Urinary Excretion Of Radioactivity Research Articles

Safety and efficacy of peptide receptor radionuclide therapy with 177Lu-DOTA0-Tyr3-octreotate in combination with amino acid solution infusion in Japanese patients with somatostatin receptor-positive, progressive neuroendocrine tumors

PurposePeptide receptor radionuclide therapy (PRRT) with 177Lu-DOTA0-Tyr3-octreotate (177Lu-DOTATATE) is one of the most reliable treatments for unresectable, progressive neuroendocrine tumors (NETs) with somatostatin receptor expression. We have, for the first time, reported the results of the tolerability, safety, pharmacokinetics, dosimetry, and efficacy of this treatment for Japanese patients with NET.MethodsPatients with unresectable, somatostatin receptor scintigraphy (SRS)-positive NETs were enrolled in this phase I clinical trial. They were treated with 29.6 GBq of 177Lu-DOTATATE (four doses of 7.4 GBq) combined with amino acid solution infusion plus octreotide long-acting release (LAR) 30 mg. The primary objective of this study was to evaluate the tolerability, safety, pharmacokinetics, and dosimetry of a single administration of this treatment in patients with SRS-positive NETs.ResultsSix Japanese patients (three men and three women; mean age 61.5 years; range 50–70 years) with SRS-positive unresectable NETs were recruited. 177Lu-DOTATATE was eliminated from the blood in a two-phase manner. Cumulative urinary excretion of radioactivity was 60.1% (range 49.0%–69.8%) within the initial 6 h. The cumulative renal absorbed dose for 29.6 GBq of 177Lu-DOTATATE was 16.8 Gy (range 12.0–21.2 Gy), and the biological effective dose was 17.0 Gy (range 12.2–21.5 Gy). Administration of 177Lu-DOTATATE was well tolerated, with no dose-limiting toxicities. Grade 3 lymphopenia occurred in two (33.3%) cases, but there were no other severe toxicities. Four patients achieved partial response (objective response rate, 66.7%), one patient had stable disease, and one patient had progressive disease.ConclusionPRRT with 177Lu-DOTATATE was well-tolerated and showed good outcomes in Japanese patients with unresectable NETs. Peptide receptor radionuclide therapy, 177Lu-DOTA0-Tyr3-octreotate .

Phase I clinical study of NMB58, a novel positron emission tomography (PET)-myocardial perfusion imaging tracer, conducted to evaluate its safety and pharmacokinetics in Japanese healthy adult males.

NMB58 is a novel positron emission tomography (PET) tracer containing flurpiridaz as an active ingredient and available as a myocardial perfusion imaging tracer that targets mitochondrial complex 1. A phase I clinical study of NMB58 was conducted to evaluate its safety and pharmacokinetics in healthy volunteers. Ten healthy Japanese volunteers received bolus injection of NMB58 (111-167MBq) intravenously and underwent imaging studies at rest on day 1. Of these subjects, 5 (day 2 cohort 1; exercise stress) and 5 (day 2 cohort 2; pharmacological stress) similarly underwent stress imaging studies on day 2. The safety of NMB58 was evaluated through monitoring of signs/symptoms, electrocardiography, vital signs, and laboratory examinations at baseline and several time points during 3days. Sequential whole-body positron emission tomography-computed tomography (PET/CT) scan data were acquired for up to 5-h post-injection, with venous blood and urine samples collected for up to 8-h post-injection. Based on the results of the biodistribution study, the absorbed radiation dose (Rad) was estimated by the Medical Internal Radiation Dose method. On day 1, the kidneys were shown to have the highest Rad, followed by the myocardium. On day 2, the myocardium was shown to have the highest Rad, followed by the kidneys. The mean effective doses (EDs) per unit activity administered were 0.021, 0.017 and 0.021mSv/MBq for overall subjects (day 1), day 2 cohort 1 and day 2 cohort 2, respectively. The estimated exposure dose of NMB58 was similar to or lower than those of radiotracers currently approved for clinical use, including 18F-Fludeoxyglucose. Biodistribution results indicated that NMB58 distributed to the myocardium exhibited high and sustained retention after administration. The cumulative urinary radioactivity excretion rate was shown to be 6.9, 2.3%, and 8.0% of the injected dose in overall subjects (day 1), day 2 cohort 1 and day 2 cohort 2. There were no drug-related adverse events, and the tracer was well tolerated in all subjects. Based on radiation dosimetry, biodistribution, and safety evaluations, NMB58 was found to be a suitable tracer for clinical use in PET myocardial perfusion imaging during exercise or pharmacological stress.

PET Imaging of PARP Expression Using 18F-Olaparib.

502 Objectives: Urothelial Bladder Cancer (UBC) affects >80,000 new patients annually. Treatment is stage dependent, thus accurate staging with conventional imaging and biopsy are crucial, but are often inaccurate. To improve visualization of primary disease, the extent of loco-regional disease and the presence or absence of metastatic lesions, a large number of PET biomarkers have been developed. However serious limitations, including urinary excretion of radioactivity, compromises their ability to accurately assess the bladder lumen and invasive tumors. This ongoing investigation is aimed to validate a hypothesis that VPAC (combined for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating peptide (PACAP)) receptors expressed in high density on UBC cells can be targeted to PET image UBC, its loco-regional disease and metastatic lesions. Materials and Methods:64Cu-TP3805, shown in our laboratory to have high affinity (3.1 x 10-9 M) for VPAC was the imaging agent. Patients (M, N=15, 44-80 yrs.) diagnosed with invasive UBC scheduled for radical cystectomy were enrolled. Chemotherapy eligible patients were treated with standard of care cisplatin regimens. All subjects were administered 148±10% MBq 64Cu-TP3805 (20 µg) intravenously. Urine and blood samples were collected at predetermined time points. Patients then underwent PET/CT imaging 90 minutes later. Images were read independently by two nuclear medicine physicians. Radical cystoprostatectomy and lymphadenectomy was performed 1 to 4 weeks later, and VPAC PET images were correlated with final surgical pathology. Results: There were no adverse events. Blood clearance, t½ (∝), was 22.3 ± 2.7 min (> 85%) and t½ (β) was 118.2 ± 4.9 min (< 15%). Urinary excretion of radioactivity was negligible. As confirmed by post cystectomy histology, PET images were true positive in the bladder for UBC in 10 patients and true negative in 4. There was one false negative image. When examining the prostate, there was PET uptake in 12 patients. Of these, 5 patients had incidental prostate cancer or HGPIN; 2 patients had UCB involving the prostate; and 5 patients had negative histology in the prostate. PET image was true positive for one lymph node, true negative for 11 and false negative in 3. In one patient several bone lesions in iliac crest and spine were seen by PET imaging. Biopsy of iliac crest confirmed metastasis. These pilot data demonstrate 64Cu-TP3805 VPAC targeting for imaging UBC has 91% sensitivity (95% CI 59%-100%), 100% specificity (95% CI 40%-100%) , and has positive predictive and negative predictive values 100% (95% CI 69%-100) and 80% (95% CI 38%-96%), respectively. Conclusions: The results of this first-in-human study to image UBC by targeting VPAC receptor are encouraging. Further investigation continues. Acknowledgement: Supported in part by NIH, NCI R01 157372 (MLT) Dean’s Translational Science Award (MLT) and Sidney Kimmel Cancer Center Award (MLT).

Metabolism, Distribution, and Elimination of Mequindox in Pigs, Chickens, and Rats.

Mequindox (MEQ), a quinoxaline-N,N-dioxide antibacterial agent used to control bacterial enteritis in various food-producing animals, is a potential violative residue in food animal-derived products. The disposition and elimination of MEQ in rats, pigs, and chickens was comprehensively investigated to identify the marker residue and target tissue of MEQ in food animals for residue monitoring. Following a single oral administration, 62-71% of MEQ was rapidly excreted via urine and feces in all species within 24 h. Urinary excretion of radioactivity was 84 and 83.5% of the administered dose in rats and pigs, respectively. More than 92% of the administered dose was excreted in all species within 15 days. Radioactivity was found in nearly all tissues at the first 6 h after dosing, with the majority of radioactivity cleared within 4-6 days. The highest radioactivity and longest persisting time were found to be in the liver and kidney. Totals of 11, 12, and 7 metabolites were identified in rats, chickens, and pigs, respectively. No parent drug could be detected in any of the tissues of pigs and chickens. 3-Methyl-2-acetyl quinoxaline (M1), 3-methyl-2-(1-hydroxyethyl) quinoxaline-N4-monoxide (M4), and 3-methyl-2-(1-hydroxyethyl) quinoxaline-1,4-dioxide (M6) were the common and major metabolites of MEQ in all three species. Additionally, 3-methyl-2-(1-hydroxyethyl) quinoxaline (M5), 3-hydroxymethyl-2-ethanol quinoxaline-1,4-dioxide (M7), and 3-methyl-2-(1-hydroxyethyl) quinoxaline-N1-monoxide (M8) were the major metabolites of MEQ in rats, pigs, and chickens, respectively. M1 was designated to be the marker residue of MEQ in pigs and chickens. These results provide scientific data for the determination of marker residues and withdrawal time of MEQ in food animals and improve the understanding of the toxicity and disposition of MEQ in animals.

Pharmacokinetic disposition of anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in rats and dogs

The pharmacokinetic disposition of anagliptin, an orally active and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated in male rats and dogs. Anagliptin was well absorbed in dogs (70.4%) and moderately to well absorbed in rats ranging from 38.1 to 85.5% depending on the dose. In situ testing indicated that anagliptin absorption from rat intestine was apparently limited by P-glycoprotein. The absorbed radioactivity was distributed rapidly throughout the body, and high levels of radioactivity were found in the tissues expressing DPP-4 at high levels, especially small intestine, kidney and liver. In both species, the major circulating component was unchanged anagliptin; major circulating metabolites were M1 resulting from hydrolysis of the cyano group and M6 and M7, both of which resulting from the oxidation-cleavage of the methylene function adjacent to the amine. After intravenous dosing, urinary excretion of radioactivity was the major route of elimination for rats (64.6%) and dogs (66.2%), and biliary excretion was demonstrated to be an important pathway in rats (25.2%). The total recovery was good (97.5-99.5%) and most of the radioactivity was excreted by 24h in both species. The renal clearance of unbound anagliptin in rats (91.7ml/min/kg) was much higher than the glomerular filtration rate, indicative of active renal elimination.

Evaluation of Breast Cancer Resistance Protein Function in Hepatobiliary and Renal Excretion Using PET with 11C-SC-62807

A quantitative PET imaging method was used to assess the in vivo kinetics of hepatobiliary and renal excretion of the breast cancer resistance protein (Bcrp) substrate (11)C-SC-62807 in mice. Serial abdominal PET scans were collected in wild-type and Bcrp knockout (Bcrp(-/-)) mice after intravenous injection of (11)C-SC-62807. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after radiotracer administration. Dynamic PET data were analyzed to determine the canalicular and brush-border efflux clearances in the liver and kidney (CL(int,bile,liver) and CL(int,urine,kidney), respectively). SC-62807 is an in vitro substrate of mouse Bcrp and human BCRP. Radioactivity associated with (11)C-SC-62807 was predominantly found in the blood, liver, bile, and urine 30 min after administration. Both biliary and urinary excretion of radioactivity was markedly lower in Bcrp(-/-) mice than in wild-type mice, suggesting greater systemic exposure in Bcrp(-/-) mice. Both the CL(int,bile,liver) and the CL(int,urine,kidney) were significantly lower in Bcrp(-/-) mice (74% ± 10% and 99% ± 1% lower than controls, respectively). We also found that (11)C-SC-62807 is a substrate of the organic anion-transporting polypeptides OATP1B1 and OATP1B3 in vitro. The present study demonstrated that Bcrp plays a significant role in the efflux of (11)C-SC-62807 in mouse liver and kidney. We also demonstrated the feasibility of PET using (11)C-SC-62807 to study the activity of BCRP in humans.

Hypouricemic effects of novel concentrative nucleoside transporter 2 inhibitors through suppressing intestinal absorption of purine nucleosides

We have developed concentrative nucleoside transporter 2 (CNT2) inhibitors as a novel pharmacological approach for improving hyperuricemia by inhibiting intestinal absorption of purines. Dietary purine nucleosides are absorbed in the small intestines by CNTs expressed in the apical membrane. In humans, the absorbed purine nucleosides are rapidly degraded to their final end product, uric acid, by xanthine oxidase. Based on the expression profile of human CNTs in digestive tract tissues, we established a working hypothesis that mainly CNT2 contributes to the intestinal absorption of purine nucleosides. In order to confirm this possibility, we developed CNT2 inhibitors and found that (2R,3R,4S,5R)-2-(6-amino-8-{[3'-(3-aminopropoxy)-biphenyl-4-ylmethyl]-amino}-9H-purin-9-yl)-5-hydroxymethyl-tetrahydrofuran-3,4-diol (KGO-2142) and 1-[3-(5-{[1-((2R,3R,4S,5R)-3,4-dihydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-1H-benzimidazol-2-ylamino]-methyl}-2-ethoxyphenoxy)-propyl]-piperidine-4-carboxylic acid amide (KGO-2173) were inhibitory. These CNT2 inhibitors had potent inhibitory activity against inosine uptake via human CNT2, but they did not potently interfere with nucleoside uptake via human CNT1, CNT3 or equilibrative nucleoside transporters (ENTs) in vitro. After oral administration of KGO-2173 along with [14C]-inosine, KGO-2173 significantly decreased the urinary excretion of radioactivity at 6 and 24h in rats. Since dietary purine nucleosides are not utilized in the body and are excreted into the urine rapidly, this decrease in radioactivity in the urine represented the inhibitory activity of KGO-2173 toward the absorption of [14C]-inosine in the small intestines. KGO-2142 almost completely inhibited dietary RNA-induced hyperuricemia and the increase in urinary excretion of uric acid in cebus monkeys. These novel CNT2 inhibitors, KGO-2142 and KGO-2173, could be useful therapeutic options for the treatment of hyperuricemia.

Metabolic Fate of 2,4-Dichlorophenol and Related Plant Residues in Rats

This study compared the metabolic fate of [(14)C]-DCP, [(14)C]-residues from radish plants, and purified [(14)C]-DCP-(acetyl)glucose following oral administration in rats. A rapid excretion of radioactivity in urine occurred for [(14)C]-DCP, [(14)C]-DCP-(acetyl)glucose, and soluble residues, 69, 85, and 69% within 48 h, respectively. Radio-HPLC profiles of 0-24 h urine from rats fed [(14)C]-DCP and [(14)C]-DCP-(acetyl)glucose were close and qualitatively similar to those obtained from plant residues. No trace of native plant residues was detected under the study conditions. The structures of the two major peaks were identified by MS as the glucuronide and the sulfate conjugates of DCP. The characterization of a dehydrated glucuronide conjugate by MS and NMR of DCP was unusual. In contrast to soluble residues, bound residues were mainly excreted in feces, 90% within 48 h, whereas total residues were eliminated in both urine and feces. For total residues, the radioactivity in feces was higher than expected from the percentage of soluble and bound residues in radish plants. This result highlighted that less absorption took place when residues were present in the plant matrix as compared to plant-free residues and DCP.

Pharmacokinetics of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist. 1st communication: absorption and excretion in rats after a single administration of 14C-NS-49.

The absorption and excretion of NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride, CAS 137431-04-0), a phenethylamine class alpha 1A-adrenoceptor agonist, were studied in rats after a single administration of 14C-NS-49. In addition, the protein binding of this drug was investigated in vivo and in vitro. After oral administration of 14C-NS-49 (1 mg/kg) to male rats, the radioactivity concentrations in the blood and plasma reached maximums within 1 h, then decreased biexponentially with respective elimination half-lives of 25.4 and 11.9 h. Most of the plasma radioactivity was due to unchanged NS-49, indicating of the poor metabolism of this drug in rats. The results of the in situ absorption study using the intestinal loop method showed that 14C-NS-49 was well absorbed from the small intestine. Systemic availability was high (86%), as determined by a comparison of the areas under the plasma concentration-time curves of unchanged NS-49 for oral and intravenous administrations. Food affected the absorption of NS-49. There were no significant sex-related differences in the plasma concentration profiles after the intravenous administration of 14C-NS-49 (p > 0.05). NS-49 was primarily eliminated by renal excretion, 76% and 62% of the dose being excreted unchanged in the urine after intravenous and oral administrations, respectively. The absorption rate, determined on the basis of the urinary excretion of radioactivity, was 83%, being almost the same as the systemic availability. First-pass metabolism of NS-49, therefore, is considered to be very limited in rats. The excretion of radioactivity in the bile within 48 h after the oral administration of 14C-NS-49 (1 mg/kg) was 5.9% of the dose, and the excretion of radioactivity in the exhaled air after the intravenous administration (0.2 mg/kg) was negligible. The percentage of 14C-NS-49 bound to serum proteins in vitro was less than 15% in all the animal species tested. The percentage of radioactivity bound to rat serum proteins after the oral administration of 14C-NS-49 (1 mg/kg) was 16-21%.

Phase I Study of the Aurora B Kinase Inhibitor Barasertib (AZD1152) to Assess the Pharmacokinetics (PK), Metabolism and Excretion in Patients (pts) with Relapsed or Refractory Acute Myeloid Leukemia (AML)

Abstract 2602 Background:Barasertib is a pro-drug that rapidly undergoes phosphatase-mediated cleavage in serum to release barasertib-hQPA (bara-hQPA), a highly potent and selective inhibitor of Aurora B kinase with antitumor activity in a broad range of hematological malignancies including AML (Löwenberg et al. Blood 2009;114:abst 2080; Tsuboi et al. Leuk Res 2011; doi: 10.1016/j.leukres.2011.04.008). Methods:In this open-label, single-arm study (NCT01019161), AML pts received 1200 mg barasertib as a 7-day continuous iv infusion every 28 days. On Day 2 of Cycle 1 only, pts also received 14C-barasertib (250 μCi; 2-h infusion). Blood, urine and feces samples were collected at various time points during Cycle 1 to characterize the PK, metabolic and excretion profiles of barasertib. Results:Of the 6 pts enrolled (median age 63 years [range, 34–74]; 3 females), 5 commenced treatment and completed Cycle 1 and were therefore eligible for analysis. Of the 4 pts evaluable for disease response, 1 achieved a complete response. No new or unexpected safety findings were reported. Maximal plasma concentrations of barasertib and bara-hQPA were achieved by the first scheduled sample, taken 24 h from the start of infusion (SOI). During infusion, the mean concentration of bara-hQPA was approximately 3-fold higher than that of barasertib (Table). Following the end of infusion (EOI), plasma concentrations of barasertib fell rapidly, reaching the limit of quantification (LoQ) by 6 h after EOI, whereas bara-hQPA plasma levels declined in a triphasic manner, with low concentrations still detectable at the final sampling time point (Day 18). Bara-hQPA was extensively distributed to the tissues, with a relatively slow rate of total clearance (Table). Urine concentrations of barasertib were below LoQ at all time points. The mean urine concentrations of bara-hQPA were approximately 4–5 μg/mL during the infusion period, declining rapidly following EOI. The renal clearance (CLR) values for bara-hQPA represent approximately 10% of the total clearance of bara-hQPA from plasma.Overall, 72–82% of radioactivity was recovered, with approximately double the amount recovered in feces (mean = 51%) compared with urine (mean = 27%). The excretion of radioactivity in urine occurred predominantly within 72 h of 14C-SOI; however, there was large inter-patient variability in the rate of recovery of radioactivity in feces. Overall, the main excreta metabolites identified were: bara-hQPA (range, 13.2–33.7%), bara-hQPA N-acetic acid (range, 7.8–10.5%), bara-hQPA desfluoroaniline N-acetic acid (range, 5.1–9.5%), N-formyl or ethoxy bara-hQPA (range, 3.5–9.2%), and bara-hQPA desfluoroaniline (range, 1.6–5.5%). Desfluoroaniline metabolites made up a significantly larger proportion of the metabolites identified in excreta (∼15%) than in plasma (∼2%). The main pathways identified in human metabolism of barasertib were (i) cleavage of the phosphate group to form bara-hQPA, followed by oxidation, and (ii) loss of the fluoroaniline moiety to form bara-hQPA desfluoroaniline, followed by oxidation.Pharmacokinetics of barasertib and bara-hQPA in plasma and urineSampleParameter*Barasertib (n=5)‡Bara-hQPA (n=5)‡PlasmaAUC, ng.h/mL†NC40400 (0.4)AUC(0–t), ng.h/mL†13840 (0.4)40080 (0.4)AUC(0–192 h), ng.h/mL†NC38230 (0.4)CSS, ng/mL†85.6 (0.5)226.8 (0.4)CL, L/hNC31.4 (11.3)t½, hNC66.3 (36.1)λZ, h-1NC0.02 (0.02)VSS, LNC669.1 (344.9)VZ, LNC2805 (1708)UrineAe, mgNC96.9 (47.2)CLR, L/hNC2.85 (1.6)fe, %NC8.1 (3.9)AUC, area under plasma concentration–time curve; CSS, steady-state drug concentration; CL, total clearance; t½, half-life; λZ, slowest disposition rate constant; VSS, volume of distribution (apparent) at steady state; VZ, volume of distribution (apparent) during terminal (λZ) phase; Ae, cumulative amount of unchanged drug excreted; CLR, renal clearance of drug from plasma; fe, fraction of drug excreted into urine; NC, not calculable*All values are arithmetic mean (standard deviation) except where indicated†Values indicate geometric mean (coefficient of variation)‡Due to sampling issues, plasma concentration data were excluded for 1 pt Conclusions:The PK profile of bara-hQPA is similar to previous studies using the same dosing regimen. The majority of clearance of bara-hQPA occurred via hepatic metabolic routes. This study is the first to characterize the metabolic pathway of barasertib in humans. Disclosures:Oliver:AstraZeneca: Employment. D'Souza:AstraZeneca: Employment, Equity Ownership. Pike:AstraZeneca: Employment, Equity Ownership. Stockman:AstraZeneca: Employment, Equity Ownership.

Sustained release of a dual antimalarial system.

Abstract The sustained release of a dual drug system in a biodegradable carrier was evaluated in rhesus monkeys and mice. The two drugs were sulphadiazine (WR-7557) (3H-labelled) and 2,4-diamino-6-(2-naphthylsulphonyl)quinazoIine (WR-158122) (14C-Iabelled). The carrier was a polymer of L-lactide (90 parts by weight) and glycolide (10 parts), with a molecular weight of 46 000. The dual system injected was a blend of two preparations, each 50% (w/w) of the appropriate drug in the polymer, in a weight ratio of ten parts of the sulphadiazine system to one part of the WR-158122 system. This blend, as cryogenically ground particles, was injected intramuscularly into three monkeys; a fourth monkey received an equivalent dose of a 10:1 mixture of the pure drugs. Excretion of radioactivity in urine and faeces was measured over 13 weeks. Similar studies were done with mice. In monkeys, 14C-labelled material derived from WR-158122 was excreted at a nearly uniform rate; expressed as WR-158122, the rate of excretion from the pure drug mix was approximately 50 μg day−1 from week three to week 13, while the drug/polymer matrix released the drug at approximately 26 μg day−1 during this period. Recovery of tritiated materials derived from sulphadiazine was approximately 82% of the injected dose in the first three weeks and only a slight difference in release characteristics of the pure drug mix and the mixed drug/polymer matrices was observed. Results of studies with both mice and monkeys were generally consistent.

The fate of intravenous (3H)glycopyrrolate in man.

Abstract Glycopyrrolate was labelled in one methyl group with tritium and its fate was studied in six patients with T-tube drainage by determining serum levels as well as the biliary and urinary excretion of radioactivity after intravenous injection. More than 90 % of the radioactivity had disappeared from serum in 5 min and after 30 min almost no radioactivity could be found. The highest radioactivity in bile was found in samples taken 30 or 60 min after the injection. However, measurable radioactivity was found in most cases after 48 h. The first urine samples (0–3 h) showed the greatest radioactivity, and in 48 h 85% of the total radioactivity was excreted into the urine. Paper chromatography showed that both in bile and in urine over 80% of the radioactivity corresponded to unchanged glycopyrrolate. That appreciable amounts of glycopyrrolate were excreted into the bile suggests that the spasmolysis achieved with glycopyrrolate could be based partly on a local action on the bile ducts.

The influence of degradable starch microspheres on liver uptake of 5-fluorouracil after hepatic artery injection in the rat.

The effect of degradable starch microspheres (DSM) on the distribution of 5-fluorouracil (5-FU) after hepatic artery injection was studied in normal rats. Carbon-14-labelled 5-FU was injected separately or together with DSM into the hepatic artery. Radioactivity was measured in liver tissue, bile, peripheral blood, and urine. When microspheres were added, the liver uptake of 5-FU was increased; its peak concentration in peripheral blood decreased, as did the early urinary excretion of radioactivity. The addition of degradable starch microspheres to hepatic artery injections of cytostatic drugs might be of value in increasing the drug concentration in tumour tissue and reducing systemic toxicity.

An improved long-acting delivery system for narcotic antagonists.

The feasibility of using cholesterol-glyceryltristearate matrix for prolonged release of naltrexone was evaluated in rats. Implantable cylindrical pellets (cholesterol 105 mg, glyceryl tristearate 15 mg and naltrexone 30 mg), diameter 4.5 mm, length 9 mm, blocked the antinociceptive action (hot plate 55 degrees C) of 10 mg/kg s.c. challenge dose of morphine in rats for 3 months. The release rate of naltrexone from 10 or 50 mg pellets approximated first-order kinetics with t1/2 alpha of 20-26 days and t1/2 beta 40-60 days. The factors affecting the release of drug from the delivery system were the ratio of cholesterol to naltrexone, drug loading level and surface area to unit volume of dosage form. The minimum release rate of naltrexone to block the effect of 10 mg/kg s.c. dose of morphine in rats was about 4 to 5 microgram/kg/hr. The cumulative urinary excretion of radioactivity from 10 mg [3H] naltrexone pellets implanted s.c. in rats after 30, 60, and 90 days was 17.7, 23.7, and 25.7% of dose respectively and the percent dose released from pellets at these times was 55.8, 68.8, and 78.2 respectively. The devices possess the desirable characteristics of simplicity, nontoxicity, nonirritability, ease of sterilization with ethylene oxide, small size for easy insertion and removal, absence of encapsulation by surrounding tissue, and an extended period of drug release unaffected by body metabolism. Neither deterioration of implant nor gross anatomic or histological changes at the site of implant occurred 6 months to 1 year after implantation and aside from some enhanced sexual activity (e.g., spontaneous penile erections) no side effects were observed in rats, which fed well and gained weight during the entire treatment. The concentrations of free morphine in brains of 30 mg naltrexone pellet-implanted rats were significantly lower (24 and 15%) as compared to the placebo controls 0.5 and 1.0 hr after a 10 mg/kg s.c. dose of [6-3H] morphine. We are currently evaluating these long-acting devices for the duration of effective antagonism to morphine in rhesus monkeys.

Pharmacokinetics of [6]-shogaol, a pungent ingredient of Zingiber officinale Roscoe (Part I).

To investigate the pharmacokinetics of [6]-shogaol, a pungent ingredient of Zingiber officinale Roscoe, the pharmacokinetic parameters were determined by using (14)C-[6]-shogaol (labeled compound) and [6]-shogaol (non-labeled compound). When the labeled compound was orally administered to rats, the maximum plasma concentration (C (max)) and the area under the curve (AUC) of plasma radioactivity concentration increased in a dose-dependent manner. When the labeled compound was orally administered at a dose of 10 mg/kg, 20.0 + or - 1.8% of the radioactivity administered was excreted into urine, 64.0 + or - 12.9% into feces, and 0.2 + or - 0.1% into breath. Thus, more of the radioactivity was excreted into feces than into urine, and almost no radioactivity was excreted into breath. Furthermore, when the labeled compound was orally administered at a dose of 10 mg/kg, cumulative biliary radioactivity excretion over 48 h was 78.5 + or - 4.5% of the radioactivity administered, and cumulative urinary radioactivity excretion over 48 h was 11.8 + or - 2.7%, showing that about 90% of the dose administered orally was absorbed from the digestive tract and most of the fecal excretion was via biliary excretion. On the other hand, when the non-labeled compound [6]-shogaol was orally administered, the plasma concentration and biliary excretion of the unchanged form were extremely low. When these results are combined with those obtained with the labeled compound, it would suggest that [6]-shogaol is mostly metabolized in the body and excreted as metabolites.

Metabolism and Excretion of Rivaroxaban, an Oral, Direct Factor Xa Inhibitor, in Rats, Dogs, and Humans

Rivaroxaban is a novel, oral, direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders. The objective of this study was to investigate the in vivo metabolism and excretion of rivaroxaban in rats, dogs, and humans. Single doses of [(14)C]rivaroxaban (3 and 1 mg/kg) were administered to rats (orally/intravenously) and dogs (orally), respectively. A single oral dose of [(14)C]rivaroxaban (10 mg) was administered to healthy human males (n = 4). Plasma and excreta were collected and profiled for radioactivity. Recovery of total radioactivity was high and > or = 92% in all species. Unchanged rivaroxaban was the major compound in plasma at all time points investigated, across all species. No major or pharmacologically active circulating metabolites were detected. Rivaroxaban and its metabolites were rapidly excreted; urinary excretion of radioactivity was 25 and 52%, and fecal excretion was 67 and 43% of the dose in rats and dogs, respectively. In humans, 66% of the dose was excreted renally (36% unchanged drug) and 28% in the feces. Radioactivity profiles in excreta were similar across species. Three metabolic pathways were identified: oxidative degradation of the morpholinone moiety (major pathway) and hydrolysis of the central amide bond and of the lactam amide bond in the morpholinone ring (minor pathways). M-1, the main metabolite in excreta of all species, was eliminated via both renal and fecal/biliary routes. In total, 82 to 89% of the dose administered was assigned to unchanged rivaroxaban and its metabolites in the excreta of rats, dogs, and humans.

Distribution in Skin of Ceramide after Oral Administration to Rats

In this study, the absorption, distribution and excretion of ceramide were examined in rats. After a single oral administration of (3)H-ceramide, mean plasma concentration of radioactivity reached maximum at approximately 10.67 hr and decreased with a T(1/2) of 67.12 hr. The mean cumulative excretion of radioactivity in urine and feces accounted for approximately 4.79% and 87.44%, respectively, of the dose. At 96 hr after dosing, 1.67% and 3.67%, respectively, of the dose were still present in the skin and carcass. The radioactivity in the skin at 12 hr was lower than that in plasma and the ratio of skin to plasma concentration was 0.7. However, at 120 hr after dosing, the ratio of skin to plasma concentration increased to 4. A detailed analysis of the distribution of radioactivity in a section of skin showed that radioactivity was located in the dermis and epidermis. At 168 hr, the radioactivity in the epidermis was 8.0% of the radioactivity in skin. The results of the present study clearly demonstrate that some ceramide orally administered is distributed gradually in the dermis after gastrointestinal absorption, followed by transfer from the dermis to the epidermis.

Disposition of Vildagliptin, a Novel Dipeptidyl Peptidase 4 Inhibitor, in Rats and Dogs

The pharmacokinetics, absorption, metabolism, and excretion of vildagliptin, a potent and orally active inhibitor of dipeptidyl peptidase 4, were evaluated in male rats and dogs. Vildagliptin was rapidly absorbed with peak plasma concentrations occurring between 0.5 and 1.5 h. Moderate to high bioavailability was observed in both species (45-100%). The distribution and elimination half-lives of vildagliptin were short: 0.57 h [82% of area under the plasma drug concentration-time curve (AUC)] and 8.8 h in the rat and 0.05 and 0.89 h (87% of AUC) in the dog, respectively. The volume of distribution was 1.6 and 8.6 l/kg in dogs and rats, respectively, indicating moderate to high tissue distribution. The plasma clearance of vildagliptin was relatively high for the rat (2.9 l/h/kg) and dog (1.3 l/h/kg) compared with their hepatic blood flow. The major circulating components in plasma after an intravenous or oral dose were the parent compound (rat and dog), a carboxylic acid metabolite from the hydrolysis of the amide bond M15.3 (dog), and a carboxylic acid metabolite from the hydrolysis of the cyano moiety M20.7 (rat and dog). After intravenous dosing, urinary excretion of radioactivity (47.6-72.4%) was the major route of elimination for rats and dogs as 18.9 to 21.3% of the dose was excreted into urine as unchanged parent drug. The recovery was good in both species (81-100% of the dose). Vildagliptin was mainly metabolized before excretion in both species. Similar to plasma, the most predominant metabolite in excreta was M20.7 in rats and dogs, and another major metabolite in dogs was M15.3.

Tissue dosimetry, metabolism and excretion of pentavalent and trivalent dimethylated arsenic in mice after oral administration

Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of administered inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic in mice after acute oral administration. Adult female mice were administered [ 14C]-DMA(V) (0.6 or 60 mg As/kg) and sacrificed serially over 24 h. Tissues and excreta were collected for analysis of radioactivity. Other mice were administered unlabeled DMA(V) (0.6 or 60 mg As/kg) or dimethylarsinous acid (DMA(III)) (0.6 mg As/kg) and sacrificed at 2 or 24 h. Tissues (2 h) and urine (24 h) were collected and analyzed for arsenicals. Absorption, distribution and excretion of [ 14C]-DMA(V) were rapid, as radioactivity was detected in tissues and urine at 0.25 h. For low dose DMA(V) mice, there was a greater fractional absorption of DMA(V) and significantly greater tissue concentrations of radioactivity at several time points. Radioactivity distributed greatest to the liver (1–2% of dose) and declined to less than 0.05% in all tissues examined at 24 h. Urinary excretion of radioactivity was significantly greater in the 0.6 mg As/kg DMA(V) group. Conversely, fecal excretion of radioactivity was significantly greater in the high dose group. Urinary metabolites of DMA(V) included DMA(III), trimethylarsine oxide (TMAO), dimethylthioarsinic acid and trimethylarsine sulfide. Urinary metabolites of DMA(III) included TMAO, dimethylthioarsinic acid and trimethylarsine sulfide. DMA(V) was also excreted by DMA(III)-treated mice, showing its sensitivity to oxidation. TMAO was detected in tissues of the high dose DMA(V) group. The low acute toxicity of DMA(V) in the mouse appears to be due in part to its minimal retention and rapid elimination.

Disposition and Metabolism of [14C]Brasofensine in Rats, Monkeys, and Humans

Brasofensine is an inhibitor of the synaptic dopamine transporter. These studies were conducted to characterize the pharmacokinetics, absolute bioavailability, disposition, and metabolism of brasofensine after i.v. and/or p.o. administrations of [(14)C]brasofensine in rats (1.5 mg/kg i.v., 4 mg/kg p.o.) and monkeys (4 mg i.v., 12 mg p.o.) and humans (50 mg p.o.). Brasofensine was rapidly absorbed after p.o. administration in rats and monkeys, with peak plasma concentrations occurring 0.5 to 1 h but 3 to 8 h for brasofensine in humans. Plasma terminal elimination half-lives were approximately 2 h in rats, approximately 4 h in monkeys, and approximately 24 h in humans. Total body clearance and steady-state volume of distribution values were 199 ml/min/kg and 24 l/kg, respectively, in the rat and 32 ml/min/kg and 46 l/kg, respectively, in the monkey. Absolute bioavailability was 7% in rats and 0.8% in monkeys. After a single p.o. dose, urinary excretion of radioactivity accounted for 20% of the administered dose in rats, 70% in monkeys, and 86% in humans, with the remainder excreted into the feces. Brasofensine had extensive first-pass metabolism following p.o. administration in humans, monkeys, and rats. It primarily underwent O- and N-demethylation and isomerization. Some of the desmethyl metabolites were further converted to glucuronides. These primary metabolites and glucuronides of demethyl brasofensine (M1 and M2) were major circulating metabolites in humans and were also observed in rat and monkey plasma.