Synthesis and excretion profile of 1,4- [14C]phenylenebis(methylene)selenocyanate in the rat

1,4-Phenylenebis(methylene)selenocyanate (p-XSC) inhibits chemically induced tumors in several laboratory animal models. To understand its mode of action, we synthesized p-[14C]XSC, examined its excretion pattern in female CD rats and also the nature of its metabolites. p- [14C]XSC was synthesized from alpha,alpha-dibromo-p-[ring-14C]xylene in 80% yield. The excretion profile of p-[14C]XSC (15.8 mg/kg body wt, 200 microCi/rat, oral administration, in 1 ml corn oil) in vivo was monitored by measuring radioactivity and selenium content. On the basis of radioactivity, approximately 20% of the dose was excreted in the urine and 68% in the feces over 3 days. The cumulative percentages of the dose excreted over 7 days were 24% in urine and 75% in feces, similar to excretion rates of selenium. According to selenium measurement, <1% of the dose was detected in exhaled air; radioactivity was not detected. Only 15% of the dose was extractable from the feces with EtOAc and was identified as tetraselenocyclophane (TSC). Most of the radioactivity remained tightly bound to the feces. Approximately 10% of this bound material converted to TSC on reduction with NaBH4. Organic soluble metabolites in urine did not exceed 2% of the dose; sulfate (9 % of urinary metabolites) and glucuronic acid (19.5% of urinary metabolites) conjugates were observed but their structural identification is still underway. Co-chromatography with a synthetic standard led to the detection of terephthalic acid (1,4- benzenedicarboxylic acid) as a minor metabolite. The major urinary conjugates contained selenium. Despite the low levels of selenium in the exhaled air, the reductive metabolism of p-XSC to H2Se cannot be ruled out. Identification of TSC in vivo indicates that a selenol may be a key intermediate responsible for the chemopreventive action of p- XSC.      

Assessment of the absorption, metabolism and excretion of [14C]pasireotide in healthy volunteers using accelerator mass spectrometry

Purpose

Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog designed to have a broader somatostatin receptor binding profile than other currently available somatostatin analogs. The purpose of this study was to evaluate the absorption, metabolism and excretion of pasireotide in healthy male subjects (N = 4) following a single, subcutaneous (sc), 600 μg dose of [¹⁴C]pasireotide.

Methods

Blood, plasma, urine and feces were collected for 240 h post-dose and analyzed for total ¹⁴C and metabolite profile by accelerator mass spectrometry (AMS) or high-performance liquid chromatography–AMS. Parent drug levels were analyzed by radioimmunoassay.

Results

[¹⁴C]pasireotide was rapidly absorbed, with a mean peak plasma ¹⁴C concentration of 16.6 ± 5.28 ngEq/mL at 0.5 h in plasma. The parent drug to total ¹⁴C AUC_0–24h ratio was 1.08, indicating that little metabolite was present in plasma up to 24 h post-dose. In pooled plasma samples (0–12 h), only unchanged [¹⁴C]pasireotide was detected. Unchanged [¹⁴C]pasireotide accounted for approximately 84 % of total excretion (feces and urine). Approximately 56 % of the administered radioactive dose was recovered within 240 h, eliminated primarily in feces (48.3 ± 8.16 %) and minimally in urine (7.63 ± 2.03 %). No serious adverse events were reported.

Conclusions

A single dose of [¹⁴C]pasireotide 600 μg sc administered to healthy male subjects was rapidly absorbed and excreted in its unchanged form primarily via the hepatic route.     

99m Tc-HYNIC-TOC人体内照射剂量研究

背景与目的：放射性显像药物在人体内的剂量分布、各器官的吸收剂量及全身有效剂量数据非常重要。研究^99mTc标记的经肼基烟酰胺修饰的奥曲肽（^99mTc-Hydrazinonicotinyl-Tyr3-Octreotide,^99mTc-HYNIC-TOC）在人体内各器官的吸收剂量、全身吸收剂量及全身有效剂量。方法：对2018年5—6月复旦大学附属肿瘤医院收治的5例神经内分泌肿瘤患者静脉注射370 MBq^99mTc-HYNIC-TOC后于0.5、1.0、2.0、4.0和8.0 h行全身平面采集,其中2.0 h平面采集后即刻行全身断层采集。断层数据经迭代重建后,将数据导入GE Dosimetry Toolkit处理,在单光子发射计算机断层显像（single photon emission computedtomography,SPECT）/CT融合图像上勾画各器官生成感兴趣区（region of interest,ROI）,获得相应时间-活度曲线并计算曲线下面积得到滞留时间。依据美国核医学会医用内照射剂量学（Medical Internal Radiation Dose,MIRD）委员会提出的内照射剂量计算方法（MIRD体系）,利用OLINDA/EXM软件计算^99mTc-HYNIC-TOC在人体内各器官的吸收剂量、全身吸收剂量和全身有效剂量。结果：脾脏、膀胱、肾脏的单位活度吸收剂量较高,男性分别为0.042、0.019和0.016 mGy/MBq,女性分别为0.026、0.027和0.017 mGy/MBq。大脑、皮肤、甲状腺的单位活度吸收剂量较低,男性分别为0.000 3、0.000 5和0.000 5 mGy/MBq,女性分别为0.000 3、0.000 5和0.000 6 mGy/MBq。对放射线敏感的器官如骨原细胞、胸腺和红骨髓的单位活度吸收剂量均较低,范围为0.001 2~0.002 2 mGy/MBq。全身平均单位活度吸收剂量男性为0.001 7 mGy/MBq,女性为0.0016 mGy/MBq。全身单位活度有效剂量男性为0.004 58 mSv/MBq,女性为0.004 55 mSv/MBq。结论：^99mTc-HYNIC-TOC可安全地用于人体,其有效剂量低于允许范围上限。该研究结果可为临床安全使用^99mTc-HYNIC-TOC提供依据,也为其他放射性药物的安全性评估和加快临床转化提供新的可行方案。     

Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer.

The purpose of this study is to characterize the absorption, metabolism, and excretion of carbon 14-labeled temozolomide (14C-TMZ) administered p.o. to adult patients with advanced solid malignancies. On day 1 of cycle 1, six patients received a single oral 200-mg dose of 14C-TMZ (70.2 microCi). Whole blood, plasma, urine, and feces were collected from days 1-8 and on day 14 of cycle 1. Total radioactivity was measured in all samples. TMZ, 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), and 4-amino-5-imidazole-carboxamide (AIC) concentrations were determined in plasma, and urine and plasma samples were profiled for metabolite/degradation products. Maximum TMZ plasma concentrations were achieved between 0.33 to 2 h (mean, 1.2 h), and half-life, apparent volume of distribution, and oral clearance values averaged 1.9 h, 17 liters/m2, and 104 ml/min/m2, respectively. A first-order absorption, one-compartment linear model, which included first-order formation of MTIC from TMZ and elimination of MTIC via degradation to AIC, and a peripheral distribution compartment for AIC, adequately described the plasma TMZ, MTIC, and AIC concentrations. MTIC systemic clearance was estimated to be 5384 ml/min/m2, and the half-life was calculated to be 2.5 min. Metabolite profiles of plasma at 1 and 4 h after treatment showed that 14C-derived radioactivity was primarily associated with TMZ, and a smaller amount was attributed to AIC. Profiles of urine samples from 0-24 h revealed that 14C-TMZ-derived urinary radioactivity was primarily associated with unchanged drug (5.6%), AIC (12%), or 3-methyl-2,3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxyl ic acid (2.3%). The recovered radioactive dose (39%) was principally eliminated in the urine (38%), and a small amount (0.8%) was excreted in the feces. TMZ exhibits rapid oral absorption and high systemic availability. The primary elimination pathway for TMZ is by pH-dependent degradation to MTIC and further degradation to AIC. Incomplete recovery of radioactivity may be explained by the incorporation of AIC into nucleic acids.     

Absorption,distribution, metabolism,and excretion (ADME) of <Superscript>14</Superscript>C-sonidegib (LDE225) in healthy volunteers

Purpose

The absorption, distribution, metabolism, and excretion of the hedgehog pathway inhibitor sonidegib (LDE225) were determined in healthy male subjects.

Methods

Six subjects received a single oral dose of 800 mg ¹⁴C-sonidegib (74 kBq, 2.0 µCi) under fasting conditions. Blood, plasma, urine, and fecal samples were collected predose, postdose in-house (days 1–22), and during 24-h visits (weekly, days 29–43; biweekly, days 57–99). Radioactivity was determined in all samples using accelerator mass spectrometry (AMS). Liquid chromatography–tandem mass spectrometry (LC–MS/MS) was used to determine concentrations of sonidegib and its main circulating metabolite in plasma. Metabolite profiles and structures were determined in pooled plasma, urine, and fecal samples using high-performance LC–AMS and LC–MS/MS, respectively.

Results

A single dose of ¹⁴C-sonidegib was well tolerated in healthy subjects. Unchanged sonidegib and total radioactivity reached peak concentration in plasma by 2 and 3 h, respectively, and demonstrated similarly long half-lives of 319 and 331 h, respectively. Absorbed sonidegib (estimated 6–7 %) was extensively distributed, and the approximate terminal volume of distribution was 2,500 L. Unchanged sonidegib and a metabolite resulting from amide hydrolysis were the major circulating components (36.4 and 15.4 % of radioactivity area under the curve, respectively). Absorbed sonidegib was eliminated predominantly through oxidative metabolism of the morpholine part and amide hydrolysis. Unabsorbed sonidegib was excreted through the feces. Metabolites in excreta accounted for 4.49 % of the dose (1.20 % in urine, 3.29 % in feces). The recovery of radioactivity in urine and feces was essentially complete (95.3 ± 1.93 % of the dose in five subjects; 56.9 % of the dose in one subject with incomplete feces collection suspected).

Conclusions

Sonidegib exhibited low absorption, was extensively distributed, and was slowly metabolized. Elimination of absorbed sonidegib occurred largely by oxidative and hydrolytic metabolism.

     

Disposition and metabolism of the food mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in rats

The disposition and metabolism of a common food mutagen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), was studied in rats. Five rats of both sexes were given a single oral dose of 14C-labeled MeIQx (3-4 mg/kg body wt). The male rats excreted 36% of the radioactivity and 15% of the mutagenic activity of the dose given in the urine collected during the first 24 h. In the females the corresponding urine contained 41% of the radioactivity and 12% of the mutagenicity. During the next 48 h only 1-3% of the radioactive dose was excreted in urine. The remaining dose was excreted in the feces except of less than 1% that was retained by the tissues after 72 h. The liver and kidney retained more radioactivity than other organs. In a separate study the metabolites of bile, urine and feces of both sexes were investigated. After a single oral dose of 20 mg 14C-labeled MeIQx/kg body wt, three major non-mutagenic metabolites were identified. These were 2-amino-4(or 5)-(beta-D-glucuronopyranosyloxy)-3,8-dimethylimidazo[4,5-f] quinoxaline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxalin-4(or 5)-yl sulfate and N-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl) sulfamate. Another two metabolites present in bile, urine and feces were 2-(beta-D-glucuronopyranosylamino)-3,8-dimethylimidazo[4,5-f ] quinoxaline and 2-amino-8-hydroxymethyl-3-methylimidazo[4,5-f]quinoxalin-4 (or 5)yl sulfate. All metabolites were essentially non-mutagenic. Most of the mutagenicity still present in bile, urine and feces could be explained by unchanged MeIQx. Unchanged MeIQx was the most abundant form excreted in urine.     

Radiation exposure of hemophiliacs after radiosynoviorthesis with 186Re colloid

Very limited data are available in the literature on the doses of unwanted radiation that patients receive following treatment with radiosynoviorthesis (RSO). OBJECTIVE: The aim of this study was to assess the radiation exposure after RSO with (186)Re colloid in hemophiliacs. METHODS: This study involved 12 hemophiliacs who were treated for hemophilic joint disease with 14 RSOs by using (186)Re colloid. Whole-body scintigrams were performed 1, 6, and 24 hours and 3 and 7 days after RSO. Measurements, using a whole-body counter, were done immediately after scintigraphy, with the treated joint protected with a lead shield. The cumulative activity of (186)Re in the body and in the lymph nodes was calculated. The distribution of (186)Re in the body was determined by using the values for small colloids as proposed by the International Commission on Radiological Protection (ICRP) Publication 53. The computer code, OLINDA/EXM (Vanderbilt University, Nashville, TN), was used for the calculation of the internal dose. A constant distance of 1 m between the ankle joint and body organs, and of 0.33 m between the elbow or shoulder joint and body organs, was used to calculate the contribution of gamma radiation to the effective radiation dose. RESULTS: The mean effective dose received by hemophiliacs after RSO with (186)Re colloid was 28 +/- 9 microSv/MBq of the activity injected into the joint. The patients received 0.8-3.7 mSv (1.9 +/- 0.8 mSv) owing to the leakage of (186)Re from the treated joint and its retention in the body. The highest doses were established in the spleen (26.0 +/- 10.7 mGy), the liver (17.6 +/- 7.2 mGy), and red marrow (3.0 +/- 0.8 mGy). The contribution of gamma radiation to the effective dose was less than 0.1 mSv in RSO of the ankle, 0.4 mSv in the elbow, and 0.6 mSv in the shoulder-joint treatment. The activity of (186)Re in the regional lymph nodes was noted in 4 of the 14 treatments. In these cases, the estimated average dose received by individual lymph nodes was 14.7 +/- 1.9 Gy. CONCLUSIONS: RSO with (186)Re colloid is a safe treatment method. The effective dose received by patients after RSO by using (186)Re colloid is low, as are the radiation doses to the most exposed organs. If (186)Re is retained in the regional lymph nodes, the lymph node radiation dose would be high.     

基于小鼠全身动态PET扫描估算16α-18F-17β-雌二醇的人体内辐射剂量

背景与目的：由小鼠全身动态PET显像数据获得药物在小鼠体内的生物分布,利用器官内剂量评估/指数模型分析软件(organ level inter dose assessment/exponential model,OLINDA/EXM)估算18F-fluo-roestradiol,18F-FES)在人体内的吸收剂量、全身有效剂量和有效剂量当量。方法：健康雌性KM小鼠尾静脉注射18F-FES后行160 min动态PET采集,经3D-OSEM/MAP算法重建获得PET图像。再行高分辨率CT显像,在PET/CT融合图像上,选取各脏器勾画感兴趣体积(volume of interest,VOI),获得相应时间-活度曲线和其曲线下面积、滞留时间、成年女性体模对应各器官的滞留时间。依据美国核医学会医用内照射剂量学委员会提出的内照射剂量计算方法(MIRD体系),利用OLINDA/EXM软件计算18F-FES在人体内的吸收剂量、全身有效剂量和有效剂量当量。最后所得数据与已公开发表计算18F-FES内照射剂量的文献数据行配对t检验,验证本文方法的有效性。结果：人体内胆囊壁、膀胱壁、小肠、上部大肠和肝脏的吸收剂量最高,分别为0.0725、0.0445、0.0430、0.0315和0.0282 mGy/MBq。大脑、皮肤、乳腺、心脏壁和甲状腺吸收剂量最低,分别为0.0052、0.0011、0.0012、0.0012和0.0013 mGy/MBq。对放射性敏感的器官如骨原细胞、胸腺和红骨髓的吸收剂量均较低,范围为0.0014~0.0218 mGy/MBq。全身平均吸收剂量为0.0147 mGy/MBq,全身有效剂量当量为0.0250 mGy/MBq,全身有效剂量为0.0190 mSv/MBq。对于常规注射185 MBq18F-FES,人体有效剂量为3.5150 mSv。与直接测量18F-FES在健康人体各主要脏器内吸收剂量的文献行配对t检验,差异无统计学意义(t=1.478,P=0.153)。结论：利用OLINDA/EXM软件根据小鼠全身动态PET/CT数据可有效估算18F-FES在人体内的吸收剂量和有效剂量。18F-FES可安全地用于人体,其有效剂量低于允许范围上限。该研究可为临床放心使用18F-FES提供依据。     

Fate and distribution of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats

Fischer 344 rats were given a single dose of 0.60 mg/animal of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by gavage; and radioactivity contained in feces, urine, blood, serum proteins, hemoglobin, and tissues was determined at 12, 24, 48 and 96 h after dosing. One major and four minor radioactivity-containing fractions were found in the urine and one major and two minor radioactivity-containing fractions were found in the feces. The feces was the major route of excretion, representing 78% of dose during the first 24 h, and unchanged PhIP in the feces accounted for 51% of the dose. Unmetabolized PhIP was also shown to be the major radioactive fraction in bile and feces from animals given a single dose by i.p. injection. Blood contained a small fraction of the dose and the major, persistently-bound form of PhIP in the blood was to hemoglobin. At 12 h after administration of the dose the colon and cecum contained the highest concentration of radioactivity, while at later times the kidney and liver showed the highest concentration. Of the tissue-contained radioactivity 80-90% was ethanol insoluble at time points later than 24 h, suggesting that it was covalently bound to macromolecules.     

Metabolism of 1-nitro[U-4,5,9,10-14C]pyrene in the F344 rat

1-Nitro[U-4,5,9,10-14C]pyrene was synthesized and administered to male F344 rats by intragastric gavage at a dose of 100 mg/kg of body weight. During the first 48 hr, 41% of the dose was eliminated in the feces, and 16% was eliminated in the urine. The corresponding figures after 120 hr were 51 and 19%. In rats with bile cannulae, 37% of the dose was excreted in the bile after 72 hr, and 6% was excreted in the urine. Fecal metabolites included 1-aminopyrene (isolated amount, 11.7% of the dose), 1-amino-6-hydroxypyrene and 1-amino-8-hydroxypyrene (4.6%), and unchanged 1-nitropyrene (6.6%). 1-Aminopyrene and the 1-aminohydroxypyrenes were identified as their acetyl-derivatives by comparison of their chromatographic retention times, mass spectra, and UV spectra to those of synthetic standards. Biliary metabolites included 1-aminopyrene, 1-amino-6-hydroxypyrene, 1-amino-8-hydroxypyrene, 1-nitro-6(8)-hydroxypyrene, and 1-nitro-3-hydroxypyrene, as well as their glucuronide and sulfate conjugates. The isolated amounts of these metabolites accounted for approximately 5% of the dose. 1-Amino-6-hydroxypyrene and 1-amino-8-hydroxypyrene and their glucuronide and sulfate conjugates were also tentatively identified in the urine and accounted for about 3% of the dose. Significant quantities of unidentified water soluble metabolites were present in the urine and bile. The results of this study indicate that metabolic reduction of the highly mutagenic 1-nitrohydroxypyrenes occurs in vivo in the rat and suggest that this is a possible activation pathway in 1-nitropyrene carcinogenesis.     

Metabolism of three radiolabeled pancreatic carcinogenic nitrosamines in hamsters and rats.

The in vivo metabolism and disposition of three radiolabeled N-nitrosamines which are carcinogenic for the pancreas of the hamster but not the rat have been examined. N-[1-14C]Nitrosobis(2-oxopropyl)amine (BOP), N-[1-14C]nitrosobis(2-hydroxypropyl)amine (BHP), and their suggested proximate pancreatic carcinogenic metabolite N-[1-14C]nitroso-(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) were metabolized and exhaled as 14CO2 to various extents somewhat proportional to their carcinogenic potency. More than 50% of the dose of BOP and HPOP was exhaled as 14CO2, whereas 26% of BHP was excreted this way, and 40% of BHP was excreted unchanged in the urine. Administered BOP was excreted to a small extent in the urine of both species as HPOP and BHP. No other nitrosamine metabolites were detected in urine. HPOP and BHP were detected in the pancreatic juice and bile of both species after administration of BOP and BHP. The results suggest that pancreatic ductular carcinogenesis in the hamster as a result of exposure to BOP is not due to secretion of carcinogenic metabolities in the pancreatic juice or reflux of bile containing nitrosamine metabolites into the ducts. Carcinogen metabolic activation appears to be by an oxidative pathway.     

Distribution and metabolism of the natural anticarcinogen phenethyl isothiocyanate in A/J mice

The distribution and metabolism of phenethyl isothiocyanate (PEITC), a naturally occurring anticarcinogen, was investigated in A/J mice. Mice were administered 5 mumol of [14C]PEITC (2 microCi/mouse) by gavage and killed at 1, 2, 4, 8, 24, 48 or 72 h after dosing. Radioactivity present in the spleen, heart, liver, lung, kidney, brain, urine and feces was measured. Lung, the target tissue of PEITC inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) lung tumorigenesis, showed maximum radioactivity between 4 and 8 h after dosing, suggesting this time period would be optimal for maximal inhibition by PEITC in A/J mice. Approximately 50% of the total radioactivity was excreted within 24 h after dosing with nearly 80% of radioactivity found in urine and feces at 72 h. Two metabolites were isolated by reverse-phase HPLC from urine of mice treated with PEITC. The identities of these metabolites were determined by comparison with synthetic standards and by NMR and MS. The major metabolite was a cyclic mercaptopyruvic acid conjugate, whereas the minor metabolite was an N-acetylcysteine conjugate. Approximately 25% of the administered dose of PEITC was excreted as the cyclic mercaptopyruvic acid conjugate and 10% as the N-acetylcysteine conjugate. These results suggest that urinary metabolites of PEITC may provide potentially useful dosimeters for this natural anticarcinogen.     

Systemic absorption of 3H-fenticonazole after vaginal administration of 1 gram in patients

Fourteen women, five with normal cervicovaginal mucosa (Group 1), five with cervical carcinoma (Group 2) and four with relapsing vulvovaginal candidiasis (Group 3) were enrolled and completed this open clinical trial. Each subject received a single dose of 1.82 +/- 0.3 g on average of vaginal paste (for ovules) containing about 1000 mg of 3H-fenticonazole nitrate (266 microCi). Twelve hours after vaginal administration, the paste was removed by vaginal washing. Blood, urine and stool samples were collected at specified time intervals for five days. Plasma, urine, stools and all used material in contact with the paste were assayed for radioactivity. No measurable levels of radioactivity were detected in plasma of subjects of Groups 1 and 3 while in 4 of the 5 subjects with cervical carcinoma (Group 2) fenticonazole was detected during the 24 h after administration with a peak level at about 8 hours. For a period of 5 days, 0.4-1.5% of the dose on average was recovered from urine, and 0.18-0.32% from feces. Based on the excretion data, the extent of vaginal absorption of fenticonazole nitrate in women with vulvovaginal candidiasis was 1.81 +/- 0.57% of the dose, while in women with normal cervicovaginal mucosa it accounted for 0.58 +/- 0.28% of the administered dose. In patients with cervical carcinoma, absorption was 1.12 +/- 0.53%. The maximum amount absorbed corresponds to an exposure of about 0.4 mg/kg of fenticonazole nitrate (for a subject weighing 50 kg). Consequently, the vaginal administration of one ovule containing 1000 mg of fenticonazole nitrate seems to be devoid of risk for patients.     

Pharmacokinetic investigation of imatinib using accelerator mass spectrometry in patients with chronic myeloid leukemia.

PURPOSE: To investigate the potential use of accelerator mass spectrometry (AMS) in the study of the clinical pharmacology of imatinib. EXPERIMENTAL DESIGN: Six patients who were receiving imatinib (400 mg/d) as part of their ongoing treatment for chronic myeloid leukemia (CML) received a dose containing a trace quantity (13.6 kBq) of (14)C-imatinib. Blood samples were collected from patients before and at various times up to 72 h after administration of the test dose and were processed to provide samples of plasma and peripheral blood lymphocytes (PBL). Samples were analyzed by AMS, with chromatographic separation of parent compound from metabolites. In addition, plasma samples were analyzed by liquid chromatography/mass spectrometry (LCMS). RESULTS: Analysis of the AMS data indicated that imatinib was rapidly absorbed and could be detected in plasma up to 72 h after administration. Imatinib was also detectable in PBL at 24 h after administration of the (14)C-labeled dose. Comparison of plasma concentrations determined by AMS with those derived by LCMS analysis gave similar average estimates of area under plasma concentration time curve (26 +/- 3 versus 27 +/- 11 microg/mL.h), but with some variation within each individual. CONCLUSIONS: Using this technique, data were obtained in a small number of patients on the pharmacokinetics of a single dose of imatinib in the context of chronic dosing, which could shed light on possible pharmacologic causes of resistance to imatinib in CML.     

Fate and distribution of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in mice at a human dietary equivalent dose.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine rodent carcinogen that is found at the ppb level in cooked meat. Most laboratory studies are at 10(4)-10(7)-fold greater concentrations than actual ingested human doses. We report the first study of the bioavailability and fate of this heterocyclic amine at a human dietary equivalent dose using the high sensitivity offered by accelerator mass spectrometry. [2-14C]PhIP was administered to C57BL/6 male mice (41 ng/kg) by gavage. Tissues and excreta were collected over the subsequent 96 h. One hundred % of the administered dose was excreted in urine (90%) and feces (10%) over the length of the study. Absorption of the radiocarbon-tagged PhIP from the gastrointestinal tract was rapid, with radiocarbon levels peaking in the whole blood and urine within 1 h of exposure. Fecal 14C levels peaked at 12 h. Tissue levels peaked by 3 h with the highest concentrations of radiolabel in the intestine, stomach, and liver, followed by the kidney, pancreas, lung, and spleen. Low levels of 14C from PhIP (0.01-0.04% of the administered dose) could be detected in the tissues 48-96 h after exposure, possibly due to covalent binding to protein or DNA. The calculated half-life of PhIP at this dose was 1.14 h. This study is the first example of how accelerator mass spectrometry can be used to gather biological information about carcinogenic compounds at environmental levels of exposure.     

Autoradiography of [14C]N-nitrosodiethanolamine in Sprague-Dawley rats

Whole-body autoradiography in Sprague-Dawley rats injected i.v. with [14C]N-nitrosodiethanolamine ([14C]NDELA) showed a localization of tissue-bound radioactivity in the liver and the nasal olfactory mucosa. Microautoradiography of the nasal olfactory mucosa showed the highest labelling over the subepithelial glands (Bowman's glands) in the lamina propria mucosae. Experiments in vitro showed a capacity of the liver and the nasal mucosa to form 14CO2 from the [14C]NDELA. Most of the injected [14C]NDELA was recovered in the urine in a non-metabolized form. A small proportion of the dose was exhaled as 14CO2. The target tissues for the NDELA carcinogenesis in Sprague-Dawley rats are the liver and the nasal mucosa. Our results indicate that a bioactivation of the NDELA will take place in the nasal mucosa, as well as in the liver.     

A mass balance and disposition study of the DNA methyltransferase inhibitor zebularine (NSC 309132) and three of its metabolites in mice.

PURPOSE: To elucidate the in vivo metabolic fate of zebularine (NSC 309132), a DNA methyltransferase inhibitor proposed for clinical evaluation in the treatment of cancer. EXPERIMENTAL DESIGN: Male, CD(2)F(1) mice were dosed i.v. with 100 mg/kg 2-[(14)C]zebularine. At specified times between 5 and 1,440 minutes, mice were euthanized. Plasma, organs, carcass, urine, and feces were collected and assayed for total radioactivity. Plasma and urine were also analyzed for zebularine and its metabolites with a previously validated high-pressure liquid chromatography assay. A similar experiment was done with 2-[(14)C]uridine, the proposed primary metabolite of zebularine. RESULTS: Maximum plasma concentrations were 462, 306, 33.6, 21.7, and 11.5 mumol/L for total radioactivity, zebularine, uridine, uracil (each at 5 minutes), and dihydrouracil (at 15 minutes), respectively. Total radioactivity, zebularine, uridine, uracil, and dihydrouracil were rapidly eliminated from plasma, and after 45 minutes, none of the individual compounds could be quantitated by high-pressure liquid chromatography. Plasma data were consistent with sequential conversion of zebularine to uridine, uracil, and dihydrouracil. 2-Pyrimidinone was not observed. Prolonged retention of radioactivity, at concentrations higher than in plasma, was observed in tissues. Recovery of given radioactivity in urine (30.3% of dose), feces (0.4% of dose), cage wash (7.9% of dose), and tissues and carcass (6.1% of dose) after 24 hours implied that up to 55% of radioactivity was expired as (14)CO(2). Comparison of zebularine and uridine pharmacokinetic data indicated that approximately 40% of the zebularine dose was converted to uridine. CONCLUSIONS: Zebularine is extensively and rapidly metabolized into endogenous compounds that are unlikely to have effects at the concentrations observed.     

Feasibility of synchronization of real-time tumor-tracking radiotherapy and intensity-modulated radiotherapy from viewpoint of excessive dose from fluoroscopy

PURPOSE: Synchronization of the techniques in real-time tumor-tracking radiotherapy (RTRT) and intensity-modulated RT (IMRT) is expected to be useful for the treatment of tumors in motion. Our goal was to estimate the feasibility of the synchronization from the viewpoint of excessive dose resulting from the use of fluoroscopy. METHODS AND MATERIALS: Using an ionization chamber for diagnostic X-rays, we measured the air kerma rate, surface dose with backscatter, and dose distribution in depth in a solid phantom from a fluoroscopic RTRT system. A nominal 50-120 kilovoltage peak (kVp) of X-ray energy and a nominal 1-4 ms of pulse width were used in the measurements. RESULTS: The mean +/- SD air kerma rate from one fluoroscope was 238.8 +/- 0.54 mGy/h for a nominal pulse width of 2.0 ms and nominal 100 kVp of X-ray energy at the isocenter of the linear accelerator. The air kerma rate increased steeply with the increase in the X-ray beam energy. The surface dose was 28-980 mGy/h. The absorbed dose at a 5.0-cm depth in the phantom was 37-58% of the peak dose. The estimated skin surface dose from one fluoroscope in RTRT was 29-1182 mGy/h and was strongly dependent on the kilovoltage peak and pulse width of the fluoroscope and slightly dependent on the distance between the skin and isocenter. CONCLUSION: The skin surface dose and absorbed depth dose resulting from fluoroscopy during RTRT can be significant if RTRT is synchronized with IMRT using a multileaf collimator. Precise estimation of the absorbed dose from fluoroscopy during RT and approaches to reduce the amount of exposure are mandatory.     

In vivo human metabolism of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

To better understand the interactions of the pathways of activation and detoxification on the metabolism of the putative carcinogen, PhIP, we administered a dose of 70-84 microg [2-14C] PhIP (17.5 [microCi 14C) 48-72 h before scheduled colon surgery. Blood and urine collected for the next 48-72 h was evaluated by linear accelerator mass spectroscopy (AMS) and scintillation counting LC-MS to identify specific PhIP metabolites. The thermostable phenol sulfotransferase (SULT1A1) phenotype was correlated with the 4'-PhIP-SO4 levels in the urine at 0-4 h (R = 0.86, P = 0.059). The CYP1A2 activity had a negative correlation with PhIP serum levels at 1 h (R = 0.94, P = 0.06) and a positive correlation with urine N-OH-PhIP levels at 0-4 h (R = 0.85, P = 0.15). This low level radioisotope method of determining the influence of phenotype on metabolism will significantly improve our understanding of the interrelationships of these pathways and provide a critical foundation for the development of individual risk assessment.     

Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors

Purpose

This study investigated the metabolism and excretion of dovitinib (TKI258), a tyrosine kinase inhibitor that inhibits fibroblast, vascular endothelial, and platelet-derived growth factor receptors, in patients with advanced solid tumors.

Methods

Four patients (cohort 1) received a single 500 mg oral dose of ¹⁴C-dovitinib, followed by the collection of blood, urine, and feces for ≤10?days. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of dovitinib by liquid chromatography–tandem mass spectrometry. Both techniques were applied for metabolite profiling and identification. A continuous-dosing extension phase (nonlabeled dovitinib 400?mg daily) was conducted with the 3 patients from cohort 1 and 9 additional patients from cohort 2.

Results

The majority of radioactivity was recovered in feces (mean 61?%; range 52–69?%), as compared with urine (mean 16?%; range 13–21?%). Only 6–19?% of the radioactivity was recovered in feces as unchanged dovitinib, suggesting high oral absorption. ¹⁴C-dovitinib was eliminated predominantly via oxidative metabolism, with prominent primary biotransformations including hydroxylation on the fluorobenzyl ring and N-oxidation and carbon oxidation on the methylpiperazine moiety. Dovitinib was the most prominent radioactive component in plasma. The high apparent volume of distribution (2,160 L) may indicate that dovitinib distributes extensively to tissues. Adverse events were predominantly mild to moderate, and most common events included nausea, vomiting, constipation, diarrhea, and fatigue.

Conclusions

Dovitinib was well absorbed, extensively distributed, and eliminated mainly by oxidative metabolism, followed by excretion, predominantly in feces. The adverse events were as expected for this class of drug.