Investigation of human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble/highly permeable drug (efavirenz).

Human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble, highly permeable, micronized drug (efavirenz) was investigated. The tablets and capsule, prepared with samarium oxide and neutron activated to produce radioactive samarium-153, were evaluated for their in vivo disintegration and gastrointestinal (GI) transit in healthy subjects under fasted condition. Scintigraphic images were acquired to coincide with blood sampling times to assess the plasma concentration-time profile in relation to in vivo disintegration and GI transit. The mean gastric emptying times were approximately the same for all three formulations. Although in vivo dosage form disintegration was faster for Tablet A as compared to Tablet B and was similar between Tablet A and the capsule, Tablet A showed a slower rate and extent of drug absorption than Tablet B and the capsule. The results of this study eliminated the initial hypothesis that the difference in in vivo performance between the two tablet formulations is due to a different rate of in vivo disintegration and suggest that for this drug the in vivo dissolution rate of the drug from its disintegrated dosage form was a more important factor affecting the rate and extent of drug absorption.

Synthesis and in-vitro evaluation of novel low molecular weight thiocarbamates as inhibitors of human leukocyte elastase.

A series of novel low molecular weight thiocarbamate esters (1e-6e) were synthesized and evaluated as inhibitors of human leukocyte elastase (HLE). The thiocarbamate esters studied consist of a substituted primary or secondary aliphatic or aromatic amine and a 1-phenyl-1H-tetrazole-5-thiol (Table I). The HLE catalyzed hydrolysis of N-methoxysuccinyl- L-Ala-L-Ala-L-Pro-L-Val-p-nitroanilide substrate was utilized as the measure of inhibition. N-n-butyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (1e) exhibited the highest inhibitory activity (k(obs) /[I] = 2.1 x 10(5) M(-1). min(-1) ) and N-allyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (2e) (K(obs) /[I] = 6.1 x 10(4) M(-1). min(-1) ) exhibited the second highest inhibitory activity of all the thiocarbamates. The aromatic N-phenyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (4e) showed the lowest inhibitory activity (K(obs) /[I] = 1.9 x 10(2) M(-1). min(-1) ) among the N-monosubstituted derivatives, similar to that of N-ethyl-N-n-butyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (5e) (K(obs) /[I] = 1.8 x 10(2) M(-1).min(-1) ). The N-isopropyl, 1-phenyl-1H-tetrazole-5-thiocarbamate (3e) (K(obs) /[I] = 3.3 x 10(3) M(-1).min(-1) ) was about 10 fold more active than (4e) and N, N-diisopropyl, 1-phenyl-1H-tetrazole- 5-thiocarbamate (6e) showed no inhibitory activity against HLE. In the present work less than 3% of HLE specific activity was regained after 24 hours incubation with each of the tested N-monosubstituted thiocarbamates (1e-4e). The time-dependent inhibition of HLE by the thiocarbamate compounds (1e-5e) seems to involve the interaction and possible chemical modification of one enzyme residue. Straight chain nonpolar aliphatic substituents on the nitrogen of the thiocarbamate functionality may be essential for high inhibitory activity. As the degree of substitution (branching) on the nitrogen of the thiocarbamate functionality increases the inhibitory activity of the compounds decreases. The time-dependent inhibition of HLE and the slow deacylation rates by the N-monosubstituted thiocarbamates are consistent with irreversible inhibition.

Bioequivalence study of stressed and nonstressed hard gelatin capsules using amoxicillin as a drug marker and gamma scintigraphy to confirm time and GI location of in vivo capsule rupture.

PURPOSE: Evaluate if crosslinked hard gelatin capsules (HGCs) having different in vitro dissolution profiles changed in vivo release times or altered bioavailability of a drug marker; assess if a two-tier dissolution test (with and without enzyme) predicted in vivo performance. METHODS: Two classifications of stressed HGCs were artificially produced by exposure to formaldehyde (HCHO). HGCs were categorized as, a) pass/pass (p/p) which met in vitro dissolution criterion (75% drug dissolution at 45 min), b) moderately crosslinked fail/pass (f/p) which failed dissolution criterion in the absence of enzymes and passed in the presence of enzymes, and c) severely crosslinked fail/fail (f/f) which failed in vitro standards with or without enzymes. A six-way, single dose bioequivalence study (n = 10) administered the three HGCs under the fasted and fed condition. In vivo capsule rupture and GI transit were monitored via gamma scintigraphy, and blood samples were collected through six hours. RESULTS: Each crosslinked HGC was bioequivalent to the control p/p capsule when using AUC(0-infinity) and Cmax for comparison. Mean in vivo disintegration of the p/p capsule was 7 +/- 5 min for the fasted condition and 11 +/- 7 min for the fed condition. In vivo rupture for the f/p capsule was 22 +/- 12 min and 23 +/- 11 min for the fasted and fed studies, respectively, while the f/f HGC ruptured at 31 +/- 15 min and 71 +/- 19 min under the fasted and fed condition, respectively. Onset of amoxicillin absorption was dependent on in vivo HGC rupture and subsequent entry of the released radioactive marker into the small intestine. Consequently, fasted Tmax values were significantly later for the f/p HGC (1.62 +/- 0.53 hr) and f/f HGC (1.85 +/- 0.58 hr) as compared to the p/p HGC (1.17 +/- 0.30 hr). Fed Tmax values were statistically different only for the f/f capsule (2.55 +/- 0.44 hr) where Tmax values for the p/p and f/p HGCs under the fed condition were 1.50 +/- 0.47 hr and 1.60 +/- 0.46 hr, respectively. CONCLUSIONS: A two-tier dissolution procedure that retested a crosslinked hard gelatin capsule with addition of gastric or intestinal enzymes provided an adequate in vitro indicator of the formulation's in vivo performance. The observed delays in the onset of amoxicillin absorption and Tmax for the severely crosslinked f/f HGC was attributed to delayed in vivo capsule rupture, however, this delay did not adversely change AUC(0-infinity) nor Cmax.

Synthesis and mechanism of action of novel thiocarbamate inhibitors of human leukocyte elastase.

Several peptidyl thiocarbamate inhibitors of human leukocyte elastase were synthesized in the molecular weight range of 700-800. Two different sequences with lysine at the P3 and ornithine at the P4 positions were synthesized. Most of the inhibitors with large molecular weights showed high inhibitory capacity with Ki values as low as 10(-8)M. Compounds immobilized on poly,alpha,beta-[N-(2-hydroxyethyl)-D,L-aspartamide] (PHEA) polymers with an average molecular weight of 36,000 showed higher inhibitory capacity than their free forms.

Novel vaginal controlled-delivery systems incorporating coprecipitates of nonoxynol-9.

The purpose of this study was to formulate Nonoxynol-9 (N-9) into a solid coprecipitate form which can be used in preparing pharmaceutically attractive and nonirritating vaginal controlled-release delivery systems (DDSs) such as gelatin capsules (HGC) and tablets. N-9 was coprecipitated with polyvinylpyrrolidone (PVP) with or without iodine to produce solid powders which were incorporated into either (a) bilayer tablet DDSs which possess a fast- (outer) and slow- (inner core) releasing compartment, and (b) HGC DDSs (named Triad HGC) composed of fast- (outer), intermediate- (granules), and slow- (pellets) releasing compartments. The rates of release of iodine and/or [14C]N-9 from the two DDSs were studied in vitro in phosphate buffer at pH 5.0, in human seminal plasma and in vivo after intravaginal administration in rabbits. In all of the above-described release studies, the DDSs were shown to release their N-9 or iodine content rapidly, reaching spermicidal levels within 3 min. This was further substantiated by experiments in which the DDSs were introduced in whole human semen containing live spermatozoa. Complete spermicidal kill was obtained in less than 1 min and in less than 3 min from the bilayer tablet and the Triad HGC, respectively. Furthermore, the release of N-9 from the two DDSs was shown to continue for at least 4 hr in buffers (pH 5.0), human seminal fluid, and after intravaginal administration in rabbits. The resulting powder from the coprecipitation of N-9 and PVP (K-30) can be appropriately formulated into a controlled-released HGC or bilayer tablet to produce vaginal controlled-release DDSs which are nonirritating and have the potential to become effective spermicidal products.

Evaluation of the feasibility and use of a prototype remote drug delivery capsule (RDDC) for non-invasive regional drug absorption studies in the GI tract of man and beagle dog.

PURPOSE: Evaluate a prototype Remote Drug Delivery Capsule (RDDC) for use in beagle dogs and human volunteers for non-invasive drug absorption studies in different regions of the gastrointestinal tract. METHODS: The device was dual radiolabeled and GI transit of the RDDC was monitored by gamma scintigraphy. Beagles were used initially to demonstrate the functional utility of the device where a solution of ranitidine hydrochloride (150 mg) was non-invasively delivered to the stomach, proximal small intestine and distal small intestine. A subsequent first time in human study enrolled twelve healthy male volunteers where the intended site of release was the stomach, early small bowel, distal small bowel or colon. RESULTS: Preliminary studies conducted in beagles indicated that the RDDC operated successfully and the onset of ranitidine serum levels were dependent on the time of capsule activation and site of drug release. Results from the human study showed that all twelve subjects swallowed the device with no discomfort. Mean gastric emptying of the RDDC was 1.50 +/- 1.28 h (range = 0.25 to 4.25 h), and total small intestine transit was 4.79 +/- 1.82 h (range = 2.00 to 8.25 h). The capsule was retrieved from the feces at 30.25 +/- 15.21 h (range = 14.12 to 74.25 h) and there were no reported adverse events. The prototype RDDC operated successfully in nine of the twelve human volunteers and the cause for the three failures was attributed to mechanical failure while the electronics assembly performed favorably. CONCLUSIONS: This prototype remote control capsule was shown to be well tolerated and functional to use in human volunteers as well as beagles. The application of the device coupled with gamma scintigraphy has the potential to be a valuable and rapid method to non-invasively evaluate regional drug absorption in the gastrointestinal tract under conditions that are both pharmaceutically and physiologically meaningful.

In vivo evaluation of the absorption and gastrointestinal transit of avitriptan in fed and fasted subjects using gamma scintigraphy.

The study was conducted to assess the bioavailability of avitriptan after a standard high fat meal, in relation to gastrointestinal transit. Six healthy male subjects were enrolled in a four-period study with a partial replicate design where each was administered 150-mg avitriptan capsule (i) after an overnight fast, (ii) 5 min after a standard high-fat breakfast, and (iii) 4 hr after a standard high fat breakfast. The treatment administered in Period 3 was repeated in Period 4 to assess intrasubject variations in pharmacokinetics and gastrointestinal (GI) transit. Avitriptan capsules were specially formulated with nonradioactive samarium chloride hexahydrate which was neutron-activated to gamma-emitting samarium before dosing. Serial blood samples were collected for analysis of avitriptan up to 24-hr postdose, and serial scintigraphic images were obtained to assess the plasma concentration-time profile in relation to the GI transit of the avitriptan capsule contents. Bioavailability of avitriptan was reduced when administered in the fed condition but only the decrease in AUC(INF) was statistically significant. Tmax was significantly delayed between the fed conditions and the fasted condition. Qualitative appearance of plasma concentration-time profiles for avitriptan could be related to the manner in which the drug emptied from the stomach. It was also apparent that avitriptan exerted a secondary pharmacologic effect that temporarily suspended gastric emptying in the fasted treatment. Thus, when gastric emptying was interrupted and then resumed, the net result was a double peak in some of the individual plasma concentration profiles. Scintigraphic analysis also demonstrated that upon emptying from the stomach, avitriptan was rapidly absorbed from the upper small intestine. In the fed state, gastric emptying was slow and continuous resulting in extended absorption and a lower occurrence of double peaks. Qualitatively, the intrasubject variability in Cmax and AUC could be explained by the intrasubject variability in gastric emptying in both fasted and fed conditions.

Detection of formaldehyde-induced crosslinking in soft elastic gelatin capsules using near-infrared spectrophotometry.

The purpose of this research was to monitor the migration of formaldehyde from a polyethylene glycol (PEG) fill into the gelatin shell of a soft elastic gelatin capsule (SEGC) using near-infrared (NIR) spectrophotometry. SEGCs were filled with five solutions of aqueous formaldehyde in PEG (0, 0.05, 0.10, 0.20, and 0.40 v/v%), stored at ambient conditions for 48 hr, emptied, and scanned in NIR spectrophotometer. Principal component regression (PCR) was employed to analyze the spectra of the empty capsules. Good correlation was established (r2 = 0.988) when actual concentrations of formaldehyde in the PEG fill of the capsules were regressed against the principal component (PC) values from NIR spectra of the emptied and washed capsules. The loadings of the first PC describe a baseline shift in the spectra that arises from a change in water concentration. Lower PC loadings reveal the presence of signals at 1780 and 2200 nm that are not due to water absorbance, confirming the hypothesis that chemical bonds are formed during the formaldehyde-induced crosslinking of the gelatin in SEGCs. Gelatin crosslinking, initiated by formaldehyde migration from the PEG fill into the shell of an SEGC, was detected by NIR spectrophotometry. When NIR was coupled to principal component analysis, a linear relationship was found between the NIR spectra of empty SEGCs and the amount of crosslinking induced by concentrations of formaldehyde in the original fill material.

Determination of extent of formaldehyde-induced crosslinking in hard gelatin capsules by near-infrared spectrophotometry.

PURPOSE: To predict the degree of crosslinking from formaldehyde-stressed hard gelatin capsules (HGCs) using near-infrared spectrophotometry (NIR). METHODS: HGCs were exposed to a 150 ppb atmosphere of formaldehyde for 2.25, 4.60, 9.42, 16.0 and 24.0 hours. The capsules were filled with fresh amoxicillin, placed in a 90 degrees conical reflector cone, and scanned in a NIR spectrophotometer. Principal component regression (PCR) was employed to analyze the spectra of the intact capsules. Dissolution profiles were then obtained for each experimental group. RESULTS: The dissolution of amoxicillin from the capsules at pH 1.2 was found to decrease with increasing time of exposure to the formaldehyde atmosphere. A set of principal components (PCs) was formed by a linear combination of the absorbance values at each wavelength scanned. A good correlation was established (r2 = 0.963) when PC values from the NIR spectra of the HGCs were regressed against percentage of amoxicillin dissolved at 45 minutes, at pH 1.2. Water content of the capsules was found to be the largest determinant in the variation between HGC spectra at each exposure time. CONCLUSIONS: NIR spectrophotometry, combined with PCR, was successful at not only predicting dissolution of HGCs exposed to formaldehyde, but also at determining which wavelengths contributed most to spectral variation of these stressed HGCs.

Synthetic macromolecular inhibitors of human leukocyte elastase. 2. Effect of loading of a peptidyl carbamate inhibitor and molecular size of polymer backbone on its inhibitory capacity.

Several macromolecular inhibitors of human leukocyte elastase (HLE) were prepared by covalently bonding a low molecular weight HLE inhibitor peptidyl carbamate, p-nitrophenyl-N-[succinyl-L-alanyl-L-ananyl-L-prolylmethyl]- N-isopropyl carbamate 1, with the neutral hydrophilic polymer, poly-alpha,beta-[N-(2-hydroxyethyl)-D,L-aspartamide], PHEA 2. These novel polymeric compounds differed in the molecular size of their PHEA polymer backbone and the extent of loading of the peptidyl carbamate, (PC). They were shown to efficiently inhibit HLE (Ki = 97 to 12.8 nM) as intact macromolecular entities and were found to be more stable to hydrolysis than the non-polymer bound low molecular weight inhibitor 1. The inhibition of HLE by the novel macromolecular inhibitors was found to be noncompetitive and reversible, proceeding via slow formation of inhibitor-enzyme complex. The effect of loading of 1 and molecular size of the PHEA 2 polymer on enzymatic parameters Ki, kon and koff is discussed and a possible mechanism of inhibition is presented.

Assessment of new formulations of nonoxynol-9 coprecipitated with polyvinylpyrrolidone and iodine as possible vaginal contraceptives.

OBJECTIVE: To assess the in vitro spermicidal activity of new formulations of nonoxynol-9, coprecipitated with polyvinylpyrrolidone (PVP) or iodinated PVP, against human spermatozoa via the use of the Sander-Cramer test and the cervical mucus penetration test. DESIGN: Solutions of PVP-nonoxynol-9 and iodinated PVP-nonoxynol-9 containing nonoxynol-9 whole molecule (oligomers 1 to 18) and its isolated fractions (oligomers 8 to 10, 4 to 6, and 1 to 3) at various concentrations (microgram/mL) were prepared via serial dilutions. Spermicidal solutions were mixed with human semen to determine the minimal lethal dose (microgram/mL). In the Sander-Cramer test, the lethal dose was reported as the minimal dose capable of killing spermatozoa within 20 seconds. In the cervical mucus penetration test, the lethal dose was reported as the minimal dose capable of preventing penetration of spermatozoa into cervical mucus beyond the second millimeter length of the capillary. SETTING: Andrology laboratory, University of Kentucky, Lexington, Kentucky. PATIENT(S): Normospermic male donors. MAIN OUTCOME MEASURE(S): Spermicidal lethal dose determination of various nonoxynol-9 preparations containing the whole nonoxynol-9 molecule and its isolated fractions coprecipitated with PVP or iodinated PVP. RESULT(S): The use of PVP increased the aqueous solubility of the nonoxynol-9 formulations containing oligomers 1 to 18 and 8 to 10 slightly. The coprecipitation of the nonoxynol-9 formulations containing nonoxynol-9 oligomers 4 to 6 and 1 to 3 with PVP significantly increased their solubilization and spermicidal action in vitro. Moreover, the incorporation of iodine significantly decreased the minimal nonoxynol-9 dose required for complete killing of spermatozoa in preparations containing nonoxynol-9 oligomers 4 to 6 and 1 to 3. CONCLUSION(S): Incorporation of all three components tested in this study (PVP, nonoxynol-9, and iodine) enhanced the efficiency of the spermicidal preparations, especially for nonoxynol-9 preparations containing nonoxynol-9 oligomers 4 to 6 and 1 to 3.

Comparative spermicidal performance of iodinated and non-iodinated contraceptive formulations of nonoxynol-9 co-precipitated with polyvinylpyrrolidone.

The objective of this study was to evaluate the spermicidal qualities of various combinations of nonoxynol-9 (N-9; whole molecule = oligomers 1-18) and its isolated fractions (oligomers 8-10, 4-6 and 1-3), co-precipitated with non-iodinated and/or iodinated (Io) polyvinylpyrrolidone (PVP) as possible vaginal contraceptives. Spermicidal qualities of known equimolar concentrations of various combinations of PVP/N-9 and PVP-Io/N-9 were tested via a modified Sander-Cramer test (SCT) using human spermatozoa. Spermicidal agents and semen samples were mixed 1:1 (v/v) and evaluated for sperm viability. Spermicidal activity was reported as the minimal concentration (microgram/mL) of spermicide capable of killing all spermatozoa within 20 sec after exposure to the spermicide. The spermicidal activity of PVP/N-9 and PVP-Io/N-9 preparations containing N-9 oligomers 1-18 and/or 8-10 was similar, and these preparations were more efficient in killing the spermatozoa than the ones containing N-9 oligomers 4-6 and 1-3. Polyvinyl-pyrrolidone proved to be an effective vehicle for PVP/N-9 and PVP-Io/N-9 preparations, especially those containing N-9 oligomers 4-6 and 1-3. Incorporation of Io into the spermicidal preparations brought about additional efficacy. The current findings could be of clinical significance in future studies when preparing and delivering those selected co-precipitates vaginally.

PIP: At the University of Kentucky in Lexington, pooled normospermic semen specimens collected after 3-4 days of sexual abstinence were co-precipitated with non-iodinated and/or iodinated (Io) polyvinylpyrrolidone (PVP) to determine the spermicidal qualities of various combinations of nonoxynol-9 (N-9) (oligomers 1-18) and its isolated fractions (oligomers 8-10, 4-6, and 1-3) as possible vaginal contraceptives. The Sander-Cramer test on human spermatozoa was used to test the spermicidal qualities of known equimolar concentrations of various combinations of PVP/N-9 and PVP-Io/N-9. The minimal lethal dose (LD) concentration (mcg/ml) of spermicide capable of killing all spermatozoa within 20 seconds after exposure to the spermicide was the definition of spermicidal activity. The LD of PVP/N-9 and PVP-Io/N-9 spermicidal preparations containing N-9 oligomers 1-18 and/or 8-10 was similar (165-166/mcg/ml for PVP/N-9 and 193-231/mcg/ml for PVP-Io/N-9). These particular preparations were more efficient in destroying spermatozoa than those containing N-9 oligomers 4-6 and 1-3 (p 0.05). PVP appeared to an efficient vehicle for the studied spermicides, particularly those containing N-9 oligomers 4-6 and 1-3. The addition of Io into PVP/N-9 preparations improved spermicidal activity, and significantly so, for N-9 oligomers 4-6 and 1-3 (495 mcg/ml for non-iodinated PVP/N-9 vs. 385 mcg/ml for PVP-Io/N-9; p 0.05). These findings will help future studies when the researchers prepare and deliver spermicides that co-precipitate vaginally.

Enzyme immunoassay of two nicergoline metabolites, 10 alpha-methoxy-9, 10-dihydrolysergol (MDL) and 1-methyl-10 alpha-methoxy-9, 10-dihydrolysergol (MMDL).

Specific and sensitive enzyme immunoassays for two nicergoline metabolites, 10 alpha-methoxy-9, 10-dihydrolysergol (MDL) and 1-methyl-10 alpha-methoxy-9, 10-dihydrolysergol (MMDL) have been developed. The hydroxyl group of hydroxymethyl at position 8 of either MDL or MMDL was carboxymethylated to introduce a carboxyl group for protein conjugation. Antibodies generated from O-carboxymethyl MDL or MMDL recognized the spacer arm between the hapten and the carrier protein and the molecular domain near the conjugation site as well. A heterologous bridge strategy was used to improve the affinity of the hapten-enzyme conjugate to the antibodies. The sensitivity of both assays was greatly increased by using such an approach. Both antibodies are specific for their own haptens. Little cross reactivity was observed with nicergoline and other metabolites. Determination of MDL and MMDL from both spiked plasma and urine showed nearly quantitative recovery. Detection of MDL and MMDL can be as sensitive as 10 pg/ml.

Studies on the influence of pH and pancreatin on 13C-formaldehyde-induced gelatin cross-links using nuclear magnetic resonance.

Carbon-13 nuclear magnetic resonance (13C-NMR) and 13C-enriched formaldehyde (13CH2O) were utilized to observe cross-linking in gelatin. Thus, when a 6% solution of gelatin in water was treated with 2000 ppm 13CH2O at 20 degrees C, the 15 hr 13C-NMR spectrum of the crosslinked gel showed peaks representing carbinolamines (methylols) of arginine and lysine, as well as a peak ascribed to a methylene cross-link between arginine and lysine. Similar results were obtained when these cross-linking reactions were conducted using only 100 ppm 13CH2O. When pancreatin (1% w/v) was added to the solution of 6% gelatin cross-linked with 2000 ppm 13CH2O, the gel began to revert to a clear fluid solution. After incubation for 24 hr at 37 degrees C, the 13C-NMR spectrum of this solution confirmed the presence of the methylols of lysine and arginine, and the lysine-arginine cross-link. When 13CH2O (2000 ppm) was added to a 6% solution of gelatin at pH 13.0, the arginine methylol and the lysine-arginine crosslinks were produced. The 13CH2O-induced crosslinking of gelatin at pH 2.0, however, yielded the lysine methylol as the sole product.

Explaining variable absorption of a hypolipidemic agent (CGP 43371) in healthy subjects by gamma scintigraphy and pharmacokinetics.

The gastrointestinal absorption of a hypolipidemic agent (CGP 43371) was investigated using an external scintigraphy technique in six healthy men. After an overnight fast, subjects received a single 800-mg oral dose of CGP 43371 (4 capsules of 200 mg each) and one capsule of radioactive samarium-153 oxide (100-130 microCi) as a nonabsorbable marker of gastrointestinal transit and fecal recovery for CGP 43371. In vivo gastrointestinal transit of samarium-153 was monitored via gamma scintigraphy for 48 hours after administration to coincide with blood sampling. Samarium-153 content in whole fecal samples was determined by external gamma scintigraphy, and CGP 43371 content in both fecal and plasma samples was determined using high-performance liquid chromatography (HPLC). The results of fecal analysis indicated that transit of the two compounds in the gastrointestinal tract were similar, and bioavailability of CGP 43371 was calculated to be 9% based on the difference between the cumulative amounts of the nonabsorbable radioactive marker and CGP 43371 found in the feces. The onset of drug absorption occurred 4 hours after administration when radioactive samarium-153 was in the distal small bowel, and peak plasma drug level occurred 6 hours after administration, which corresponded with the arrival of samarium-153 in the terminal ileum and ileal/cecal junction. This observation supported the concept that primary absorption of this compound was in the distal to terminal portion of the ileum. Although the onset of drug absorption was delayed, it was curious that the rate of gastric emptying also affected the extent of absorption. A positive correlation (r = 0.91) between area under the drug curve (AUC) and area under the transit curve (AUTC) of the gastric emptying showed that longer gastric residence improved oral absorption of CGP 43371.

Biodegradable indium-111 labeled microspheres for in vivo evaluation of distribution and elimination.

Short-lived gamma emitting radioisotopes can be incorporated into polylactide/glycolide polymeric microspheres with various specific activities for possible use in understanding the in-vivo deposition, distribution and clearance of microparticulate drug carrier systems. The incorporated radiolabel is stable with negligible leaching out of the microspheres. These microspheres are suitable for studying the oral uptake of particles, lung distribution after inhalation delivery and evaluation of in-vivo fate following parenteral administration in systemic circulation or in specific tissue compartments.

Studies with [11C]alprazolam: an agonist for the benzodiazepine receptor.

We have built a system for the synthesis of high specific activity carbon-11 alprazolam (Xanax), a high affinity agonist for the benzodiazepine receptor. The system produces 30-40 mCi of the compound with a specific activity of > 12,000 Ci per millimole. Using this compound we have performed PET studies on 6 normal subjects and studied the cerebral influx and efflux of the compound. The uptake in the brain was low, approx. 1% of the administered dose. However, the levels of the compound in the circulation at early time points are heavily affected by the specific activity of the tracer, i.e. when pharmacologically active doses are used as blocking doses the concentration of radioactive material is higher in the circulation and more material enters the brain. We attribute this to a depot effect where the compound is trapped in saturatable sites in an organ, probably the lungs, and is slowly released over time. In the presence of blocking doses of agonist, the compound washes out of the brain more quickly suggesting that some blockade of the receptors is occurring. However, the pharmacological activity of the compound does not permit the administration of enough material to ensure complete receptor blockade. The compound shows definite signs of acting as a receptor binding ligand but the unusual pharmacokinetics complicate the interpretation of the data.

Synthesis and in vivo disposition studies of 18F-labeled HFA-134a.

A rapid synthesis of the chlorofluorocarbon replacement compound 1,1,1,2-tetrafluoroethane (HFA-134a) was identified and utilized to prepare 99+% radiochemically pure [18F]HFA-134a in 20-35% radiochemical yield. Four rats were then exposed to no-carrier-added (NCA) [18F]HFA-134a, and monitored via coincidence detection. Following withdrawal of the test atmosphere of [18F]HFA-134a, the mean half-life of [18F]HFA-134a in four rats was determined to be 7.8 +/- 1.5 min following a 10 s exposure and 8.1 +/- 1.7 minutes following a 10 min exposure.

Dynamic monitoring of total-body absorption by 19F NMR spectroscopy: one hour ventilation of HFA-134a in male and female rats.

Six male and six female Sprague-Dawley rats were ventilated head-only for 1 h on a 15% atmosphere of 1,1,1,2-tetrafluoroethane (HFA-134a) in air in a magnetic resonance imaging spectrometer. Results from these dynamic 19F NMR studies suggest that a steady-state in vivo concentration of HFA-134a was approached at approximately 25 min into the exposure. Quantitative integration analysis using an external standard estimated this plateau to be 58.3 +/- 11.9 mg of absorbed HFA-134a per rat. The HFA-134a 19F NMR signal disappeared rapidly following removal of the test atmosphere, with an elimination half-life of 4.6 +/- 0.6 min in the male rats and 4.9 +/- 1.5 min in the female rats. The data suggest that there was no statistical difference between the sexes in amount absorbed or in elimination half-lives.