid were used for subtracting out the interfering background from normal organ concentrations. The procedure provided the parameter capabilities for localization of the abscesses as well as information on their shape and size. Compared to nonsubtraction Ga procedures, 53% more abscesses were diagnosed using the subtraction technique.

Radiolabeling of an enteric coated tablet by (n,γ) radioactivation of erbium-170 for scintigraphic imaging

Abstract Enteric coated tablets containing small quantities of a stable erbium isotope were irradiated in a neutron flux to produce radioactive tablets labeled with erbium-171. The radiolabeled tablets were used to monitor their transit through the GI tract in human volunteers using external scintigraphy. The absorbed radiation dose to the subjects was found to be within acceptable guidelines. The low toxicity of erbium oxide after oral administration makes the use of this agent ideal for the production of radioactive dosage forms that are difficult or impossible to radiolabel by conventional methods, and leads to products of high radiochemical purity.

Biologic Gastric Emptying Time Using Tc-99m TETA Polystyrene Resin in Various Clinical Conditions

In 82 subjects 82 gastric emptying studies using Tc-99m triethylene tetramine polystyrene resin were retrospectively evaluated. All six patients with diabetic gastroenteropathy (GE) had delayed biologic gastric emptying time (BGET) that responded well to metoclopramide (MP) injection. In 11 diabetics without GE, only two had prolonged BGET with good response to MP. All 11 patients with gastric outlet obstruction also had prolonged BGET, but no significant response to MP was found in 6 studies. Five of 7 patients with active gastric ulcer had delayed BGET. Three of ten patients with previous Billroth I or II operation had accelerated BGET, and 3 of 9 patients with previous vagotomy had delayed BGET with good response to MP. Markedly prolonged BGET with significant response to MP was also observed in 3 patients with disordered gastric motility. Delayed BGET was found in one patient with bile reflux gastritis and in 2 of 6 patients with reflux esophagitis. No prolongation of BGET was observed in 7 symptomatic patients whose radiographic and endoscopic examinations were negative. BGET studies with this agent appear to be reliable and very helpful in the management of patients with gastric symptoms and for obtaining an objective measurement of the response to therapy.

Dual-Isotope Imaging of Neutron-Activated Erbium-171 and Samarium-153 and the in Vivo Evaluation of a Dual-Labeled Bilayer Tablet by Gamma Scintigraphy

The feasibility of dual-label scintigraphic studies which use the neutron-activated isotopes erbium-171 and samarium-153 is described. Experimental details are provided to correct and minimize the compton scatter contribution of 171Er into the lower-energy 153Sm window. The results from this study demonstrate that this dual-label procedure is sensitive enough to monitor simultaneously the behavior of two discrete regions of the same unit dose in the gastrointestinal tract of man.

Drug Distribution and Biliary Excretion Pattern of a Cyclic Somatostatin Analog: A Comparison of 14C Labeled Drug and a 131I lodinated Drug Analog

A cyclic somatostatin analog was compared to an iodinated analog of the same compound with respect to organ distribution and biliary excretion in the rat. The cyclic hexapeptide was radiolabeled with either 14C or 131I (tyrosine). Organ distribution of the iodinated compound as a function of time was nearly identical to that observed for the non-iodinated compound. Results indicated a rapid uptake by the liver and subsequent rapid excretion of the intact peptide in bile. Activity in other organs examined tended to fall off in a manner similar to the activity in blood with sequential samples. Because of the similarity in the in vivo behavior of the two compounds, the iodinated analog was deemed a suitable model for less invasive distribution studies, and was further examined in the dog using external gamma scintigraphy. In the unanesthetized dog the iodine activity was rapidly taken up by liver and collected in the gallbladder, thus exhibiting a similar rapid excretion pattern to that observed in the rat.

Noninvasive Monitoring of the In Vivo Release Characteristics of Rectal Drug Delivery Devices

The rational design of controlled rectal delivery devices suggests that for a given drug there are preferred patterns of controlled release that may optimize the therapeutic value of a drug. The optimized temporal pattern designed within the dosage form should utilize, control or modify the physiological/biochemical environment in which the drug release is occurring.