Excretion Of Radioactivity Research Articles

Distribution and Elimination of [2-14C]Amino-3, 8-Dimethylimidazo [4, 5-f] quinoxaline in Mice. Analysis by Whole Animal Autoradiography

1. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a potent bacterial promutagen and carcinogen, formed when beef is cooked. In mammals, MeIQx is metabolized and activated by liver enzymes, but induces tumours in both hepatic and extrahepatic tissues. 2. Intravenous administration of [14C]MeIQx and whole animal autoradiography has been employed to examine the disposition of MeIQx. Within 10 min, radiolabel was distributed throughout body tissue. Liver levels of radioactivity rapidly rose and remained elevated in comparison to other tissues, throughout the period of study (4 d). 3. At early time points radioactivity accumulated in the stomach, kidney and salivary glands then later in the intestine. Radioactivity was rapidly eliminated from the majority of tissues although did persist in liver and intestines throughout the duration of the study, probably due to covalently bound material. No radioactivity could be detected in the central nervous system, thus neither MeIQx nor its metabolites cross the blood-brain barrier to any significant extent. 4. The rapid elimination of radioactivity from the tissues is in good agreement with the time course of excretion of MeIQx. Irrespective of the route of administration (i.v., i.p., p.o.), a substantial proportion of the labelled material is excreted within 24 h and is present in both urine and faeces in similar quantities. 5. Thus MeIQx is extensively bioavailable, is distributed throughout body tissue and, although the majority is quickly cleared, some remains bound to liver and intestine.

The effect of uninephrectomy on osteocalcin metabolism in sheep: a direct evaluation of renal osteocalcin clearance

Indirect evidence has suggested that the kidney is a major organ of clearance for osteocalcin, a circulating marker of osteoblast function. The objectives of the present study were (1) to confirm the role of the kidney in osteocalcin clearance (2) to quantify the contribution of extrarenal sites and (3) to investigate the renal mechanism(s) of osteocalcin clearance. Plasma osteocalcin levels, osteocalcin plasma clearance rate (PCR) and plasma production rate (PPR) were determined in oophorectomized (OX) and uninephrectomized oophorectomized (UOX) sheep. The osteocalcin renal extraction efficiency (REE) and the effective renal plasma flow (ERPF) were measured, and the osteocalcin renal clearance rate (RCR) was calculated. The osteocalcin PCR was reduced significantly in UOX compared with OX sheep (2.0 +/- 0.1 (n = 9) vs 2.5 +/- 0.1 litres/h (n = 44); P less than 0.0005). In UOX sheep with plasma creatinine levels less than or equal to 130 mumol/l, the osteocalcin REE was 9 +/- 1.3% and the osteocalcin RCR was 50-91% of osteocalcin PCR (n = 4). In UOX sheep with plasma creatinine levels in the range 100-440 mumol/l, there was a linear relationship between osteocalcin PCR and ERPF; the osteocalcin RCR was related to the osteocalcin PCR (RCR = 0.9 x PCR - 0.50). Intravenous infusion of the synthetic glucocorticoid triamcinolone acetonide (TA) in UOX sheep led to marked decrements in plasma osteocalcin levels and the osteocalcin PPR, and a significant increase in the osteocalcin PCR. These changes were accompanied by a 44% increase in ERPF.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluticasone propionate in Crohn's disease.

Fluticasone propionate, a topically active corticosteroid of low systemic bioavailability after oral administration, has been used in a pilot study for the treatment of mild and moderately active Crohn's disease. Twelve patients received oral fluticasone propionate for three weeks, and the effects were monitored using the Crohn's disease activity index and by 111In granulocyte scanning, assessing inflammation from scan appearances, four day faecal excretion of radioactivity, and whole body excretion of radioactivity. All patients completed the trial. No serious side effects were reported. There was a significant fall in Crohn's disease activity index values over the three week treatment period (193 (84) v 122 (51), p less than 0.01). 111In leucocyte scan images were improved (seven patients) or unchanged (five patients). There was a significant fall in excretion of injected radioactivity calculated from whole body data (28 (21)% v 14 (0.7)%, p less than 0.05). There were no changes in plasma cortisol values, either basal or synacthen stimulated. Fluticasone propionate is a promising therapeutic agent for Crohn's disease that offers the possibility of controlling inflammation without inducing systemic corticosteroid side effects and which merits evaluation in a double blind trial versus conventional corticosteroids.

Disposition and excretion of intravenous 2,3,7,8-tetrabromodibenzo- p-dioxin (TBDD) in rats

Polybrominated dibenzodioxins and dibenzofurans are of toxicologic interest due to potential occupational and environmental exposure and because of their structural similarity to the highly toxic chlorinated analogues. The excretion and terminal tissue distribution of [ 3H]TBDD was studied in male F344 rats for 56 days following single iv doses of .001 or 0.1 μmol/kg. The major tissue depots of radioactivity were liver, adipose tissue, and skin, and tissue distribution was dose-dependent. At 56 days, liver concentrations in the high dose group were disproportionately increased compared to those of the low dose group. Liver:adipose tissue concentration ratios were 0.2 and 2.6 at the low and high doses, respectively. Elimination of radioactivity in the feces, the major route of excretion, and urine was also nonlinear with respect to dose. By Day 56, feces accounted for approximately 50% of the administered dose at the low dose versus 70% at the high dose. Based on fecal excretion, the apparent terminal whole body half-life was estimated to be 18 days for both dose groups. The time-dependent pattern of tissue disposition was characterized at the low dose over a 56-day period. Blood levels of radioactivity declined rapidly with 2% remaining in the blood by 24 hr. Radioactivity levels in the liver peaked by 7 hr and then gradually declined concomitant with a slow accumulation in adipose tissue. The terminal excretion half-life of radioactivity in adipose tissue was estimated to be 60 days. Liver:adipose tissue concentration ratios declined with time. Thus, the overall disposition of TBDD appears similar to that observed for the chlorinated analogue, 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). The results of these studies are consistent with the hypothesis that TBDD, like TCDD, induces a binding species in the liver which accounts for higher liver:adipose tissue concentration ratios at the high dose. The dose-dependent tissue disposition and excretion kinetics of these compounds suggest important considerations for extrapolations from high to low doses.

Bioavailability in Vivo of Benzo[a]Pyrene Adsorbed to Diesel Particulate

To evaluate health risks associated with exposure to particulates in the environment, it is necessary to quantify the bioavailability of carcinogens associated with the particulates. Direct analysis of bioavailability in vivo is most readily accomplished by adsorbing a radiolabeled form of the carcinogen to the particulate. A sample of native diesel particulate collected from an Oldsmobile diesel engine that contained 1.03 micrograms benzo[a]pyrene (BaP)/g particulate was supplemented with exogenous [3H]-BaP to produce a particulate containing 2.62 micrograms BaP/g. To insure that elution of BaP from native and [3H]-BaP-supplemented particulate was similar, in vitro analyses were performed. When using phospholipid vesicles composed of dimyristoylphosphatidylcholine (DMPC), 1.52% of total BaP was eluted from native particulate into the vesicles in 18 hrs; from [3H]-BaP supplemented particulate, 1.68% was eluted. Using toluene as eluent, 2.55% was eluted from native particulate, and 8.25% from supplemented particulate, in 6 hrs. Supplemented particulate was then instilled intratracheally into male Sprague-Dawley rats and distribution of radioactivity was analyzed at selected times over 3 days. About 50% of radioactivity remained in lungs at 3 days following instillation, with 30% being excreted into feces and the remainder distributed throughout the organs of the rats. To estimate the amount of radioactivity that entered feces through swallowing of a portion of the instilled dose, [3H]-BaP-supplemented particulate was instilled intratracheally into rats that had a cannula surgically implanted in the bile duct. Rate of elimination of radioactivity into bile was monitored; 10.6% of radioactivity was recovered in 6 hr, an amount slightly lower than the 12.8% excreted in 6 hrs into feces of animals with intact bile ducts. Our studies provide a quantitative description of the distribution of BaP and its metabolites following intratracheal instillation of diesel particulate. Because rates of elution of BaP in vitro are similar for native diesel particulate and particulate with supplemental [3H]-BaP, our results provide a reasonable estimate of the bioavailability in vivo of BaP associated with diesel particulate.

Effect of the leukotriene receptor antagonists FPL 55712, LY 163443, and MK-571 on the elimination of cysteinyl leukotrienes in the rat

1. Leukotriene elimination via bile and urine is an important mechanism of inactivation for these potent lipid mediators. We investigated whether the elimination of cysteinyl leukotrienes is a target for the action of leukotriene receptor antagonists. 2. Experiments were performed in male rats under deep thiopentone anaesthesia. The bile duct and the urinary bladder were cannulated. Tritium labelled leukotrienes and leukotriene receptor antagonists were given via central venous catheters. Elimination of leukotrienes produced in vivo was studied following stimulation of endogenous leukotriene biosynthesis by operative trauma. 3H-leukotriene metabolites were identified by h.p.l.c. analysis. Leukotrienes produced in vivo were measured by combined use of h.p.l.c. and RIA. 3. Under control conditions, 49 +/- 12% of the injected 3H-leukotriene radioactivity was recovered in bile and 1 +/- 0.8% in urine within 90 min. Operative trauma resulted in initial hepatobiliary secretion of 887 +/- 206 pmol kg-1 h-1 of the endogenous leukotriene metabolite N-acetyl leukotriene E4 (LTE4NAc). 4. FPL 55712 strongly inhibited hepatobiliary elimination of 3H-leukotriene radioactivity in a dose-dependent manner after i.v. injection of [3H]-LTC4, [3H]-LTD4 or [3H]LTE4, respectively. Biliary [3H]-LTD4 was reduced most effectively. The leukotriene antagonist potently prevented biliary elimination of LTE4NAc produced in vivo. Bile flow and elimination from blood into bile of [3H]-ouabain were also impaired by FPL 55712, but to a lesser extent. 5. LY 163443 reduced biliary [3H]-LTD4 after i.v. administration of [3H]-LTD4. However, the total elimination of 3H-leukotriene metabolites into bile was not significantly inhibited by the drug. 6. MK-571 reduced the biliary concentration of tracer after administration of 3H-leukotrienes most potently with respect to [3H]-LTD4. In contrast, the total recovery of 3H-leukotrienes in bile tended to increase. This is explained by a drug-induced increase in bile flow. 7. Urinary elimination of 3H-leukotrienes, quantitatively less important in the rat, was not significantly influenced by the leukotriene receptor antagonists. Recovery of 3H-leukotriene radioactivity in liver and kidneys was quantitatively insignificant. 8. From our data, we conclude that leukotriene receptor antagonists have the potential to affect leukotriene elimination by a mechanism not necessarily related to receptor blockade. Inhibition of elimination by the receptor antagonists may prolong the biological half life of leukotrienes. This effect may counteract the antagonistic properties of these drugs.

Differences in kinetics of pure and soil-adsorbed toluene in orally exposed male rats

Assessment of health risk following exposure to chemically contaminated soil has primarily utilized results from studies conducted with pure chemicals. However, complex interactions with soil may alter the way in which a chemical subsequently interacts with the body. This study was conducted to determine if adsorption to either of two New Jersey soils qualitatively or quantitatively altered the way in which toluene is absorbed, distributed, metabolized or excreted by the body following oral exposure. Adult, male rats were gavaged with an aqueous suspension of 14C-toluene in the presence or absence of either an Atsion (sandy soil) or a Keyport soil (clay soil). Both soils reduced the peak plasma concentration of radioactivity, while sandy soil also reduced the time to reach peak vs toluene alone. Clay soil produced a statistically significant decrease in the half-life (t1/2) of elimination of radioactivity from plasma vs toluene alone. However, neither soil altered the area under the plasma radioactivity-time curve (AUC) vs toluene alone. Three-h post administration, stomach and fat contained the highest concentrations of radioactivity. No differences were detected in the tissue concentrations of radioactivity between the treatment groups. Urine was the primary excretion route of radioactivity in all treatment groups with lesser amounts excreted in expired air and negligible amounts in feces during the 48 h following exposure. Unmetabolized toluene represented greater than 98.8% of radioactivity in expired air of all treatment groups. Clay soil produced a statistically significant decrease in the excretion of radioactivity in expired air at the 0-1, 0-12, 0-24 and 0-48 periods vs toluene alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in the Renal Excretion of Valproate and Its Metabolites After Chronic Treatment

Urinary excretion of valproate (VPA, administered as its sodium salt) and its various metabolites was studied in rats before and after 6 weeks of chronic treatment with intraperitoneal (i.p.) injection of 200 mg/kg VPA three times daily. Urinary excretion was determined after i.p. injection of a single dose of 200 mg/kg VPA, to which [14C]labeled VPA had been added to yield a dose of 1 microCi/kg body weight. Unlabeled VPA and metabolites were determined in urine by gas chromatography-mass spectrometry (GC-MS). After injection of a single dose of VPA before onset of chronic treatment, approximately 40-50% of the dose administered was excreted in the urine within 24 h, mainly in the form of conjugated VPA and omega-oxidation products, i.e., 5-hydroxy-VPA and 2-propyl-glutaric acid. After chronic treatment, urinary excretion of total radioactivity increased approximately 75% as compared with activity before chronic treatment, demonstrating a marked increase in elimination rate of VPA during prolonged administration. Determination of VPA and metabolites in urine by GC-MS indicated that this enhanced elimination resulted mainly from increases in glucuronidation and beta-oxidation of VPA, whereas omega-oxidation was apparently not altered or was even reduced. The data strongly indicate that at least in rats VPA produces induction of its own metabolism during prolonged treatment.

Pharmacokinetics and metabolismof nilutamide

Data are available on the pharmacokinetics and metabolism of nilutamide in the rat, dog, and human (normal volunteers and patients with advanced prostatic carcinoma). Studies using 14Carbon-nilutamide, radioimmunoassay, and high-performance liquid chromatography (HPLC) are reviewed. In the rat, bioavailability by the oral route was complete. The majority of the plasma radioactivity was unchanged nilutamide up to six hours, t1/2 was seven hours, and clearance was 150 mL/hour/kg body weight. Metabolism studies identified 6 urinary metabolites. The major metabolites result from reduction of the nitro group initially to an hydroxylamine (17%) and then to a primary amino (26%) group. In normal volunteers the compound was rapidly absorbed, displayed linear kinetics over a dose range of 100-300 mg, and declined slowly in plasma with a terminal phase t1/2 of forty-three to forty-nine hours. In studies in 12 patients with advanced (Stage D) prostatic carcinoma, single-dose kinetics after 14C-nilutamide and kinetics with repetitive twice-daily dosing of two to seven weeks were measured. Terminal phase plasma t1/2 of unchanged nilutamide was 56 +/- 19 hours and of total radioactivity 87 +/- 27 hours (mean +/- SD). Area under the curve of plasma radioactivity was 23 to 38 percent unchanged nilutamide. Urinary excretion of radioactivity was slow and incomplete because the collection time was not long enough in regard to t1/2 (mean after 5 days, 62 +/- 10%) and consisted almost entirely of metabolites. Steady-state plasma levels of nilutamide were reached in about two weeks. It can be concluded that in humans, unlike other species, plasma decay of nilutamide is very slow. Elimination is almost exclusively by metabolism. Single-daily dosing is appropriate. Hepatic impairment could be expected to prolong plasma decay; renal impairment is likely to have little effect.

Studies on the Metabolic Fate of Neticonazole. (I): Absorption, Distribution, Metabolism and Excretion in Rats after a Single Subcutaneous Administration.

The absorption, distribution, metabolism and excretion of 14C-neticonazole (14C-SS717) were studied in rats after a single subcutaneous administration of 25mg/kg.1. Blood levels of the radioactivity reached the maximum of 2.Olμg equiv. of SS717/ml (male) or 1.59μg equiv. of SS717/ml (female) at 4hr after dosing, and then declined slowly during 4 ?? 24hr with half-lives of 21 and 15hr in male and female rats, respectively. The elimination half-lives at the terminal phase (48 ?? 168hr) were 64hr (male) and 58hr (female).2. Within 120hr after dosing in male rats, 65.4 and 29.5% of the dose were excreted in the urine and feces, respectively. No sex difference was observed in the excretion of radioactivity.3. Biliary excretion of the radioactivity within 48hr after dosing was 51.9 and 46.7% in male and female rats. respectively. In male rats, 46. 7 and 2.0% of the dose were excreted in the urine and feces, respectively, while the excretion of radioactivity in female rats was 49. 6% of the dose in the urine and 2.7% of the dose in the feces. Also, the partial reabsorption of biliary excreta occurred from the intestinal tract.4. Maximum levels of the radioactivity in most of tissues were reached at 4hr after dosing in male rats, and a high level of the radioactivity was observed in the adrenal gland, liver, kidney, aorta, fat and harderian gland. The distribution of radioactivity in the stomach was also visualized by the whole body autoradiography.5. The extent of in vitro binding of 14C-SS717 to plasma proteins was 98.7 ?? 99.0% in rats, and 99.2-99.7% in human. The percent of in vivo binding of 14C-SS717 and/or its radioactive metabolites to the rat plasma proteins were 62.0-79.3% within 24hr after dosing.6. In the plasma samples drawn from male rats at lhr after dosing, the percent of radioactivity of the unchanged drug was 20.5% and that of U-1 ?? U-3, U-5, U-6 and M3 metabolites were 1.9 ?? 7.8%. Subsequently, the unchanged drug declined gradually, but the most of metabolites increased until 4hr after dosing and thereafter declined.In the urine excreted within 24hr after dosing, the percent of radioactivity of U-2 and U-6 metabolites were 17.1 and 14.1%, respectively, and that of U-1, U-3 ?? U-5 and five unknown metabolites were 0.5 ?? 9.7%. In the bile sample excreted within 24hr after dosing, the percent of radioactivity in U-2, U-5, U-6 and six unknown metabolites were 0. 2-2.2%. Meanwhile, in the enzymatically hydrolyzed samples, that of U-5, U-3, U-2, U-6 and 12 unknown metabolites were 0.59.5%, however, the most of those were observed for the first time.

A pharmacokinetics study on Oxiracetam in rats. (II): Plasma levels profile, tissue distribution, metabolism and excretion during and after the repeated oral administration.

The absorption, distribution, metabolism and excretion of Oxiracetam (CT-848) were studied in male rats during and after the consecutive oral administration of 10mg/kg of 14C-CT-848 for 14 days. 1. The plasma concentrations of radioactivity at 1hr and 6hr after each dose were not affected by repeated administration. After the 14th doses, radioactivity in plasma reached Cmax at 1hr and decreased with a half-life of 1.6hr (2 ?? 8 hr). 2. The concentrations of radioactivity in tissues at 6hr were not significantly different between after 7th and 14th doses and 1st dose. The elimination of radioactivity from tissues was rapid after the 14th dose. Accumulation of radioactivity in tissues was not observed. 3. The extents of excretion in urine and feces during consecutive oral do sing were 27.2 ?? 31.3%, and 52.7?? 72.1%, respectively. The elimination of radioactivity from the body was completed by 48hr after the final administration. 4. After repeated oral administration to non-fasting male rats, only unchanged compound was observed in plasma at 1hr and 6hr. In urine and feces up to 24hr after 1st and 14th doses only about 1 % of the recovered radioactivity was corresponded to unknown metabolites and the remainder was unchanged compound.

Studies on the Metabolic Fate of NZ-105. (III). Absorption, Metabolism and Excretion in Dogs and Protein binding.

Absorption, metabolism and excretion of 14C-NZ-105 were studied in male dogs after oral (10mg/kg) administration. Serum protein binding was investigated in the rat, dog and human. 1. Blood levels of radioactivity reached a peak level (564ng eq./ml) at 2hr after administration and then decreased with the half-life of 3. 1hr until 12hr. 2. The excretion of radioactivity in urine and feces within 120hr after oral administration was 3.1% and 98.5% of dose, respectively. 3. The in vitro binding to rat, dog and human serum proteins was 98% or more at 200, 600 and 2000ng/ml. That observed in vivo was 85.8 ?? 89.7% at 0.5, 2 and 6hr after oral administration in rats and 38.5 ?? 45.6% at 2, 4 and 8hr after dosing in dogs. 4. The unchanged drug and oxidatively deaminated compound (AL) were mainly detected in the plasma.

Metabolic Fate of Dopamine Prodrug TA-870. (2): Metabolic Fate of TA-870 after Repeated Oral Administration in Male Rats.

ラットに14C-TA-870を30mg/kgの用量で1日1回，14日間反復経口投与した際の全血中放射能濃度，組織内放射能濃度および尿糞中排泄について検討した．1．各回投与後1時間(Tmax)における全血中放射能濃度は反復投与開始初期にブラトーに達し，反復投与による上昇傾向は認められなかった．また，各ファーマコキネティックハラメーターは，単回投与群と比べ14回投与群の方が高い値を示したが有意な差ではなかった．2．最終投与後1時間における組織内放射能濃度は，単回投与群と14回投与群の間に大きな差は認められなかったが，24あるいは72時間後では14回投与群の方が高い傾向を示した．3．反復投与期間中の尿糞中への放射能排泄割合は変動が少なく，放射能の回収率は投与量の97.5%であった．

Metabolic Fate of Dopamine Prodrug TA-870. (3): Foeto-placental Transfer and Excretion into Milk after Oral Administration of 14C-TA-870 to Rats.

Foeto-placental transfer and excretion of radioactivity into the milk after oral administration of 14C-TA-870 at a dose of 30mg (64μmol)/kg were investigated in the pregnant and lactating rats.The distribution patterns of radioactivity in the pregnant and lactating rats after dosing of 14C-TA-870 were similar to those of male and normal female rats1).Both in fetus and suckling, the radioactivity transferred from maternal rats was lower than 0.05% of administrated radioactivity and did not remain in their organs and tissues at 24hr after oral administration.

The disposition of loxistatin and metabolites in normal and dystrophic hamsters

1. The absorption, distribution and excretion of loxistatin were studied in normal and dystrophic hamsters. 2. After oral administration of 14C-loxistatin to normal hamsters, the plasma level of radioactivity reached a maximum at 0.5 h and declined with an elimination half-life of 2.3 h. The ratios of metabolites M-1 and M-4, which are pharmacologically active, to the total radioactivity in the plasma were 63% and 25% at 0.5 h after dosing, respectively. 3. After oral administration to hamsters, excretion of radioactivity in urine, faeces and expired air during 120 h were 64%, 28% and 6% of the dose, respectively. 4. The highest radioactivity was observed in kidney followed by liver. From the microautoradiographic study, radioactivity was found to be located in the cardiac and skeletal muscle fibre cells, which are target organs of the drug, in both dystrophic and normal hamsters.

Studies on the Metabolic Fate of Felodipine. (II): Absorption, Distribution, Metabolism and Excretion after Repeated Oral Administration to Rats.

The absorption, distribution, metabolism, and excretion of 14C-Felodipine were investigated during and after its repeated oral administration to male rats at a daily dose of 1mg/kg for 28 days. 1. The concentration of radioactivity in the blood (24hr after daily dosing) almost reached a steady state after the 25th dosing and was 1.9 times higher after the 28th dosing than that found after the 1st dosing. The Cmax after the 28th dosing was 1.3 times higher than that in the single dosing. The half-life up to 48hr was 1.4 times longer and the half-life from 72hr to 168hr was 2.2 times longer than that found in the single dosing. 2. The excretion of radioactivity in the urine and feces reached almost a steady state by the 14th dosing. 3. Most of the tissues tended to reach a steady state by the 14th dosing. The disappearance of radioactivity after the 28th dosing was slower than that in the single dosing. The fractionation of radioactivity in the fat 168, 336 and 1, 008hr and liver 168hr after the 28th dosing suggested that radioactivity in the fat and liver was not due to the metabolites of Felodipine but due to the labelled carbon which is taken up by biological components. 4. The relative amounts of metabolites in the plasma and urine did not change with repeated dosing.

Metabolic Fate of a New Dihydropyridine Calcium Antagonist, NB-818. (III). Absorption, Distribution,Metabolism and Excretion after Repeated Administration in Rats and Dogs.

The absorption, distribution, metabolism and excretion of isopropyl methyl (±)-2-carbamoyloxymethyl-4-(2, 3-dichlorophenyl)-1, 4-dihydro-6-methyl-3, 5-pyridinedicarboxylate (NB-818) were studied after repeated oral doses to rats (10mg/kg/day, 3weeks) and dogs (5mg/ kg/day, 54 weeks).1. The levels of radioactivity in the plasma at 24hr after each administration of 14C-NB-818 to male rats increased by repeated dosing until the 18th dosing. The average level after the last dosing was 1.8 times higher than that after the first dosing. The plasma levels of radioactivity after the last dosing reached the peak of 6.4μg equiv./ml at 3.5hr, and declined with a half-life of 11.8hr.2. At 24hr after the last of 21 daily oral treatments, the concentrations of radioactivity in most of the male rat tissues were 2-14 times higher than those after the single dose. However, the tissue distribution patterns in both cases were similar. Disappearance of radioactivity from the tissues after 21 days of dosing was slower than after single dosing, but radioactivity did not remain in the tissues for a long period.3. The excretion of radioactivity in urine and feces was nearly constant during the period of repeated administration in male rats. Within 168hr after the last dosing, urinary and fecal excretion amounted to 7.6% and 82.3% of administered dose, respectively.4. In the case of the repeated oral dosing of NB-818 for 54 weeks to male and female dogs, plasma levels of unchanged drug showed little change.5. The profile of the urinary metabolites showed no marked change during the period of repeated administration in male and female dogs.

Disposition of Marograstim (KW-2228) (1) : Plasma concentration, distribution, metabolism and excretion of <SUP>125</SUP>I-KW-2228 after intravenous or subcutaneous administration to rats

Plasma concentration, distribution, metabolism and excretion of 125I-KW-2228, a mutant of human granulocyte colony stimulating factor, were studied in rats after single intravenous or subcutaneous administration. 1. After intravenous administration of 125I-KW-2228, total radioactivity and trichroloacetic acid(TCA)-insoluble radioactivity in the plasma were eliminated biexponentially. TCA-insoluble radioactivity showed a rapid elimination as compared with total radioactivity. Maximum concentrations of total and TCA-insoluble radioactivity were reached at 2hr after subcutaneous administration. After that, TCA-insoluble radioactivity was eliminated more rapidly than total radioactivity in a case of intravenous administration. The results of SD S-PAGE suggested that most of antibody-bound able radioactivity in the plasma were unchanged KW-2228 in both administration routes. 2. TCA-insoluble radioactivity was distributed to the kidney at the highest concentration, suggesting that the kidney might play the major role in metabolism and elimination of 125I-KW-2228. Other tissues showed a difference in the distribution pattern of 125I-KW-2228 after intravenous and subcutaneous administrations. In the bone marrow, the target organ of KW-2228, the elimination of radioactivity was slower after subcutaneous administration, which was thought to contribute to higher WBC increasing effect. A high level of radioactivity was observed in the thyroid gland, stomach and skin, which might be related to the 125I released from 125I-KW-2228. 3. The major excretion route of 125I-KW-2228 was urine and there was no difference between administration routes. Most of radioactivity in the urine consisted of low molecular weight metabolites or free 125I.

Pharmacokinetic studies of a novel tricyclic antidepressant, quinupramine in the old rats.

In the present study, we examined the effects of aging on the pharmacokinetics of 14Cquinupramine in male rats, following the administration to the aged (2 and 1-year old) and young (8 weeks old) rats.1. The concentration of radioactivity in blood of young rats reached the maximum 1hr after oral administration. In the older animals, Tmax was more delayed. The blood concentration of radioactivity declined with the similar half-life times (Tα1/2=0.87-1.66hr., Tβ1/2-19.2 -25.1hr ) in all groups of rats studied. Cmax and the area under the blood concentration-time curve (AUC) in the aged rats were 2.8 and 2.7 times higer, respectively, than those in the young rats.2. Two hours after oral administration of 14C-quinupramine, the tissue levels of radioactivity in the aged (2 years old) rats were 1.6-10.3 times higher than those in the young rats. The difference became more pronounced 24hr after administration. The distribution pattern of radioactivity in the aged rats was similar to that in the young rats. These findings were consistent with the results of whole body autoradiography.3. The in vitro plasma protein binding assay of 14C-quinupramine showed that more than 80% was bound to the protein in every group of animals. In vivo plasma protein binding of radioactivity was 46.5% 2hr and 58.5% lhr after oral administration of 14C-quinupramine in the aged (2 years old) and young rats, respectivery.4.The hepatic microsomal drug metabolizing activities (aminopyrine N-demethylation and aniline p-hydroxylation) and the content of cytochrome P-450 in rats decreased with aging. In vitro metabolic study of 14C-quinupramine with rat liver microsomes revealed that 48.2% and 8.4% of quinupramine remained unchanged in the aged (2 years old) and young rats, respectively.After oral administration of 14C-quinupramine, the aged (2 years old) rats showed higher content of the unchanged form in the urine, faces, plasma, heart, liver and kidney than the young rats.5. Within 24hr after oral administration, the recovery of radioactivity in excreta was 92.4 %, and 66.5% and 51.5% in the young and aged (1 and 2 years old) animals, respectively. The cumulative urinary excretion of radioactivity was 27.5%, 28.1% and 37.2% within 168hr after dosing in the young and aged (1 and 2 years old) rats, respectively.

Metabolism of mephentermine in male guinea pigs and male mice

1. Urinary metabolites of mephentermine (MP), after i.p. administration of MP to male Hartley guinea pigs and mice, were identified by g.l.c.-electron impact (EI) mass spectrometry. Excretion of urinary radioactivity, and metabolites of 3H-MP, after i.p. administration, were determined by preparative t.l.c.-liquid scintillation counting. 2. About 27% of the radioactivity administered was excreted in the 24 h urine of guinea pigs, and 36% dose was excreted in 5 days. In mice, about 47% of the radioactivity was excreted in the 24 h urine, and 52% in 5 days. 3. Excretion rates of metabolites detected in the 24 h urine of guinea pigs were phentermine (Ph, 7.8%), a conjugate of N-hydroxyphentermine (N-hydroxy-Ph, 3.6%), p-hydroxyphentermine (p-hydroxy-Ph, 1.0%) and its conjugate (2.9%), and other metabolites (conjugates of MP and Ph, N-hydroxymephentermine (N-hydroxy-MP) and its conjugate, p-hydroxymephentermine (p-hydroxy-MP) and its conjugate, and N-hydroxy-Ph; less than 1.0%). The rates of excretion for mice were Ph (11.7%), conjugates of p-hydroxy-MP (3.1%), Ph (2.7%) and p-hydroxy-Ph (1.6%), and N-hydroxy-Ph (1.2%) and other metabolites (conjugates of MP and N-hydroxy-Ph, N-hydroxy-MP and its conjugate, p-hydroxy-Ph, and p-hydroxy-MP; less than 1.0%). 4. These results indicate that MP administered to mice is metabolized mainly to Ph and p-hydroxy-MP by N-demethylation and p-hydroxylation of the parent compound, and in guinea pigs the primary metabolic reaction of MP is N-demethylation producing Ph.(ABSTRACT TRUNCATED AT 250 WORDS)