Excretion Of Radioactivity Research Articles

Disposition of S-1108, a new oral cefem antibiotic, in experimental animals (1) blood concentration and excretion of radioactivity after oral administration of [7-14C]:-S-1108 to rats and dogs

Disposition of S-1108, a new oral cefem antibiotic, in experimental animals (1) blood concentration and excretion of radioactivity after oral administration of [7-<SUP>14</SUP>C]:-S-1108 to rats and dogs

Disposition of rhIGF-I. (3). Plasma level, distribution and excretion of 125I-rhIGF-I after repeated subcutaneous administration to rats.

125I-rhIGF-I was administered subcutaneously to rats at the dose of 1 mg/kg for 7 consecutive days. After seventh subcut aneous administration of 125I-rhIGF-I, the plasma levels of total and trichloroacetic acid (TCA)precipitable radioactivity declined more slowly than those after a single administration. However, it might be caused by an endogenous proteins which had incorporated a free 125I and low molecular weight fragments of 125I-rhIGF-I and the plasma levels of rhIGF-I itself were thought not to be changed after repeated administration. Except the thyroid, the permeability of rhIGF-I to tissues did not change, and no accumulation of 125I-rhIGF-I in any particular tissue was observed after repeated administration. During repeat ed administration, the excretion of radioactivity in urine and feces was almost similar to that after a single administration, and 80% and 9 % of the administered dose was excreted within 168 hours after the last dosing to urine and feces, respectively. Most of radioactivity in t he urine consisted of free 125I which indicates that 125I-rhIGF-I was well metabolized. Thus, it appears that 125I-rhIGF-I does not accumulate in tissue.

Metabolic fate of KRN5702: Plasma level, distribution, metabolism and excretion of 125I-KRN5702 after repeated subcutaneous administration to rats.

The plasma levels, tissue distribution and excretion of 125I-KRN5702 after repeated subcutaneous administration were investigated in male rats. After seventh subcutaneous administration of 125I-KRN5702 at a dose of 200IU/kg, no difference in the plasma level profiles of total and trichloroacetic acid (TCA) precipitable radioactivity was observed, whereas immunoreactive radioactivity showed relatively low level when compared to that after a single administration. Both the area under the plasma concentration vs time curve (AUC) and the maximum level (Cmax) of immunoreactive radioactivity after repeated administration were 17 and 16% lower than that after single administration, respectively. We consider that the increase in utilization of this material by target organs might be responsible for increased plasma clearance. In the majority of tissues, the levels of radioactivity at 8 hours after each dose during repeated administration were same or slightly higher than those after initial administration. High levels of radioactivity were observed in the plasma, kidney and at the site of administration, independently of the numbers of injection. Whereas those in the spleen, bone marrow and thyroids were relatively higher as compared with those of the initial administration. After final administration, the most of tissues showed a maximum level of radioactivity at 8 hours after administration and then decreased in parallel with plasma level in any time interval. Beyond 48 hours after final administration, the radioactivity in the site of injection decreased to below 2 % of that at 2 hours after administration, and no accumulation in any particular organs or tissues was observed in repeated administration of 125I-KRN5702. Excretion of radioactivity in urine and feces was almost constant, i. e. 80 ?? 90% and 4 ?? 60% of each administered dose, respectively, during repeated administration. Finally, within 7th days after final administration, radioactivity excreted in urine and feces were 96.2% and 8.0% of total dosing, respectively.

Studies on the Metabolic Fate of Sodium Hyaluronate (SL-1010) after Intra-articular Administration. (I). Distribution, Metabolism and Excretion after Intra-articular Injection into Rabbit Knee.

Metabolic fate of a high molecular-weight s odium hyaluronate (SL-1010), a highly purified preparation from the culture medium of Streptococcus zooepidemicus, was studied in rabbits after intraarticular injection into the knee. 1. Radioactivity in the synovial fluid was eliminated biphasically with apparent half-life of 32hr during the first phase, when most radioactivity was eliminated. Gel filtration patterns showed that the SL-1010, a low molecular-weight fraction, was eliminated from the joint cavity faster than the high molecular-weight fraction. 2. In joint region, higher radioactivity was detected in the synovial tissue, and much less radioactivity was observed in the articular cartilage, meniscus and ligament. Total radioactivity in the rest of the whole body was less than that in the knee joint. The highest levels were in Harder's gland, and followed by reticuloendothelial tissues, such as the liver and spleen. Radioactivity was much lower in other tissues including plasma, and there was no radioactivity in the sodium hyaluronate (HA) fraction isolated from liver and plasma. Gel filtraton patterns showed that the main molecular-weight distribution of HA isolated from synovial tissue 24, 48 and 72hr after injection was similar to that of 14C-SL-1010 except for a small quantities of a low molecular-weight fraction. This suggests that 14C-SL-1010 was only slightly metabolized in the synovial tissue. 3. The route of elimination of 14C-SL-1010 from the joint cavity was mainly via the lymphatic system, since any time after elimination of 14C-SL-1010 from the joint cavity the level of radioactivity in the iliac lymph node was much higher than that in the liver. The radioactivity derived from HA in the iliac lymph nodes 24hr after injection and identified as HA-specific hyaluronidase treatment, was 5.6 to 11.7% of the total radioactivity. In in vitro study, metabolic activity in the lymph node was higher than that in the liver. It is suggested that most of the 14C-SL-1010 injected into the knee joint was eliminated and was mainly metabolized in the lymphatic system. 4. Excretion of radioactivity at 144 hr was 70, 3.5 and 0.8% in expired air, urine and feces, respectively. 5. Sex related differences in the distribution of radioactivity either in blood or plasma were negligible.

Metabolism and time-course excretion of murideoxycholic acid, a 6β-hydroxylated bile acid, in humans

The metabolism and time-courses of urinary and fecal excretions of murideoxycholic acid (MDCA; 3 alpha,6 beta-dihydroxy-5 beta-cholanoic acid), a 6 beta-hydroxylated bile acid, was investigated in man. The study was carried out in two groups of subjects. Six cholecystectomized patients fitted with a cystic duct drain ingested 100 mg of a tracer dose of 3H-MDCA. Time-course of radioactivity in plasma was then followed for an 8-h period. Biliary, urinary and fecal excretions of radioactivity were measured for a 5-day period and excreted MDCA metabolites were identified. Five lithiasic patients with intact enterohepatic circulation ingested 500 mg of the same tracer dose of 3H-MDCA. Radioactivity in plasma was followed for a 49-h period and urinary and fecal excretions of radioactivity were measured daily for 7 days. In the first group, the excretion of the radioactivity by the three routes (bile+urine+feces) reached 97.8 +/- 1.5% of the ingested dose but dropped to 75 +/- 8.3% (urine+feces) in patients in the second group. In cholecystectomized patients, the estimation of intestinal MDCA absorption was dependent on cystic duct drain flow rate and gave values ranging from 20% to 87%. The biological half-life of MDCA in lithiasic patients averaged 3.4 +/- 0.7 days. Radioactivity appeared in the plasma in the first hour and reached a maximum 6 and 3 h after the beginning of the experiment in group I and II respectively. In the second group, another peak of radioactivity in plasma was observed just after breakfast.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the Metabolic Fate of Leukotriene Antagonist ONO-1078. (2). Absorption, Distribution, Excretion and Effects on Drug Metabolizing Enzyme Activities after Repeated Oral Administration to Rats.

ONO-1078(4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate)をラットに反復経口投与したときの体内動態および肝薬物代謝酵素に対する影響について検討した． 1．3H-ONO-1078を2mg/kg/day1日1回15日間反復経口投与したとき，各回投与後24時間の血漿中放射能濃度は5～7日目までにほぼ定常状態に達した． 2．14C-ONO-1078を2mg/kg/day1日1回7日間反復経口投与しても，臓器および組織内への蓄積は認められず，最終投与後の消失も速やかであった． 3．3H-ONO-1078を2mg/kg/day1日1回7あるいは15日間反復経口投与したとき，肝臓や腎臓など多くの臓器で7日目までにほぼ定常に達した．しかし，白色脂肪および褐色脂肪では，15日間の反復投与では定常状態に達せず，これらの組織では蓄積傾向が認められたが，毒性に影響をおよぼすものではないと考えられた． 4．14Cあるいは3H-ONO-1078を2mg/kg/day反復経口投与したときの尿および糞中への放射能の排泄は単回投与の場合と同様であった． 5．ONO-1078は1.0g/kg/day1日1回15日間の反復経口投与したとき，肝重量が対照群の1.08倍増加したが，ミクロゾーム蛋白量および薬物代謝酵素活性には影響を与えなかった．

Studies on the Metabolic Fate of L-Carnosine in Rats and Humans.

The metabolic fate of L-carnosine in rats was studied after administration of [14C-U-histidine]-L-carnosine (14C-(his)-L-carnosine) or [14C-β-alanine]-L-carnosine (14C-(ala)-L-carnosine). 1. The blood level of radioactivity reached the maximum concentration (Cmax) at 4hr after oral administration of 14C-(his)-L-carnosine in rats, and the level was almost constant thereafter up to 120hr. On the other hand, the blood levels of radioactivity reached the Cmax at 0.5hr after oral administration of 14C-(ala)-L-carnosine, and declined with a half-life of 3.9hr within the first 6hr and the half-lives in the periods between of 6-24hr and 24-120hr were 19.7hr and 91.9hr, respectively. 2. Male rats excreted 7.9% of administered dose in urine, 6.3% in feces and 37.0% with expired air during 120hr after oral administration of 14C-(his)-L-carnosine. On the other hand, after administration of 14C-(ala)-L-carnosine the excretion of radioactivity into the urine, feces and expired air were 5.4%, 1.8% and 80.2%, respectively. The radioactivity in the carcass after administration of 14C-(his)-L-carnosine and 14C-(ala)-L-carnosine were 44.4% and 9.6%, respectively. 3. The blood concentrations and excretion of radioactivity of [14C-U]-L-carnosine were similar to those after administration of 14C-(his)-L-carnosine. 4. The disappearance of unchanged L-carnosine in plasma followed first-order kinetics with the half-life of 15min after intravenous administration of 14C-(his)-L-carnosine to rats, and then the appearance of L-carnosine (the metabolite of L-carnosine) was very rapid and reached the Cmax at 0.5hr. When the plasma sample after intravenous administration was treated with sulfosalicylic acid (SSA), the radioactivity of SSA supernatant declined as a function of time. 5. In vitro, L-carnosine was converted to L-histidine in the presence of human plasma within 15min at room temperature. 6. The present studies indicade that L-carnosine was converted to L-histidine and β-alanine in rats and humans, of which L-histidine was further utilized for the incorporation of endogenous high molecular substances.

Metabolic Fate of Eptastigmine, a New Competitive Inhibitor of Acetylcholinesterase. (I). Absorption, Distribution and Excretion of 3H-Eptastigmine after Single Oral Administration in Rats.

Eptastigmine, ((3aS, 8aR)-1, 2, 3, 3a, 8, 8a-hexahydro-1, 3a, 8-trimethylpyrrolo [2, 3-b] indol-5-ol-heptylcarbamate L-tartrate), is a competitive inhibitor of acetylcholinesterase. Absorption, distribution and excretion of radioactivity were investigated in rats (n=3) after single oral or intravenous administration of 3H-eptastigmine. 1. After oral administration of doses ranging from 2 to 8mg/kg, blood levels of radioactivity increased proportionally to administered dose with peak blood concentration occurring at about one hour and declined with half-lives (t1/2β) of 13-16hr. Based on the AUC values obtained after intravenous and oral administration, oral absorption ratio of 3H-eptastigmine was estimated to be 70-100%. 2. After oral dosin g, the radioactivity was rapidly and widely distributed to tissues and maintained in high concentrations in the liver and gastrointestinal tract. Radioactivity in most of tissues declined slower than that in the plasma. At 24hr, the level in each tissue decreased to about 10% of the corresponding maximum level. There was no evidence of accumulation of 3H in any tissue. 3. Mean excretion of radioactivity was 60.5 and 18.1% of the dose in the urine and feces, respectively, within 24hr after intravenous dosing. In case of oral dosing, the mean excretion of radioactivity in urine and feces were 40.2-51.3 and 29.0-33.5% of the dose, respectively. 4. Mean plasma levels of unchanged eptastigmine reached the maximum concentration at 0.5hr after oral dosing, and then declined with half-life of 1.1hr. The AUC value for unchanged eptastigmine accounted only for 0.4% of that for the total radioactivity. 5. Marked inhibition of RBC acetylcholinesterase activity was o bserved after administration of the 8mg/kg. At 1hr after dosing, the mean value of acetylcholinesterase activity decreased to 15% of the pre-dosing level and remained suppressed for up to 8hr after dosing. 6. Based on the results from the blood profile of radioactivity and time course of acetylcholinesterase inhibition, we concluded that at least one active metabolite exists in the blood.

Fate of 125I-labeled Compounds in Rats after Intravenous Injection. (I). Metabolic Fate of Sodium-125I-iodide.

After the pretreatment with the potassium iodine containing drinking water, so called iodine-block, the absorption, distribuion, and excretion of radioactivity in rats were observed compared with those in the non-treated (control) rats after intravenous injection of 125I-NaI. Consequently, the differences are found as follows ; 1) The change of the radioactivity level in plasma of the iodineblock rats was slightly different from that of the control through 8hr after the injection. From 8hr to 24hr, the plasma levels were remarkably different ; rapid decline was observed in the case of iodine-block rats. Since 24hr, a similar half life was found in each condition, though the curve of the iodine-block was about 1/15 of the control. 2) A few % of the total radioactivity in plasma was found in the acid insoluble fraction through an early period after the injection. After that, the ratio in the acid insoluble fraction increased with time elapsed, and its ratio reached about 40% in the case of the iodine-block, and about 70% for the control. When the plasma samples 5min and 2hr after the injection were subjected to electrophoresis, the radioactive fraction was found to be present in the albumin fraction. 3) The 125I-NaI was recovered mainly in urine. The cumulative excretion percent of the dose for 72hr was about 98% for the iodine-block rats, though it was about 74% for the control. The remaining fractions were retained mostly in the body, but a slight fecal excreti on was also observed. 4) Biliary excretion of the radioactivity within 48hr after the injection was 34% and 27% for the iodine-block and the control, respectively. 5) The autoradiographic data 5min after the injection indicated a saturated photo density over the stomach contents, kidney and urinary bladder. And a relatively higher density over the skeletal muscle was observed in the case of the iodine-block rat than the control rat. Fourty eight hours after the injection, saturated density over the thyroid in control rats was present, but the iodine-block rat did not show any density over the whole body section. The radioactive proteins of the thyroid were separated by the electrophoresis. The results indicated that remarkable radioactivity was associated with a thyroglobulin spot.

The disposition of recombinant human erythropoietin (EPOCH) after subcutaneous administration. (2). The disposition of 125I-EPOCH after single subcutaneous administration in rats.

We studied the absorption, distribution, excretion and metabolism of 125I-EPOCH after single subcutaneous administration to rats. 1. The levels of immunoreactive rad ioactivity reached the maximum at 8 to 12 hours after dosing and declined monoexponentially with a half-life ranging from 5.77 to 7.47 hours at the doses of 0.5, 1, 5 and 25μg/kg. The MRT of immunoreactive radioactivity after sc dosing ranged from 13.83 to 17.01 hours at any dose levels. F value (AUCsc/AUCiv), which ranged from 0.31 to 0.48, tend to increase in proportion to the administered dose. 2. Most of tissues showed the highest level of total radioactivity at 10 hour after dosing. The level of radioactivity in tissues were lower, than that of serum, except the thyroid gland whose level was the highest. They declined parallel with disappearence of the radioactivity in serum. The level of radioactivity in brain was extremely low. The elimination half-life of radioactivity from the injection site was calculated to be 9h and 1.97% of the dose still remained there at 48 hour. 3. Until 96h after sc administration of 125I-EPOCH at the dose of 1μg/kg, urinary excretions of total, the TCA-precipitable and the immunoreactive radioactivity were 75.89%, 0.35%, 0.05%, respectively. Fecal excretion of total radioactivity was 2.97%, until 96h after dosing. 4. Gel filtration of the plasma showed that the radioactivity of low molecular weight was iodo ion, and that related to radioactivity of high molecular weight appeared mainly as an unchanged 125I-EPOCH.

Zatebradine: Pharmacokinetics of a novel heart-rate-lowering agent after intravenous infusion and oral administration to healthy subjects

AbstractZatebradine (1; UL-FS 49 CL; 1, 3, 4, 5-[tetrahydro-7, 8-dimethoxy-3-[3-[[2-(3, 4-dimethoxyphenyl)ethyl]methylamino]propyl]-2H-3-benzazepin-2-on-hydrochloride)] is the proposed INN name for a nonchiral, novel, specific heart-rate-lowering drug that is suitable for the treatment of stable angina pectoris. The pharmacokinetics of 1 and of total radioactivity in healthy volunteers (n = 6) were determined after intravenous infusion and oral administration of an experimental drug solution containing 7.5mg (1.85MBq) of 14C-labeled drug. Concentrations in plasma and urine were measured by a specific, sensitive, reversed-phase automated high-performance liquid chromatography system with fluorimetric detection at 285nm Ex, 315nm Em and by liquid scintillation counting. Recovery of total radioactivity was 89.8 ± 2.3% (infusion) and 92.2 ± 3.0% (oral). Renal elimination of total radioactivity was 62.5 ± 2.0% (infusion) and 48.8 ± 3.1% (oral). After intravenous infusion and oral administration, 27.3 ± 2.4 and 43.4 ± 3.9%, respectively, of the administered dose was eliminated in the feces. Absorption, based on renal excretion of total radioactivity following oral and intravenous dosing, was 79.2 ± 15.3% (mean ± standard deviation). Unchanged parent drug contributed 28.4 ± 5.8% (infusion) and 12.4 ± 3.7% (oral) of the dose to renal excretion. Zero to three minutes after cessation of the 20-min infusion, the maximum concentration of parent drug in plasma was 161.9 ± 70.9ng/mL. After oral administration, a mean peak concentration in plasma of 24.3 ± 6.7ng/mL (0.5-3h postadministration) was reached. Data regarding levels of 1 in plasma could be adequately fitted with an open, two-compartment model. The dominant terminal half-life (infusion) of 1 was 2.80 ± 0.8h (range 1.82–3.40h). Mean residence times were 3.2 ± 0.8h (infusion) and 4.6 ± 0.8h (oral administration), and total body clearances were 630 ± 243mL/min (infusion) and 1197 ± 538mL/min (oral). Absolute bioavailability was 51.5 ± 17.8% (range 29.0–80.0%) based on data from the area under the curve of concentration in plasma versus time and 45.0 ± 17.0% (range 30.0–70.0%) based on renal excretion of parent drug.

Distribution and Elimination of the Somatostatin Analogue (111In-DTPA-D-Phe1)-Octreotide (OctreoScan111)

The distribution and elimination characteristics of the 111In-labelled somatostatin analogue OctreoScan111 were studied in 23 patients with malignant tumours. The substance exhibited a rapid blood elimination following a bi-phasic pattern. The initial part of the elimination curves showed a t1/2a of between 0.27 and 3.6 h. The patients investigated had creatinine clearance rates ranging from 33 to 124 ml/min. However, within this range, no apparent correlation was found between the OctreoScan111 elimination rate and kidney function. Also no correlation was observed between the amount of administered activity and the elimination rate of OctreoScan111. The serum radioactivity of 6 patients was analyzed with respect to molecular size. These experiments showed that OctreoScan111 circulated unbound in serum. About 3% of the radioactivity, most probably representing 111In-chloride of DTPA-111In-chloride, circulated protein-bound. The elimination of OctreoScan111 radioactivity in urine displayed a bi-phasic pattern. Size separation of the radioactivity appearing in the urine after 24 h showed a higher molecular weight when compared with OctreoScan111, indicating the existence of a metabolite of the injected substance. The results obtained are discussed in the light of a potential role for the substance in systemic radiotherapy.

The disposition and metabolic fate of 14C-meropenem in man.

1. The metabolism and pharmacokinetics of 14C-meropenem were studied in five volunteers who received 0.5 g (40 microCi) of the radiolabelled drug by i.v. infusion. 2. The maximum concentration of drug in plasma was 27 +/- 2 micrograms/ml (70 microM) corresponding to 98% of plasma radioactivity at the end of a 30 min infusion. The elimination half-life for meropenem in plasma was 1 h and meropenem remained the major radioactive component up to 6 h, but represented a decreasing proportion of the plasma radioactivity with time. One metabolite (the ring-open lactam) accounted for most of the remaining plasma radioactivity. The maximum concentration of metabolite was 1 +/- 0.1 micrograms/ml and the concentration of total radioactivity decreased to 2% of the peak value by 8 h. 3. Over the 5 days of the study, urinary excretion of radioactivity accounted for 99 +/- 0.5% dose, most of which was recovered in the first 8 h. There was negligible excretion in faeces. 4. Structural confirmation of the drug-related components in urine was accomplished by h.p.l.c.-mass spectrometry. Meropenem accounted for 71 +/- 2% dose of 14C and the ring-open lactam metabolite for most of the remainder, no other metabolites were detected. 5. Meropenem was the major radioactive component in urine up to 8 h after dosing and is therefore remarkably stable to human renal dehydropeptidase (DHP-1) compared with other carbapenems in clinical use.

Pharmacokinetics of dirithromycin.

Dirithromycin is a new member of the macrolide class of antibiotics and has been developed for oral administration. Dirithromycin is a 14-membered lactone ring macrolide and is the C9-oxazine derivative of erythromycylamine. The human pharmacokinetics and clinical pharmacology of dirithromycin have been studied. Dirithromycin has unique pharmacokinetics which distinguish it from erythromycin. In man, following an oral 500 mg dose of dirithromycin, a mean peak plasma concentration (Cmax) of 0.48 mg/L (range 0.1-1.97) was observed at 4 h. The mean area under the plasma concentration versus time curve (AUC0-24h) measured 3.37 mg.h/L (range 0.39-17.16). No plasma accumulation was observed with multiple-dose administration. Dirithromycin may be taken without regard to meals, although food and H2-receptor antagonists may increase the systemic bioavailability in some patients. Based upon drug interaction studies performed with antipyrine and theophylline, dirithromycin has shown less potential to interact with other drugs metabolized by the cytochrome P450 system that does erythromycin. Plasma concentrations and AUCs were low due to rapid movement of the drug from the vascular space to the extravascular compartment, as reflected by tissue concentrations, which exceeded plasma concentrations 4 h after dosing. Dirithromycin achieves relatively high tissue concentrations (approximately 0.8-5.0 mg/kg) 4-24 h after dosing. The extensive tissue penetration is reflected in a large mean apparent volume of distribution of 800 L (range 504-1041). Dirithromycin is rapidly converted by non-enzymatic hydrolysis during absorption to erythromycylamine, which is microbiologically active. In a 14C-radiolabelled study, 60-90% of the administered dose was hydrolysed to erythromycylamine within 35 min of infusion. After 1.5 h, conversion to erythromycylamine in serum was virtually complete. Plasma protein binding was determined to be 15-30% by ultracentrifugation. Dirithromycin is characterized by a plasma elimination half-life of 44 h (range 16-65 h) that permits once-daily administration. Total body clearance was 226-1040 mL/min in the 14C-radiolabelled study. The primary route of elimination of dirithromycin/erythromycylamine was faecal/hepatic. Following intravenous administration, approximately 17-25% of the radioactivity appeared in the urine and 62-81% appeared in the stool, indicating predominantly hepatic excretion. With oral administration 1.2-2.9% of the radioactivity appeared in the urine and 81-97% in the stool. The major part of urinary excretion occurs within the first 48 h post-administration; however, urinary excretion of radioactivity lasted longer than 240 h. The absolute bioavailability calculated from dose-corrected urinary excretion data was 10% (6-14%).

Metabolic Fate of Zolpidem. (II). Pharmacokinetics of Zolpidem in Rats after Multiple Oral Dosing.

The 14C-labelled compound of zolpidem hemitartrate, a new hypnotic drug, was given orally in a dose of 3.29mg/kg to male rats once a day for a maximum of 28 days, and its absorption, distribution, metabolism and excretion were examined. The results are summarized as follows. 1. Area under the blood radioactivity-time curves (AUCs) up to 24 hours after the 1st, 7th, 14th, 21st and 28th dosing were 1.74, 1.35, 1.92, 1.73 and 2.14μg eq.hr/ml respectively. Since there was no the difference among AUCs after the 14th, 21st and 28th dosing, the blood radioactivity was considered to have reached a steady state. The increase of AUCs during multiple dosing was of low extent because those after the 14th and 28th dosing were only 1.1 and 1.2 times higher than those after the 1st dosing. 2. Tissue to plasma concentration ratios of radioactivity after the 14th or 21st dosing were almost constant in many tissues including the blood, lung, liver, kidneys and skin whose the concentrations of radioactivity were higher than in the plasma. This showed that the tissue radioactivity was probably reaching a steady state after the 14th or 21st dosing. 3. The disappearance of radioactivity after the 28th dosing was slow er in the kidneys, spleen and skin than that in the plasma. Seventy two hours after the last dosing, however, the concentrations of radioactivity in these tissues were less than 1 % of the 5 min-value, and no radioactivity was detected at 70 days. 4. After the 28th dosing, the zolpidem was not detected in the urine and feces, and M-I accounted for 57.4 and 59.0% of radioactivity excreted in the urine and feces, respectively. Each amount of M-II ?? M-V in the excreta was 1/10 of that of M-I. The metabolism of zolpidem was unaffected by multiple oral dosing (28 times). 5. Urinary and fecal excretion of radioactivity was almost constant during multiple oral dosing.

Studies on the Metabolic Fate of Sodium Hyaluronate (SL-1010) after Intra-articular Administration. II. Distribution, Metabolism and Excretion after Repeated Intra-articular Injection into Rabbit Knee.

A 1 % 14C-SL-1010 solution (3mg/kg) was administered repeatedly into the cavitas articulare of left rabbit knee at 4 day intervals for a total of 7 times. 1. Residual radioactivity in synovial fluid was approximately 60% of each dose at 24hrs after the 4th and 7th administrations and was comparable to that observed after the first administration. The clearance of radioactivity from synovial fluid observed after the 7th administration was comparable to a simulated curve projected from results for the first administration study group, and no accumulation was observed as a result of repeated administration. 2. Plasma levels of radioactivity reached the steady state following the 3rd administration and gradually decreased from 5 days after the 7th administration with an elimination half-life of 106. Ohrs. The observed plasma profile of radioactivity was similar to that simulated from results of the single dose study. 3. The primary route of excretion was the expired air. The cumulative excretion of radioactivity in expired air reached the steady state after the 6th administration and reached 81.5% of the total dose at 14 days after the 7th administration. The cumulative excretion of radioactivity in urine and feces were 3.3% and 2.9%, respectively. These results were similar to those observed in the single dose study. 4. The levels of radio activity in various tissues surrounding the dosing side of the knee joint gradually increased with repeated administration. At 24hrs after the 4th administration, the level had risen to 0.9-2.8 times higher levels of that at 24hrs following the first administration, and the peak concentration observed after the 7th administration was 1.4-3.2 times higher than the level at 24hrs following the first administration. The level of radioactivity was highest in the synovial tissue and was followed in order of decreasing radioactivity by the infrapatellar fat pad, meniscus, patellar ligament, cartilage and patella. 5. The level of radioactivity in the principal tissues beyond the knee joint tended to increase gradually with repeated administration, reaching a peak at 24hrs following the 7th administration. The peak values for liver, lung, kidney, spleen, Harderian gland, adrenal gland and heart were 2.6-13.6 times higher than the levels at 24hrs after the first administration. At 14 days after the 7th administration, these concentrations had decreased to 10-60% of peak values.

Studies on the Metabolic Fate of a New Thromboxane A2 Receptor Antagonist, S-1452. (II). Distribution and Excretion after Single and Repeated Oral Administration to Rats.

The tissue distribution and excretion of S-1452 were studied in rats after a single and repeated oral administration of 14C-S-1452 at a dose of 5mg/kg or 5mg/kg/day for 10 days. 1. The level of radioactivity in the liver was markedly higher than those in other tissues after both single and repeated dosing. 2. Whole body autoradiography after a single or repeated administration demonstrated that the radioactivity in the hepatic vein was markedly weaker than that in the portal vein. This phenomenon suggests that the hepatic first-pass effect of (+)-S-145 in rats was the extensive one. 3. The daily excretions of radioactivity in urine and feces were constant during repeated administration. Within 168hr after the last dosing, 8.3% and 89.2% of the administered radioactivity were recovered from the urine and feces, respectively. 4. After both single and repeated administration, the radioactivity tended to disappear slowly from the whole blood, spleen and bone marrow. 5. After repeated administration of 14C-S-1452 for 10 days, no accumulation of radioactivity in the tissues was observed.

Metabolism of triallate in Sprague-Dawley rats. 1. Material balance, tissue distribution, and elimination kinetics

Triallate isotopically labeled with 14C and 13C in the C-1 allylic carbon position was administered orally to male and female Sprague-Dawley rats at dose levels of 5 and 500 mg/kg of body weight. Most of the dose was rapidly eliminated within 72 h after administration, and dose recoveries averaged 92% and 96 % for the low-dose and high-dose animals, respectively. Approximately 42-52% of the dose was excreted via the urine and 33-46% via the feces. Expired 14CO2 accounted for approximately 4% of the dose, while the residual carcass at sacrifice contained approximately 2%. Radioactivity in blood was associated principally with hemoglobin. Kinetics for whole-body elimination of radioactivity were consistent with a two-compartment open model. The half-life of the a phase varied from 5.9 to 22.8 h, and that of the beta phase from 171 to 265 h.

Radioiodinated 1-(2-Fluoro-4-Iodo-2,4-Dideoxy-β-L-Xylopyranosyl)-2-Nitroimidazole: A Novel Probe for the Noninvasive Assessment of Tumor Hypoxia

1-(2-Fluoro-4-iodo-2,4-dideoxy-beta-L-xylopyranosyl)-2-nitroimidazole (FIAZP) has been synthesized and labeled with radioiodine (125I). Radioiodinated FIAZP is one of a series of sugar-coupled 2-nitroimidazoles developed in our laboratory as probes for noninvasive scintigraphic assessment of tumor hypoxia. An in vivo biodistribution study with [125I]FIAZP in the murine BALB/c EMT-6 tumor model showed a tumor-to-blood ratio of 6, 24 h after injection, with 0.5% of the injected dose present per gram of tumor. These values are several times higher than the respective ratios and distribution values in any of the organs, with the exception of liver. Radioactivity from tissues other than tumor and liver declined with time, following the decline of blood radioactivity. Rapid whole-body elimination of radioactivity was observed (> 96% in 24 h). The thyroid showed little uptake of radioactivity, indicating minimal in vivo deiodination. 1-(2-Fluoro-4-iodo-2,4-dideoxy-beta-L-xylopranosyl)-2-nitroimidazo le appears to undergo hypoxia-dependent binding in tumor tissue at levels comparable to those of other sugar-coupled 2-nitroimidazoles. The potential for imaging with this compound is discussed.

A bifunctional HBED-derivative for labeling of antibodies with 67Ga, 111In and 59Fe. Comparative biodistribution with 111In-DPTA and 131I-labeled antibodies in mice bearing antibody internalizing and non-internalizing tumors

To investigate whether bifunctional ligands containing chelating structures other than EDTA and DTPA and metallic radiotracers other than 111In will reduce the non-specific radioactivity uptake in the liver during immunoscintigraphy, we synthetized an isothiocyanato-substituted phenolic polyaminocarboxylic acid (HBED-CI) for labeling of MAbs with 67Ga, 111In and 59Fe. Biodistribution of HBED-CI-labeled MAbs was compared to that of 131I and 111In-DTPA labeled MAbs in nude mice bearing tumors, which differ with regard to intracellular internalization and catabolism of the corresponding MAb-antigen complex. In the liver a continuous radioactivity excretion for 67Ga-HBED-CI-labeled MAbs was observed with kinetics that parallel 131I clearance after administration of 131I-MAbs, while 111In-HBED-CI-labeling led to a constant 111In liver level quite similar to that of 111In-DTPA-MAbs. In tumors, 67Ga-HBED-CI-MAb uptake again paralleled that of 131I-MAbs, showing continuous accumulation in tumor tissues when internalization of the MAb-antigen complex was not involved. A much lower uptake, which peaked between 24 and 48 h, was found in the case of MAb-antigen internalization. 111In of 111In-HBED-CI- and 111In-DTPA-labeled MAbs continuously accumulated in both types of tumors. Compared with 111In-DTPA-MAbs, an improvement in tumor-to-liver ratios, due to the reduced liver radioactivity associated with 67Ga-HBED-CI-labeled MAbs, could only be obtained with non-internalizing tumors. The time course of radioactivity distribution in the liver and in MAb-internalizing tumors after administration of 67Ga-HBED-CI-, 111In-HBED-CI- and 111In-DTPA-labeled MAbs further indicates a dominating influence of the metallic radiotracer rather than the ligand on retention or excretion of radioactivity in MAb-catabolizing tissues.