Radioactivity In Urine Research Articles

Systemic iodine 125 activity after GliaSite brachytherapy: Safety considerations

Purpose After contaminated radioactive linens were detected on the completion of intracranial brachytherapy for a patient episodically incontinent of urine, the systemic absorption of iodine 125 from the GliaSite Radiation Therapy System was studied. Diffusion and leakage of 125I through the walls of the GliaSite balloon catheter have previously been reported to be negligible in both animal and human studies examining the radioactivity of urine during and after treatment. Our study estimated total systemic absorption based on activity defect measurements rather than using urinary excretion as a surrogate. Methods and materials Six patients treated with complete data were reviewed. The activity at the time of injection was compared to the activity recovered on completion of treatment after adjustment for decay. Results By comparing the activity of 125I infused with the activity recovered, 0.5–5.5% of infused 125I remained unaccounted after adjusting for decay over the 4-day treatment period. The patient with contaminated hospital linens due to urinary incontinence had unaccounted activity of 2.3%. Comparisons of the volume of liquid 125I and saline removed on completion to treatment to the volume originally instilled revealed no difference using hand-held syringes. Conclusions The systemic absorption of 125I is much greater than previously appreciated with potential clinical sequelae and safety concerns. GliaSite should be used with caution in patients incontinent of urine, and a Foley catheter should be placed to collect contaminated urine for incontinent patients.

Pharmacokinetics of Plerixafor (AMD3100) in Volunteers with Renal Impairment.

Introduction: Plerixafor (AMD3100) is a first-in-class, small molecule inhibitor of the CXCR4 chemokine receptor that blocks binding of its cognate ligand, SDF-1α. In clinical studies conducted in non-Hodgkin's lymphoma and multiple myeloma patients, plerixafor when used with G-CSF was shown to be safe and effective in mobilizing CD34+ cells for autologous hematopoietic stem cell transplantation. Non-clinical studies conducted using radiolabeled plerixafor have shown 60-70% recovery of total radioactivity in urine within 24 hours after subcutaneous (SQ) administration. Based on this observation, we hypothesized that plerixafor clearance from plasma is likely to be reduced in patients with impaired renal function, which is commonly observed in multiple myeloma patients. The purpose of this study was to determine the pharmacokinetic parameters of plerixafor in subjects with renal impairment.Methods: This open-label study examined the pharmacokinetics of a single 240 mcg/kg SQ dose of plerixafor in subjects with varying degrees of renal impairment. Otherwise healthy subjects of normal weight and liver function, not requiring kidney dialysis, were classified into 4 groups of varying renal function, based on 24 hour creatinine clearance collected within 2 weeks prior to plerixafor administration. Approximately 6 subjects are to be enrolled into each group. Serial blood and urine samples were collected over a 24 hour period for analysis of plerixafor concentration using a validated LC-MS method. Plerixafor pharmacokinetics were characterized using noncompartmental methods.Results: Data were available from 18 subjects (aged 36–74 years) at the time this abstract was prepared. Pharmacokinetic parameters from available subjects are summarized in Table 1.Plerixafor clearance was dependent upon renal function. A statistically significant correlation between decreasing renal function, as determined by creatinine clearance, and reduced plerixafor clearance was observed, p < 0.001. Median clearance values were reduced from 3.96 L/hr in control subjects to 1.65 L/hr in subjects with severe renal impairment. A corresponding increase in half-life was observed from 4.7 hours in control subjects to 12.5 hours in subjects with severe renal impairment. No significant change in Cmax was observed across the groups, with time to Cmax observed at the 0.5 or 1 hour sampling time points in all subjects.Conclusions: These preliminary findings indicate a correlation between decreasing renal function and reduced plerixafor clearance from plasma. While peak exposures to plerixafor were apparently independent of renal function, total drug exposure over time was dependent on renal function. Preliminary review of the available results suggests that dose reduction of plerixafor may be warranted in patients with moderately to severely impaired renal function.Pharmacokinetic Parameters1CohortCrCl (mL/min)Cmax(ng/mL)AUC0-24h(ng*hr/mL)t1/2(hr)CLCR(L/hr)Control (n=6)136 (107-455)895 (812-1260)5089 (3886-6218)4.7 (4.3-5.7)3.96 (3.65-5.63)Mild (n=2)73 (71-74)738 (705-770)5563 (4580-6545)7.1 (6.0-8.2)3.09 (2.51-3.66)Moderate (n=6)41 (31-51)964 (559-1270)7096 (4661-8388)11.1 (8.8-15.0)2.03 (1.67-4.74)Severe (n=4)11 (9-14)781 (609-1140)7840 (5807-8010)12.5 (12.1-22.0)1.65 (1.59-1.80)1values shown are median (range)

Reductive Isoxazole Ring Opening of the Anticoagulant Razaxaban Is the Major Metabolic Clearance Pathway in Rats and Dogs

Razaxaban is a selective, potent, and orally bioavailable inhibitor of coagulation factor Xa. The molecule contains a 1,2-benzisoxazole structure. After oral administration of [(14)C]razaxaban to intact and bile duct-cannulated rats (300 mg/kg) and dogs (20 mg/kg), metabolism followed by biliary excretion was the major elimination pathway in both species, accounting for 34 to 44% of the dose, whereas urinary excretion accounted for 3 to 13% of the dose. Chromatographic separation of radioactivity in urine, bile, and feces of rats and dogs showed that razaxaban was extensively metabolized in both species. Metabolites were identified on the basis of liquid chromatography/tandem mass spectrometry and comparison with synthetic standards. Among the 12 metabolites identified, formation of an isoxazole-ring opened benzamidine metabolite (M1) represented a major metabolic pathway of razaxaban in rats and dogs. However, razaxaban was the major circulating drug-related component (>70%) in both species, and M1, M4, and M7 were minor circulating components. In addition to the in vivo observations, M1 was formed as the primary metabolite in rat and dog hepatocytes and in the rat liver cytosolic fraction. The formation of M1 in the rat liver fraction required the presence of NADH. Theses results suggest that isoxazole ring reduction, forming a stable benzamidine metabolite (M1), represents the primary metabolic pathway of razaxaban in vivo and in vitro. The reduction reaction was catalyzed by NADH-dependent reductase(s) in the liver and possibly by intestinal microflora on the basis of the recovery of M1 in feces of bile duct-cannulated rats.

Pharmacokinetics and Metabolism of 14C-Brivaracetam, a Novel SV2A Ligand, in Healthy Subjects

This study was designed to investigate the human absorption, disposition, and mass balance of (14)C-brivaracetam, a novel high affinity SV2A ligand with potent anticonvulsant activity. Six healthy male subjects received a single p.o. dose of (14)C-brivaracetam (150 mg, 82 microCi, or 3.03 MBq). Serial blood and complete urine and feces were collected until 144 h postdose. Expired air samples were obtained until 24 h. Brivaracetam was rapidly absorbed, with C(max) of 4 mug/ml occurring within 1.5 h of dosing. Unchanged brivaracetam amounted to 90% of the total plasma radioactivity, suggesting a modest first-pass effect. Plasma protein binding of radioactivity was low (17.5%). Urinary excretion exceeded 90% after 2 days, and the final mass balance reached 96.8% of the radioactivity in urine and 0.7% in feces. Only 8.6% of the radioactive dose was recovered in urine as unchanged brivaracetam, the remainder being identified as non-cytochrome P450 (P450)- and P450-dependent biotransformation products resulting from hydrolysis of the amide moiety (M9, 34.2%), hydroxylation of the n-propyl side chain (M1b, 15.9%), and a combination of these two pathways leading to the hydroxy acid (M4b, 15.2%). Minor amounts of taurine and glucuronic acid conjugates and other oxidized derivatives were also identified. Brivaracetam is completely absorbed, is weakly bound to plasma proteins, extensively biotransformed through several metabolic pathways, and eliminated renally.

Biotransformation and mass balance of tipranavir, a nonpeptidic protease inhibitor, when co-administered with ritonavir in Sprague-Dawley rats

In this study, tipranavir (TPV) biotransformation and disposition when co-administered with ritonavir (RTV) were characterized in Sprague-Dawley rats. Rats were administered a single intravenous (5 mg kg(-1)) or oral (10 mg kg(-1)) dose of [(14)C]TPV with co-administration of RTV (10 mg kg(-1)). Blood, urine, faeces and bile samples were collected at specified time-points over a period of 168 h. Absorption of TPV-related radioactivity ranged from 53.2-59.6%. Faecal excretion was on average 86.7% and 82.4% (intravenous) and 75.0% and 82.0% (oral) of dosed radioactivity in males and females, respectively. Urinary excretion was on average 4.06% and 6.73% (intravenous) and 9.71% and 8.28% (oral) of dosed radioactivity in males and females, respectively. In bile-duct-cannulated rats, 39.8% of the dose was recovered in bile. After oral administration, unchanged TPV accounted for the majority of the radioactivity in plasma (85.7-96.3%), faeces (71.8-80.1%) and urine (33.3-62.3%). The most abundant metabolite in faeces was an oxidation metabolite R-2 (5.9-7.4% of faecal radioactivity, 4.4-6.1% of dose). In urine, no single metabolite was found to be significant, and comprised <1% of dose. TPV when co-administered with RTV to rats was mainly excreted in feces via bile and the parent compound was the major component in plasma and faeces.

Absorption, metabolism, and excretion of 14C gimatecan (LBQ707) after oral administration in patients with advanced cancer

2564 Background: Gimatecan (Gim), a new potent oral topoisomerase I inhibitor is a lipophilic 7-oxyiminomethyl derivative of camptothecin. Its in vitro cytoxicity is more sustained than CPT-11 and topotecan, it has excellent anti-tumor activity in mouse xenografts, and shown good tolerability with Ph I activity. The study aim was to profile its disposition in cancer patients. Methods: 4 patients with advanced cancer received a single oral 1.5 mg dose of [14C] Gim (60 μCi) followed by standard Gim treatment on Day 15. Whole blood, plasma, urine, and feces were collected over 7 days with spot fecal collections up to Day 19. Total radioactivity was measured by liquid scintillation counting. Gim and metabolite concentrations in plasma and excreta were measured by LC- MS/MS and HPLC with radiometric detection. Results: Gim showed a rapid first-order absorption and a long elimination phase and was well tolerated. The median (range) Tmax for Gim was 1 h (0.5 to 3 h) and mean t1/2 and oral clearance values were 91 h and 0.6 L/h, respectively. Gim was the major moiety and its active metabolite LCF775 (t-butyl-mono-hydroxy Gim) was the main metabolite (albeit minor, 2–9%) in plasma. Trace glucuronide and sulfate metabolites were also detected in plasma. Mean recovery of radioactivity in urine (0-Day 7) and feces (0-Day 11) was 70.5 % (56.2–80.0%) of the dose. Incomplete recovery is attributed to opiates use in 2 patients and incomplete (sporadic) fecal sampling at later timepoints. Fecal excretion (0-Day 11) was prolonged and major in 3/4 patients (46- 73% of the dose, of which 14–23% is the unchanged Gim suggesting the drug is well absorbed). An additional 1.3–3.5% was recovered in spot collections (Days 14, 15 and 19). Urine excretion (0-Day 7) was 7.2–10.3% of the dose in 3 patients, one patient (cachectic, on opiates) excreted only 21% in feces and 46% in urine. Gim and several Gim metabolites (and glucuronide conjugates thereof) were the major components in excreta. Conclusions: Gim and its minor metabolite, LCF775 were the principal pharmacologically active components in plasma. Fecal excretion is the main elimination pathway in most patients. A long half-life (90hr) of Gim, uncomplicated metabolism, and good oral absorption make Gim an attractive candidate for Ph II development. [Table: see text]

Steady-State Disposition of the Nonpeptidic Protease Inhibitor Tipranavir when Coadministered with Ritonavir

The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 microCi of [(14)C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. Blood, urine, and feces were collected for mass balance and metabolite profiling. Metabolite profiling and identification was performed using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The median recovery of radioactivity was 87.1%, with 82.3% of the total recovered radioactivity excreted in the feces and less than 5% recovered from urine. Most radioactivity was excreted within 24 to 96 h after the dose of [(14)C]TPV. Radioactivity in blood was associated primarily with plasma rather than red blood cells. Unchanged TPV accounted for 98.4 to 99.7% of plasma radioactivity. Similarly, the most common form of radioactivity excreted in feces was unchanged TPV, accounting for a mean of 79.9% of fecal radioactivity. The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. In conclusion, after the coadministration of TPV and RTV, unchanged TPV represented the primary form of circulating and excreted TPV and the primary extraction route was via the feces.

Metabolism and excretion of CP-122,721, a non-peptide antagonist of the neurokinin NK1 receptor, in dogs: Identification of the novel cleaved product 5-trifluoromethoxy salicylic acid in plasma

The metabolism and excretion of a potent and selective substance P receptor antagonist, CP-122,721, have been studied in beagle dogs following oral administration of a single 5 mg kg−1 dose of [14C]CP-122,721. Total recovery of the administered dose was on average 89% for male dogs and 95% for female dogs. Approximately 94% of the radioactivity recovered in urine and feces was excreted in the first 72 h. Male bile duct-cannulated dogs excreted a mean of ∼56% of the dose in bile, ∼11% in feces, and ∼25% in urine. The sum of radioactivity in bile and urine indicates >80% of the [14C]CP-122,721-derived radioactivity was absorbed by the gastrointestinal tract. CP-122,721 was extensively metabolized in dogs, and only a small amount of parent CP-122,721 was excreted as unchanged drug. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or feces. The major metabolic pathways of CP-122,721 were O-demethylation, aromatic hydroxylation, and indirect glucuronidation. The minor metabolic pathways included: Aliphatic oxidation at the piperidine moiety, O-dealkylation of the trifluoromethoxy group, and N-dealkylation with subsequent sulfation and/or oxidative deamination. In addition, the novel cleaved product 5-trifluoromethoxy salicylic acid (TFMSA) was identified in plasma. These results suggest that dog is the most relevant animal species in which the metabolism of CP-122,721 can be studied for extrapolating the results to humans.

Metabolism, Pharmacokinetics, and Excretion of a Nonpeptidic Substance P Receptor Antagonist, Ezlopitant, in Normal Healthy Male Volunteers: Characterization of Polar Metabolites by Chemical Derivatization with Dansyl Chloride

The excretion, biotransformation, and pharmacokinetics of ezlopitant [(2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-yl)-(5-isopropyl-2-methoxy-benzyl)-amine], a substance P receptor antagonist, were investigated in healthy male volunteers after oral administration of a single 200-mg (approximately 93 microCi/subject) dose of [(14)C]ezlopitant. The total recovery of administered radioactive dose was 82.8 +/- 5.1, with 32.0 +/- 4.2% in the urine and 50.8 +/- 1.4% in the feces. Mean observed maximal serum concentrations for ezlopitant and total radioactivity were achieved at approximately 2 h after oral administration; thus, ezlopitant was rapidly absorbed. Ezlopitant was extensively metabolized in humans, since no unchanged drug was detected in urine and feces. The major pathway of ezlopitant in humans was the result of the oxidation of the isopropyl side chain to form the omega-hydroxy and omega-1-hydroxy (M16) metabolites. M16 and omega,omega-1-dihydroxy (1,2-dihydroxy, M12) were identified as the major circulating metabolites accounting for 64.6 and 15.4% of total circulating radioactivity, respectively. In feces, the major metabolite M14 was characterized as the propionic acid metabolite and formed by further oxidation of the omega-hydroxy metabolite. The urinary metabolites were the result of cleaved metabolites caused by oxidative dealkylation of the 2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-yl moiety. The metabolites (M1A, M1B, and M4), approximately 34% of the total radioactivity in urine, were identified as benzyl amine derivatives. These were polar metabolites that were further characterized using the reaction with dansyl chloride to derivatize the primary amines and phenol moieties to less polar analytes. The other metabolites were the result of O-demethylation, dehydrogenation of the isopropyl group, and oxidation on the quinuclidine moiety.

Why isd-serine nephrotoxic and α-aminoisobutyric acid protective?

D-Serine selectively causes necrosis of S(3) segments of proximal tubules in rats. This leads to aminoaciduria and glucosuria. Coinjection of the nonmetabolizable amino acid alpha-aminoisobutyric acid (AIB) prevents the tubulopathy. D-serine is selectively reabsorbed in S(3), thereby gaining access to peroxisomal D-amino acid oxidase (D-AAO). D-AAO-mediated metabolism produces reactive oxygen species. We determined the fractional excretion of amino acids and glucose in rats after intraperitoneal injection of d-serine alone or together with reduced glutathione (GSH) or AIB. Both compounds prevented the hyperaminoaciduria. We measured GSH concentrations in renal tissue before (control) and after D-serine injection and found that GSH levels decreased to approximately 30% of control. This decrease was prevented when equimolar GSH was coinjected with D-serine. To find out why AIB protected the tubule from D-serine toxicity, we microinfused D-[(14)C]serine or [(14)C]AIB (0.36 mmol/l) together with [(3)H]inulin in late proximal tubules in vivo and measured the radioactivity in the final urine. Fractional reabsorption of D-[(14)C]serine and [(14)C]AIB amounted to 55 and 70%, respectively, and 80 mmol/l of AIB or D-serine mutually prevented reabsorption to a great extent. D-AAO activity measured in vitro (using D-serine as substrate) was not influenced by a 10-fold higher AIB concentration. We conclude from these results that 1) D-AAO-mediated d-serine metabolism lowers renal GSH concentrations and thereby provokes tubular damage because reduction of reactive oxygen species by GSH is diminished and 2) AIB prevents d-serine-induced tubulopathy by inhibition of D-serine uptake in S(3) segments rather than by interfering with intracellular D-AAO-mediated D-serine metabolism.

Nuclear imaging of neuroendocrine tumours

The diagnosis of neuroendocrine tumours (NETs) and monitoring of therapy in many patients relies mainly on morphological imaging techniques such as computed tomography (CT), ultrasound (US) and magnetic resonance imaging (MRI). However, functional imaging modalities--such as somatostatin receptor scintigraphy (SRS)--have great impact on patient management by providing tools for better staging of the disease, visualization of occult tumour, and evaluation of eligibility for somatostatin analogue treatment. Positron emission tomography (PET) using (18)F-fluoro-deoxy-glucose (FDG) is a powerful functional modality for oncological imaging. Unfortunately, FDG is not accumulated in NETs except in the case of dedifferentiated tumours and tumours with high proliferative activity. Based on the concept of amine precursor uptake and decarboxylation (APUD), the (18)F- and (11)C-labelled amine precursors L-dihydroxyphenylalanine and 5-hydroxy-L-tryptophan (5-HTP) have been utilized for PET imaging of NETs. In comparative studies of patients with a variety of NETs, (11)C5-HTP-PET proved better than CT and SRS by visualizing additional small lesions. With carbidopa premedication orally before (11)C5-HTP-PET examination the tumour uptake could be increased and the urinary radioactivity concentration considerably reduced. This concept may also be applied to (18)F-L-DOPA-PET, a method which in a limited number of studies has gained additional diagnostic information in NET patients compared to SRS and morphological imaging. (68)Ga is available from an in-house generator and has been utilized for labelling of somatostatin analogues for PET imaging of NETs with promising results in a small number of patients. However, SRS is an established functional imaging method for patients with NETs, whereas the role for PET in the clinical routine needs further evaluation in comparative studies in larger groups of patients.

Noninvasive monitoring of ovarian endocrine activity in the chinchilla ( Chinchilla lanigera)

Reproductive endocrinology information is limited for Chinchilla lanigera, a South American species characterized by extremely long gestation and estrus cycle compared with others rodents. This study was designed to validate a non-invasive technique for monitoring ovarian endocrine activity. Animals were exposed indoors to natural photoperiod (31°S–64°W, Argentina); temperature range: 17–26 °C, with food and water ad libitum. Radiolabelled infusion ( n = 4): 3H-estradiol ( 3H-E 2) and 14C-progesterone ( 14C-P 4) were injected (i.p). Biochemical validation: HPLC-UV detector was employed to determine natural steroids in urine and fecal extracts and to determine immunoreactive metabolites. Physiological validation: (1) pregnancy ( n = 5): body weight and urinary and fecal steroidal metabolites were measured until birth; (2) Seasonality ( n = 9): urine and feces were collected in May, August, November, and February. Total 3H-E 2 and 14C-P 4 radioactivity recovered was 60.5 ± 15.5 and 74.5 ± 19.4%, respectively. After 3H-E 2 injection, urinary radioactivity peaked at 7.0 ± 0.6 hr; in contrast, urinary 14C-P 4 excretion peaked at 44.0 ± 4.0 hr ( p = 0.000). Peak radioactivity in feces occurred between 24–48 hr for both hormones. Several correlations were detected during pregnancy between body weight vs. urinary progestagens/day ( r = 0.44, p < 0.03); vs. urinary progestagens/creatinine ( r = 0.73, p = 2.9 × 10 −5); vs. urinary estrogens/day ( r = 0.74; p < 0.2); and vs. urinary estrogens/creatinine ( r = 0.74; p < 2.0 × 10 −5). On the other hand, urinary and fecal progestagen excretion exhibited significant seasonal fluctuations and urinary estrogen concentrations showed a similar pattern ( p = 0.062 for winter–spring vs. summer–autumn). This methodology proved to be useful for monitoring ovary endocrine activity in urine of chinchilla female.

THE EVALUATION OF RADIOLABELED ARTESUNATE ON TISSUE DISTRIBUTION IN RATS AND PROTEIN BINDING IN HUMANS

The present study reports the tissue distribution, pharmacokinetics, mass balance, and elimination of [(14)C] artesunate (AS) following single intravenous administration in rats. Protein binding was performed with rat and human plasma. Radioactivity and drug levels in blood, plasma, tissues, urine, and feces up to 192 hours were collected and measured. The mean terminal half-life of plasma (76 h) and blood (105 h) radioactivity was prolonged compared with that of unchanged AS (0.43 h) and dihydroartemisinin (0.75 h), an active metabolite of AS. Drug was widely distributed after 1 hour in select tissues. After 24 hours, the radioactivity rapidly declined in all tissues except spleen until 96 hours. Only 1% of total radioactivity was detected in brain tissue. AS revealed a higher binding capacity with human and rat plasma proteins (73-81%). The radioactivity in whole blood was higher (two to fourfold) than that in plasma throughout the period of the treatment, suggesting that AS binding to RBCs may relate to its powerful antimalarial activity.

Effect of Sodium [36Cl]Chlorate Dose on Total Radioactive Residues and Residues of Parent Chlorate in Growing Swine

An experimental chlorate-based product has been shown to be efficacious in eliminating economically important, Gram-negative human pathogens in the gastrointestinal tracts of food animals. Prior to the commercial marketing of such a product, the magnitude and chemical nature of residues remaining in edible tissues must be determined. Thus, the objective of this study was to determine the tissue distribution and elimination of sodium [36Cl]chlorate in orally dosed swine. Three sets of pigs, each consisting of a barrow and a gilt, were orally dosed with a total of 20, 40, or 60 mg of sodium [36Cl]chlorate per kg body weight via the drinking water. Urine and feces were collected throughout the 30 h study. Twenty-four hours after the last exposure to [36Cl]chlorate, each pig was harvested and both edible and inedible tissues were collected. Urine and tissue samples were analyzed for total radioactive residues and for chlorate metabolites. Elimination of radioactivity in urine averaged 81.6, 83.7, and 83.9% of the total dose for the low, medium, and high doses, respectively. Fecal elimination of radioactivity averaged 1.1% of the dosed radiochlorine across all doses. Parent chlorate always represented greater than 97.4% of the urinary radiochlorine with the remaining radiochlorine being excreted as chloride ion. Chlorate represented 39-77% of fecal radioactivity, depending upon dose. Chlorate concentrations in edible tissues ranged from 0.01 to 0.49 ppm, with residues in liver and skeletal muscle generally lower than those in kidney and adipose tissue. Chlorate residues were concentrated in thyroid tissues (7.7-25.4 ppm) relative to edible tissues. No evidence for the presence of chlorite was observed in excreta or in tissues. Results of this study suggest that further development of chlorate as a preharvest food safety tool in swine merits consideration.

A Mass Balance and Disposition Study of the DNA Methyltransferase Inhibitor Zebularine (NSC 309132) and Three of Its Metabolites in Mice

To elucidate the in vivo metabolic fate of zebularine (NSC 309132), a DNA methyltransferase inhibitor proposed for clinical evaluation in the treatment of cancer. 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. 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. Zebularine is extensively and rapidly metabolized into endogenous compounds that are unlikely to have effects at the concentrations observed.

Absorption, Metabolism, and Excretion of [ 14 C]Viramidine in Humans

Absorption, metabolism, and excretion of [14C]viramidine, a prodrug of ribavirin, were studied in humans following a single oral dose (600 mg). Viramidine was rapidly absorbed, with a time to maximum concentration of the drug in plasma of 1.5 h. Viramidine and ribavirin accounted for only 4.3% and 42% of plasma area under the concentration-time curve (AUC) for radioactivity, respectively, indicating extensive conversion of viramidine to ribavirin, followed by further metabolism of ribavirin. The drug was largely trapped in red blood cells (RBC), with an RBC-to-plasma radioactivity AUC0-infinity ratio of 108. Excretion of total radioactivity in urine and feces accounted for 50.8% and 26.1% of the dose, respectively. The metabolic profile in urine (0 to 24 h) indicated that viramidine was excreted primarily as triazole carboxamide (TCONH2), triazole carboxylic acid nucleoside (TCOOH), and ribavirin with a small amount of unchanged viramidine, which each accounted for 64.1%, 17.0%, 15.7%, and 3.2% of urinary radioactivity, respectively. The amounts of unchanged viramidine (3.4% of dose) and ribavirin (10% of dose) in urine were small after oral administration of viramidine.

11C-choline positron emission tomography in bladder cancer: Report of four cases

Little work has been done with positive emission tomography (PET) in bladder tumors because high urinary excretion of (18)F-FDG makes visualization of the bladder tumor difficult. (11)C-choline has recently been reported as a new tracer which lacks urinary radioactivity. We report the result of (11)C-choline PET in four patients with invasive bladder tumors. In one case, (11)C-choline PET could detect bladder tumor effectively without urinary activity and bone metastasis despite negative bone scintigraphy. On the other hand, an intense accumulation of the tracer in the bladder hampered the interpretation on PET scanning in three patients. The mechanisms of the (11)C-choline accumulation in the bladder were reported to be due to inflammatory and proliferative changes in the mucosa of the bladder from previous catheterization or other factors. Further study is necessary to prove the value of (11)C-choline PET for detecting primary bladder cancer and bone metastasis.

Metabolism and disposition of 1-bromopropane in rats and mice following inhalation or intravenous administration

Workplace exposure to 1-bromopropane (1-BrP) can potentially occur during its use in spray adhesives, fats, waxes, and resins. 1-BrP may be used to replace ozone depleting solvents, resulting in an increase in its annual production in the US, which currently exceeds 1 million pounds. The potential for human exposure to 1-BrP and the reports of adverse effects associated with potential occupational exposure to high levels of 1-BrP have increased the need for the development of biomarkers of exposure and an improved understanding of 1-BrP metabolism and disposition. In this study, the factors influencing the disposition and biotransformation of 1-BrP were examined in male F344 rats and B6C3F1 mice following inhalation exposure (800 ppm) or intravenous administration (5, 20, and 100 mg/kg). [1,2,3-(13)C]1-BrP and [1-(14)C]1-BrP were administered to enable characterization of urinary metabolites using NMR spectroscopy, LC-MS/MS, and HPLC coupled radiochromatography. Exhaled breath volatile organic chemicals (VOC), exhaled CO(2), urine, feces, and tissues were collected for up to 48 h post-administration for determination of radioactivity distribution. Rats and mice exhaled a majority of the administered dose as either VOC (40-72%) or (14)CO(2) (10-30%). For rats, but not mice, the percentage of the dose exhaled as VOC increased between the mid ( approximately 50%) and high ( approximately 71%) dose groups; while the percentage of the dose exhaled as (14)CO(2) decreased (19 to 10%). The molar ratio of exhaled (14)CO(2) to total released bromide, which decreased as dose increased, demonstrated that the proportion of 1-BrP metabolized via oxidation relative to pathways dependent on glutathione conjugation is inversely proportional to dose in the rat. [(14)C]1-BrP equivalents were recovered in urine (13-17%, rats; 14-23% mice), feces (<2%), or retained in the tissues and carcass (<6%) of rats and mice administered i.v. 5 to 100 mg/kg [(14)C]1-BrP. Metabolites characterized in urine of rats and mice include N-acetyl-S-propylcysteine, N-acetyl-3-(propylsulfinyl)alanine, N-acetyl-S-(2-hydroxypropyl)cysteine, 1-bromo-2-hydroxypropane-O-glucuronide, N-acetyl-S-(2-oxopropyl)cysteine, and N-acetyl-3-[(2-oxopropyl)sulfinyl]alanine. These metabolites may be formed following oxidation of 1-bromopropane to 1-bromo-2-propanol and bromoacetone and following subsequent glutathione conjugation with either of these compounds. Rats pretreated with 1-aminobenzotriazole (ABT), a potent inhibitor of P450 excreted less in urine (down 30%), exhaled as (14)CO2 (down 80%), or retained in liver (down 90%), with a concomitant increase in radioactivity expired as VOC (up 52%). Following ABT pretreatment, rat urinary metabolites were reduced in number from 10 to 1, N-acetyl-S-propylcysteine, which accounted for >90% of the total urinary radioactivity in ABT pretreated rats. Together, these data demonstrate a role for cytochrome P450 and glutathione in the dose-dependent metabolism and disposition of 1-BrP in the rat.

Clinical Pharmacokinetics of Ranolazine

Ranolazine is a compound that is approved by the US FDA for the treatment of chronic angina pectoris in combination with amlodipine, beta-adrenoceptor antagonists or nitrates, in patients who have not achieved an adequate response with other anti-anginals. The anti-anginal effect of ranolazine does not depend on changes in heart rate or blood pressure. It acts through different pharmacological mechanisms where inhibition of the late inward sodium current (reducing calcium overload and thereby left ventricular diastolic tension) is one plausible mechanism of reduced oxygen consumption. Initial studies used an oral solution or an immediate-release (IR) capsule, but subsequently an extended-release (ER) formulation was developed to allow for twice-daily administration with maintained efficacy. Following administration of an oral solution or IR capsule, peak plasma concentrations (C(max)) are observed within 1 hour. After administration of radiolabelled ranolazine, 73% of the dose was excreted in urine, and unchanged ranolazine accounted for <5% of radioactivity in both urine and faeces. The absolute bioavailability ranges from 35% to 50%. Food has no effect on rate or extent of absorption from the ER formulation. Ranolazine protein binding is about 61-64% over the therapeutic concentration range. Volume of distribution at steady state ranges from 85 to 180 L. Ranolazine is extensively metabolised by cytochrome P450 (CYP) 3A enzymes and, to a lesser extent, by CYP2D6, with approximately 5% excreted renally unchanged. Elimination half-life of ranolazine is 1.4-1.9 hours but is apparently prolonged, on average, to 7 hours for the ER formulation as a result of extended absorption (flip-flop kinetics). Elimination occurs through parallel linear and saturable elimination pathways, where the saturable pathway is related to CYP2D6, which is partly inhibited by ranolazine. Oral plasma clearance diminishes with dose from, on average, 45 L/h at 500 mg twice daily to 33 L/h at 1000 mg twice daily. The departure from dose proportionality for this dose range is modest, with increases in steady-state C(max) and area under plasma concentration-time curve (AUC) from 0 to 12 hours of 2.5- and 2.7-fold, respectively. Ranolazine pharmacokinetics are unaffected by sex, congestive heart failure and diabetes mellitus. AUC increases up to 2-fold with advancing degree of renal impairment. Ranolazine is a weak inhibitor of CYP3A, and increases AUC and C(max) for simvastatin, its metabolites and HMG-CoA reductase inhibitor activity <2-fold. Digoxin AUC is increased 40-60% by ranolazine through P-glycoprotein inhibition. Ranolazine AUC is increased by CYP3A inhibitors ranging from 1.5-fold for diltiazem 180 mg once daily to 3.9-fold for ketoconazole 200 mg twice daily. Verapamil increases ranolazine exposure approximately 2-fold. CYP2D6 inhibition has a negligible effect on ranolazine exposure.

Distribution and metabolism of the antipsychotic agent mazapertine succinate in rats

The pharmacokinetics and drug disposition of 14C 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoy]piperidine succinate (RWJ-37796, mazapertine, Mz) have been investigated in male and female Sprague–Dawley rats. Approximately 93% of the orally administered radioactive dose (30 mg/kg) was recovered after 7 days. Fecal elimination accounted for approximately 63% of the dose while urine accounted for 30%. The rate of elimination of 14C Mz was rapid with 81% of the total fecal and 94% of the total urinary radioactivity being excreted within 24 h. There were no significant gender differences in the overall excretion pattern. The maximal plasma concentration of Mz and total radioactivity occurred at 0.5 h after dosing and plasma concentrations were consistently higher in female rats. The Mz concentration declined rapidly in plasma with a terminal half-life <2 h. The total radioactive dose in plasma displayed a considerably longer terminal half-life of 9–13 h. Mz and a total of 15 metabolites were isolated and identified in these samples. Unchanged Mz accounted for <5% of the radioactive dose in excreta samples and <8% of the sample in plasma (0–24 h). Metabolites were formed by phenyl hydroxylation, piperidyl oxidation, O-dealkylation, N-dephenylation, oxidative N-debenzylation and glucuronide conjugation.