Plasma Concentrations Of Radioactivity Research Articles

Clinical Pharmacokinetics of Lercanidipine

Summary:(±) Lercanidipine hydrochloride (HCl) (Zanidip) is an antihypertensive drug structurally related to dihydropyridine calcium-entry blockers: lercanidipine is weakly basic (pK′a = 6.83 at 37°C) and highly lipophilic (log P octan-1-ol/water = 6 at 20-25°C). After oral administration of 10-20-mg

Metabolic Fate of the Sympathoneural Imaging Agent 6-[18F]Fluorodopamine in Humans

We examined the metabolism of 6-[18F]fluorodopamine, by assaying arterial plasma concentrations of radioactivity, 6-[18F]fluorodopamine, and 6-[18F]fluorodopamine metabolites in untreated subjects or subjects given desipramine to block neuronal uptake of catecholamines or tyramine to displace vesicular amines. After the 3-min 6-[18F]fluorodopamine infusion, plasma 6-[18F]fluorodopamine levels declined precipitously, total radioactivity declining slowly. After 30 min, the main identified metabolite was 6-[18F]fluorodopamine-sulfate. Desipramine attenuated the rapid increase in plasma 6-[18F]fluorodihydroxyphenylacetic acid levels, and tyramine briefly increased 6-[18F]fluorodopamine levels. Neither drug affected 6-[18F]fluorodopamine-sulfate levels. The results indicate that soon after 6-[18F]fluorodopamine infusion, plasma radioactivity corresponds mainly to 6-[18F]fluorodopamine metabolites; that sympathetic nerves rapidly remove 6-[18F]fluorodopamine, which then undergoes oxidative deamination in the neuronal cytoplasm and sequestration in sympathetic vesicles; and that sulfoconjugation of [18F]fluorodopamine occurs extraneuronally.

Intravenous infusion of RMP-7 increases ocular uptake of ganciclovir.

The ability of intravenous (i.v.) infusions of the bradykinin agonist, RMP-7, to permeabilize the blood-ocular barriers (BOB) to the antiviral agent ganciclovir was investigated in guinea-pigs. Different i.v. dosing regimens included pre-treatment with RMP-7 (0.2 microg/kg/min for 5 min) followed by either [3H]-ganciclovir (1 microCi/0.2 ml/min) alone, and/or co-infusion with RMP-7 and [3H]-ganciclovir. At specific times the animals were sacrificed, their eyes removed, and the retina and lens epithelium dissected and analyzed for the amount of radioactivity. Using the ratio of tissue vs. integrated plasma radioactivity concentration, a two-fold increase in ganciclovir steady-state levels were observed in the retina as well as lens epithelium following RMP-7 pretreatment. Peak uptake effects were achieved with a 4.5 min ganciclovir infusion. Neither longer infusions of ganciclovir alone, nor co-infusions of RMP-7 and ganciclovir further enhanced the uptake effects. Kinetic analysis indicated that RMP-7 increased the rate of ganciclovir entry (K(IN)) in studied ocular tissues, while the efflux of drug (K(OUT)) was not affected by this treatment. Finally, ganciclovir retina:plasma ratios elevated by RMP-7 pre-treatment, remained higher than control ratios within 60 min following cessation of 4.5 min ganciclovir infusion. These data offer further evidence that BOB and in particular the blood-retinal barrier can be permeabilized via bradykinin receptor stimulation. As the i.v. infusions of RMP-7 enhanced the retinal uptake of ganciclovir, it is suggested that a combination of RMP-7 and ganciclovir may provide a novel approach for treating cytomegalovirus retinis.

Oxidation of plasma low-density lipoprotein accelerates its accumulation and degradation in the arterial wall in vivo.

The aim of the present study was to investigate whether oxidized LDL (ox-LDL) in the arterial intima could be derived from LDL already oxidized in plasma. Rabbits received an intravenous injection of 125I-labeled normal LDL (N-LDL) mixed with 131I-labeled LDL that had been mildly oxidized through exposure to Cu2+. The aortic accumulation of undegraded labeled LDL was expressed as plasma equivalents and cakulated as radioactivity in the intima/inner media (cpm/cm2) divided by the time-averaged concentration of radioactivity in plasma (cpm/nL): for the thoracic aorta, the accumulation of undegraded ox-LDL in the intima/ inner media exceeded that of undegraded N-LDL by 286% (n = 6, P < .04), 863% (n = 7, P < .02), and 364% (n = 8, P < .01) after 1, 3, and 24 hours of exposure, respectively. There was a strong positive association between the extent of oxidation and the excess accumulation of undegraded ox-LDL compared with N-LDL (thoracic aorta; 3 hours of exposure: r = .97, n = 14, P < .00001). To measure degradation of N-LDL and ox-LDL, 125I-LDL labeled with 131I-tyramine cellobiose was injected intravenously 24 hours before the aortic intima/inner media was removed: for the thoracic aorta, the accumulation of degradation products from ox-LDL (n = 6) exceeded that from N-LDL (n = 6) by 301% (P < .04). The present data suggest a novel mechanism: mildly oxidized LDL may circulate in plasma for a period sufficiently long to enter, accumulate, and be degraded in the arterial intima in preference to N-LDL.

Absorption, metabolism and excretion of tamsulosin hydrochloride in man.

1. The absorption, excretion and metabolism of tamsulosin hydrochloride (TMS), a potent alpha 1-adrenoceptor blocking agent, were studied in four healthy male subjects after a single oral administration of 14C-TMS at a dose of 0.2 mg. 2. Plasma and blood radioactivity concentrations attained peak levels (Cmax) within 1 h after dosing and then declined biphasically. Mean terminal elimination half-lives were 11.8 h for plasma and 9.1 h for blood. The respective mean area under the radioactivity concentration-time curves (AUC0-infinity) were 122.8 and 57.8 ng equivalents h/ml. 3. Mean plasma Cmax of unchanged TMS was 13.0 ng/ml. Plasma levels of TMS declined biphasically. Mean terminal elimination half-life and AUC0-infinity were 8.4 h and 90.3 ng h/ml. The percentage of unchanged TMS to total radioactivity was 91% for Cmax and 74% for AUC0-infinity indicating small amounts of metabolites in plasma. 4. By 1 week post-dosing, 76.4% of the administered radioactivity was recovered in urine and 21.4% in faeces. The major part of radioactivity excreted in urine was recovered within the first 24 h (62.2% of the dose). 5. Unchanged TMS and 11 metabolites in 0-24-h urine samples were quantified. TMS accounted for 8.7% of the dose. Extensive excretion of the sulphate of the O-deethylated metabolite (M-1-Sul) and o-ethoxyphenoxy acetic acid (AM-1) was seen, accounting for 15.7 and 7.5% of the dose respectively.

Pharmacokinetics of ethylene glycol. III. Plasma disposition and metabolic fate after single increasing intravenous, peroral, or percutaneous doses in the male Sprague-Dawley rat.

1. The pharmacokinetic fate of [1,2-14C]-ethylene glycol (EG) was evaluated in the male Sprague-Dawley rat in order to characterize its overall uptake and elimination. Doses of 10 and 1000 mg/kg were administered by the intravenous (i.v.), peroral (p.o.), or percutaneous (p.c.) route; additional doses of 400, 600 and 800 mg/kg were evaluated by the p.o route. 2. Baseline data obtained by the i.v. route for bioavailability comparisons showed that while plasma radioactivity concentrations declined in a biexponential manner with t1/2 beta of 26-37 h, the disappearance of unmetabolized EG from the plasma was quite rapid (t1/2 beta of 0.8-1.2 h). Peroral doses were rapidly and almost completely absorbed, showing t1/2 abs in the order of minutes, and a bioavailable fraction for unmetabolized EG of 92-100%. Conversely, EG applied to rat skin was slowly and rather poorly absorbed, showing t1/2 abs which were an order of magnitude longer than for comparable p.o. and i.v. doses, and a bioavailability of approximately 22%. 3. The major route of elimination for the 10 mg/kg dose by any route was by metabolism to 14CO2 and exhalation, while urinary elimination of 14C was the secondary excretion pathway. 4. Plasma clearance of 14C was linear with increases in p.o. doses over the 400-800 mg/kg range, with AUC proportional to dose for these and the 10 mg/kg p.o. dose levels. However, a dose-dependent shift in excretion routes was observed following the p.o. 1000 mg/kg dose, with urine becoming the major excretion route, and similar capacity limited pharmacokinetics were observed for the i.v. 1000 mg/kg dose. Plasma pharmacokinetic data for unchanged EG after i.v. and p.o. doses demonstrated an apparent first-order kinetic behaviour between the 10 and 1000 mg/kg dose levels for the disappearance of EG. 5. Following both i.v. and p.o doses, dose-independent relationships were seen in the values obtained for the area under the plasma curve (AUC infinity), the total clearance of EG (CltotalEG), mean residence time (MRT infinity), apparent volume of distribution at steady state (Vdss), the terminal half-life (t1/2 beta) and the renal and metabolic clearance values. However, this dose-linear plasma time course was not apparent from the dose-dependent excretion profiles for these two exposure routes. 6. Increases in urinary 14C-glycolate were also observed when the i.v. or p.o. doses were increased from 10 to 1000 mg EG/kg, indicating that metabolism of EG makes a substantial contribution to AUC infinity in the beta disposition phase of the plasma curves for this high dose. Oxalate, a metabolite found in man after EG exposure, was detected at very low levels after both the 10 and 1000 mg/kg dose levels and by either i.v or p.o. routes. 7. Thus, EG given by three different routes demonstrated apparent first-order pharmacokinetic behaviour for disposition in and the elimination from plasma in the male rat, but dose-dependent changes occurred for the elimination of metabolites in urine and as 14CO2 after single i.v. and p.o. doses, but not for the p.c. routes.

Plasma input function determination for PET using a commercial laboratory robot

A commercial laboratory robot system (Zymate PyTechnology II Laboratory Automation System) was interfaced to standard and custom laboratory equipment and programmed to perform rapid radiochemical assays necessary for plasma input function determination in quantitative PET studies in humans and baboons. A Zymark XP robot arm was used to carry out two assays: (1) the determination of total plasma radioactivity concentrations in a series of small-volume whole blood samples and (2) the determination of unchanged (parent) radiotracer in plasma using only solid phase extraction methods. Steady state robotic throughput for determination of total plasma radioactivity in whole blood samples (0.350 mL) is 14.3 samples/h, which includes automated centrifugation, pipetting, weighing and radioactivity counting. Robotic throughput for the assay of parent radiotracer in plasma is 4–6 samples/h depending on the radiotracer. Percents of total radioactivities present as parent radiotracers at 60 min. postinjection of 25 ± 5.0 ( N = 25), 26 ± 6.8 ( N = 68), 13 ± 4.4 ( N = 30), 32 ± 7.2 ( N = 18), 16 ± 4.9 ( N = 20), were obtained for carbon-11 labeled benztropine, raclopride, methylphenidate, SR 46349B (trans, 4-[(3Z)3-(2-dimethylamino-ethyl) oxyimino-3 (2-fluorophenyl)propen-1-yl]phenol), and cocaine respectively in baboon plasma and 84 ± 6.4 ( N = 9), 18 ± 11 ( N = 10), 74 ± 5.7 ( N = 118) and 16 ± 3.7 ( N = 18) for carbon-11 labeled benztropine, deprenyl, raclopride, and methylphenidate respectively in human plasma. The automated system has been used for more than 4 years for all plasma analyses for 7 different C-11 labeled compounds used routinely in our laboratory. The robotic radiotracer assay runs unattended and includes automated cleanup procedures that eliminates all human contact with plasma-contaminated containers.

Transfer of lipoprotein(a) and LDL into aortic intima in normal and in cholesterol-fed rabbits.

To study the relative atherogenic potential of lipoprotein(a) [Lp(a)], the transfer of Lp(a) and LDL into the arterial wall was compared in normal rabbits, cholesterol-fed rabbits, and normal rabbits in which the plasma concentration of Lp(a) before injection of labeled lipoproteins was increased by an intravenous mass injection of 45 mg Lp(a). Aorta was removed either 60 minutes or 180 minutes after intravenous injection of a mixed preparation of human 125I-Lp(a) and 131I-LDL; intimal clearance was calculated as radioactivity in aortic intima/inner media divided by the average concentration of the appropriate radioactivity in plasma and by the length of the exposure time. The intimal clearance of labeled Lp(a) and LDL in the aortic arch after 60 minutes of exposure was 87 +/- 9 and 47 +/- 7 nL.cm-2.h-1 (n = 9) in normal rabbits and 82 +/- 14 and 62 +/- 10 nL.cm-2.h-1 (n = 10) in cholesterol-fed rabbits; after 180 minutes of exposure, the intimal clearance of labeled Lp(a) and LDL was 62 +/- 14 and 84 +/- 21 nL.cm-2.h-1 (n = 6) and 30 +/- 6 and 47 +/- 12 nL.cm-2.h-1 (n = 4) in cholesterol-fed and Lp(a)-injected rabbits, respectively. Linear regression analysis showed positive associations between intimal clearance of the two lipoproteins in all four groups of rabbits in the aortic arch, the thoracic aorta, and the abdominal aorta. Aortic immunoreactivity of human apolipoprotein(a) was detected in the intima in association with fatty streak lesions, predominantly within the cytoplasm of foam cells. These results suggest that Lp(a) is transferred into the aortic intima by a mechanism similar to that for LDL and that Lp(a) can be taken up by intimal foam cells; however, Lp(a) and LDL may be metabolized differently upon entrance into the arterial wall.

Metabolic Fate of 4-amino-1-hydroxybutylidene-1,1-bisphosphonate(alendronate). (II). Plasma Concentration, Distribution and Excretion after Repeated Intravenous Administration to 7-week Old Rats and after Single Intravenous Administration to 30-week Old Rats, and Transfer into the Fetus and Milk in Rats.

Plasma concentration, distribution, and excretion of [14C]-alendronate were investigated after repeated intravenous administration once a day for 7 days to 7-week old male rats and after a single intravenous administration to 30-week old male rats. Feto-placental transfer in pregnant rats and the transfer into the milk in lactating rats were also investigated.1. The plasma radioactivity after repeated administration at 0.05 mg/kg of [14C]-alendronate to 7-week old male rats was higher than in single administration. However, there was no difference in the half-lives. The level of radioactivity in noncalcified tissues after repeated administration were also higher than in a single administration, but no accumulation was observed. The maximum level of radioactivity in bones was 6.2-7.5 times higher than in a single dose experiment. The concentration in vertebra was the highest among bones, followed by long bones (femur, tibia, humerus) and calvaria. By the 24th day after final administration, 32.2% of the dosed radioactivity was excreted in the urine and 2.1% in the feces, and the excretion in urine was almost completed within 24 hours. These results suggest that there is no alteration in the disposition of alendronate after repeated administration compared with single administration.2. The AUC of plasma radioactivity after single administration of 0.05 mg/kg of [14C]-alendronate to 30-week old male rats was 2 times higher than in 7-week old rats. The radioactivity in the liver, kidneys, spleen, and heart was also higher. The maximum level of radioactivity in calvaria in 30-week old rats were similar to those in 7-week rats, but was approximately 50% lower in vertebra and long bones than in 7-week old rats. Therefore, the difference of concentration among bones in 30-week old rats was less than in 7-week old rats. The cumulative urinary excretion at 216 hours after administration to 30-week rats was higher (46% of dose) than in 7-week old rats. On the basis of these results, it is suggested that the increase of concentration of radioactivity in plasma and noncalcified tissues and urinary excretion in 30-week rats is due to the decrease in the bone uptake of alendronate as a consequence of decline of bone turnover.3. After single administration of [14C]-alendronate at 0.05 mg/kg to female rats on day 19 of pregnancy, the concentration of radioactivity in plasma was similar to that of 7-week old male rats. Radioactivity was not detected in fetus, indicating that feto-placental transfer of alendronate was low.4. After administration of [14C]-alendronate to female rats 14 days post parturn, the concentration of radioactivity in the milk was higher than in plasma. The transfer of radioactivity into milk was observed.

Studies on Metabolic Fate of 14C-RU44570: Placental Transfer, Transfer into Milk, Absorption Site and Repeated Dosing in Rats, and Metabolism in Rats and Dogs.

The placental transfer, excretion into milk and site of absorption of 14C RU44570 were investigated in normal rats and male rats with ligated loops of gas trointestinal tract. The absorption, distribution, metabolism and excretion of 14C-RU44570 were examined during and after repeated oral administration to male rats at a daily dose of 1 mg/kg for 21 days. In addition, the metabolism of 14C-RU44570 in male dogs was studied after a single oral administration at a dose of 1 mg/kg. 1. In pregnant rats, receiving orally 1 mg/kg of 14C-RU44570 on the 18th days gestation, the level of radioactivity in fetus was lower than that in maternal plasma, and then ratio of the radioactivity was only 0.01% of the dose. In most of fetal tissues, the radioactivity levels decreased rapidly, however, relatively higher level was observed in the lung at 24 hr after the dosing. 2. The maximum concentration of radioactivity in the milk was found at 8 hr following oral administration of 14C-RU44570 at 1 mg/kg to lactating rats. The radioactivity concentration decreased with a half-life of 43 hr. 3. In a study of gastrointestinal absorption in situ, the most of 14C-RU44570 was found to be absorbed from duodenum and jejunum. 4. During repeated daily oral administration, plasma concentration of radioactivity at 24 hr did not increase significantly after the 7th dose. The elimination half-life of plasma radioactivity after the final dosing was comparable to that after the 1st dose. The radioactivity in most of tissues reached a steady state after the 7th or 14th dose during repeated administration. At 672 hr after the final dose, higher level of radioactivity was observed in the lung, while the concentration in other tissues decreased to lower level or even below the detection limit. 5. In plasma, urine, feces, bile or tissues, RU44403, which is a pharmacologically active form, was mainly found after both of single and repeated oral administration to male rats. Unchanged compound, RU44570, was not observed in plas ma and tissues. In addition, any conjugates of the metabolites were not found. 6. In plasma, urine or feces of male dogs, RU44403 was found as a major metabolite, however, RU44570 was also observed in dog plasma.

Placental transfer, lacteal transfer and plasma protein binding of gemcitabine.

1. The placental transfer, lacteal transfer and plasma protein binding of gemcitabine have been studied in rat and dog after single intravenous administration of 10 mg/kg 14C-gemcitabine. 2. Radioactivity was distributed to the foetuses at 5 min after administration to rat on days 12 and 18 of gestation. The concentrations of radioactivity in the foetal liver, lung and kidney on day 18 of gestation were 4.0-6.4 times higher than in the maternal blood at 4 h after administration. Relatively high levels of radioactivity were noted in foetal tissues 24 h after administration, indicating slow elimination from the foetus. 3. The concentration of radioactivity in milk reached a maximum at 15 min after administration to the lactating rat on day 10 after delivery, then declined in a biphasic manner, and was below the detection limit at 48 h. The concentrations of radioactivity in milk were lower than plasma concentrations of radioactivity. 4. Plasma protein binding ratios were 10-16 and 1-7% between 5 min and 8 h after administration to the male rat and dog respectively. When fresh plasma from male rat, dog and adult man was spiked with 14C-gemcitabine at concentrations of 0.1-25 micrograms/ml, the plasma protein binding ratios were about 7% in both rat and dog, and 10% in man.

Pharmacokinetics of acridine-4-carboxamide in the rat, with extrapolation to humans

The pharmacokinetics of N-[2-(dimethyl-amino)ethyl]acridine-4- carboxamide (AC) were investigated in rats after i.v. administration of 18, 55 and 81 mumol/kg [3H]-AC. The plasma concentration-time profiles of AC (as measured by high-performance liquid chromatography) typically exhibited biphasic elimination kinetics over the 8-h post-administration period. Over this dose range, AC's kinetics were first-order. The mean (+/- SD) model-independent pharmacokinetic parameters were: clearance (Cl), 5.3 +/- 1.1 1 h-1 kg-1; steady-state volume of distribution (Vss), 7.8 +/- 3.0 l/kg; mean residence time (MRT), 1.5 +/- 0.4 h; and terminal elimination half-life (t1/2Z), 2.1 +/- 0.7 h (n = 10). The radioactivity levels (expressed as AC equivalents) in plasma were 1.3 times the AC concentrations recorded at 2 min (the first time point) and remained relatively constant for 1-8 h after AC administration. By 6 h, plasma radioactivity concentrations were 20 times greater than AC levels. Taking into account the species differences in the unbound AC fraction in plasma (mouse, 16.3%; rat, 14.8%; human, 3.4%), allometric equations were developed from rat and mouse pharmacokinetic data that predicted a Cl value of 0.075 (range, 0.05-0.10; 95% confidence limits) 1 h-1 kg-1 and a Vss value of 0.63 (range, 0.2-1.1) l/kg for total drug concentrations in humans.

Metabolic Fate of Zolpidem. (III). Transfer into the Fetus and Milk in Rats after Single Oral Dosing.

14C-Zolpidem hemitartrate, a new hypnotic drug, was given orally in a dose of 3.29mg/kg to pregnant and lactating rats and its transfer into the fetus and milk was studied. The results are summarized as follows. 1. After oral dosing to a rat on day 18 of gestation, the radioactivity in the fetus was lower than that in the maternal blood. The radioactivity in the fetal tissues declined rapidly, and no radioactivity was detected 48 hours after dosing. 2. The whole body autoradiograms of rats, which were given the 14C-labelled compound orally on days 13 and 18 of gestation, showed that the radioactivity in the fetus was lower than that in the maternal blood and that the distribution of radioactivity to the fetus was higher in the perinatal period than in the organogenic period. 3. Thirty minutes after oral dosing to lactating rats, the radioactivity in the milk reached a maximum of 267ng eq/ml, and then declined with a half-life of 4.9 hours up to 24 hours. The radioactivity levels in the milk were almost the same or lower than those in the plasma up to 4 hours after dosing, but were 1.1 ?? 1.8 times higher thereafter. The ratio of AUCm to AUCp, which was calculated from the concentrations of radioactivity in milk and plasma respectively, was about 0.65. This suggested that zolpidem and/or its metabolites were less easily transfered into the milk.

Pharmacokinetics of [14C]FCE 22891, a penem antibiotic, following oral administration to healthy volunteers.

FCE 22891 is a prodrug of the penem antibiotic FCE 22101 and is suitable for oral administration. The pharmacokinetics of FCE 22891 were investigated in four healthy male volunteers following the oral administration of 500 mg of [14C]FCE 22891. Levels of radioactivity in plasma were always higher and persisted for longer than those of FCE 22101. The time to the maximum concentration of radioactivity in plasma generally coincided with that of FCE 22101. The respective values for the maximum concentrations of radioactivity in plasma were, on average, 8.57 +/- 2.95 micrograms equivalent/ml and 2.97 +/- 2.05 micrograms/ml. Over a 5-day period, mean urinary and fecal recovery of radioactivity accounted for 53.2 and 41.0% of the dose, respectively. The average amount of FCE 22101 excreted in urine and feces corresponded to 9.0 and 1.6% of the dose, respectively. The urinary recovery of the open-ring metabolite P1 and of its 5-S epimer P2 accounted for about 6.5 and 1.2% of the dose, respectively. Other chromatographic peaks corresponding to nonidentified compounds accounted for about 14.0% (polar metabolite fraction; peak P), 3.7% (less polar fraction; peak X), and 15.4% (least polar fraction) of the dose. Elimination of radioactivity and FCE 22101 in urine was rapid. Intersubject variability in the kinetics of total radioactivity in plasma was far less than that observed for FCE 22101. The results of the present study support suggestions that presystemic metabolism of FCE 22101 and/or transformation of the prodrug to compounds other than FCE 22101 are the main cause of intersubject variability in the kinetics of FCE 22101 produced in plasma following oral administration of its prodrug.

Studies on the Metabolic Fate of 3H-TJN-101. (VI). Blood and Plasma Concentration Profiles and Excretion after Intravenous Administration to Rats and Dogs.

The distribution (blood or plasma concentration) and excretion of 3H-TJN-101 were examined in male rats and dogs after intravenous administration (4 mg/kg). 1. In male rats, the blood level of radioactivity ranged from 1.00 to 1.13μg/ml (TJN-101 base) at 5 min through 1hr after dosing. Thereafter, the blood level decreased with a half-life of 1.4hr from 2 to 6hr, and with a half-life of 25hr from 8 to 72hr after drug treatment. The AUC for 168hr after treatment was 5.75μg·hr/ml. 2. Within 168hr after injection, the radioactivily excreted in urine and feces in male rats was 11.7% and 80.5% of the dose, respectively. In urine collected for 168hr, the unstable tritium equivalent to 1.2% of the administered radioactivity was detected. 3. When the concentration of radioactivity in the blood of male dogs was determined by the dry method, the level was 3.03μg/ml (TJN-101 base) at 5min, which was first measurment period after dosing. Thereafter, the blood level decreased with a half-life of 43min up to 45min, with a half-life of 2.6hr from 1 to 4hr, and with a half-life of 6.1hr from 6 to 24 hr after dosing. At 48hr, the blood level decreased below the detection limit. The AUC for 24hr after dosing was 8.56μg·hr/ml. The concentration of radioactivity in plasma, determined by the dry method, was 5.05μg/ml at 5min. Thereafter, plasma level followed a course similar to that of blood level. The ratio of unstable tritium in plasma was below 6 % until 12hr, 27% at 24hr, and 50 ?? 75% from 48 to 120hr. The distribution ratio of radioactivity in blood cell simultaneously determined was 4.7 ?? 14.0% during the first 24hr. 4. Within 168hr after injection, radioactivity excreted in urine and feces in male dogs was 38.9% and 60.0% of the dose, respectively.

Absorption and disposition of 14C-labelled oxiracetam in rat, dog and man.

The absorption and disposition of the nootropic drug oxiracetam (4-hydroxy-2-oxo-pyrrolidine-1-yl acetamide) were studied in rats and dogs (10 mg/kg i.v. and 10, 50 and 3000 mg/kg p.o.) and two healthy male volunteers (800 mg p.o.) using a [14C]-labelled preparation. Peroral absorption of [14C]-oxiracetam was incomplete in rats (28-42%), high in dogs (81-90%) and intermediate in man (about 56%). The rate of absorption was high in all species. Elimination was biphasic and the concentration of total radioactivity in blood and plasma declined rapidly with an initial elimination half-life of 1-3 h in all species. The specific systemic exposure to [14C]-oxiracetam was lowest in the rat, intermediate in the dog and highest in man. In all species the systemically available radioactivity was nearly exclusively excreted in urine in the form of unmetabolized oxiracetam. Whole-body autoradiography and quantitative determination of the radioactivity in various organs following i.v. and p.o. administration of [14C]-oxiracetam to rats demonstrated extensive distribution of the compound with high levels in kidney, liver, lung and skin, and very low levels in the brain. The radioactivity was rapidly eliminated from the body and minimal accumulation was observed upon repeated administration of 10 mg/kg for 8 days. Levels in the brain were still low, but higher than following a single dose, indicating slow diffusion across the blood-brain barrier. In pregnant rats treated with [14C]-oxiracetam radioactivity passed reversibly and to a limited extent through the placenta into fetal tissue.

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)

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.

A Method for the In Vivo Investigation of the Serotonergic 5‐HT2 Receptors in the Human Cerebral Cortex Using Positron Emission Tomography and 18F‐Labeled Setoperone

Following previous validation in baboons, we have studied the characteristics of [18F]setoperone as a radioligand for investigating serotonergic 5-hydroxytryptamine2 (5-HT2) receptors in the normal, unmedicated human brain with positron emission tomography (PET); subjects orally pretreated with therapeutic amounts of ketanserin, sulpiride, or prazosin were also studied to evaluate the specificity and sensitivity of [18F]setoperone brain specific binding. In controls (n = 10), the tracer showed a clear-cut retention in both frontal cortex and striatum (known to contain a high density of 5-HT2 receptors) relative to cerebellum (known to be devoid of 5-HT2 receptors). In the seven young controls (20-39 years old), the frontal cortex/cerebellum and striatum/cerebellum ratios increased during the first hour to reach similar values of 2.53 +/- 0.12 and 2.38 +/- 0.11 (mean +/- SEM), respectively, and were essentially stable during the second hour. Pretreatment with ketanserin (a 5-HT2 blocker) significantly reduced the frontal cortex/cerebellum ratio to 0.7-1.0 at 65 min, whereas the striatum/cerebellum ratio was significantly, but only partially, reduced. During sulpiride treatment (a D2 blocker), the frontal cortex/cerebellum ratio was not altered, whereas the striatum/cerebellum ratio was significantly, but only partially, reduced. With prazosin pretreatment (an alpha 1-adrenergic blocker), neither the frontal cortex/cerebellum nor the striatum/cerebellum ratio was modified. These data in humans with PET demonstrate that [18F]setoperone labels with high sensitivity and selectivity 5-HT2 receptors in the frontal cortex; in striata, however, binding is to both 5-HT2 and D2 receptors. The deproteinated-to-whole plasma radio-activity concentration ratio increased with time following injection. The mean percentage of intact [18F]setoperone, in deproteinated plasma, was 82, 74, 53, 45, 30, and 22% at 5, 10, 20, 30, 60, and 110 min following injection, respectively. These data indicate that [18F]setoperone (a) is significantly bound to plasma proteins and (b) is significantly metabolized into several labeled metabolites that are much more hydrophilic than setoperone and, hence, presumably do not cross the blood-brain barrier. These results suggest the suitability of [18F]setoperone data for modeling of 5-HT2 receptor binding in brain.

Studies on the metabolic fate of carvedilol. (V). Transfer into the fetuses in rats.

The transport of carvedilol to fetuses via placenta was studied in pregnant rats on days 12 and 19 of gestation after a single oral administration of 14C-carvedilol at a dose of 10mg/kg.1. On day 12 of gestation, the concentrations of radioactivity in the fetus were lower than that in the maternal blood as determined by liquid scintillation counting and autoradiography. The percentage distribution of radioactivity in a fetus amounted to less than 0.01% of dose.2. On day 19 of gestation, the concentrations of radioactivity in fetal plasma, fetal blood and fetal liver at 1 hr were nearly half as high as that in the maternal plasma. The percentage distribution of radioactivity in a fetus amounted to 0.01% of dose.Biliary excretion in fetus was suggested from the observation of relatively high concentration of radioactivity in fetal intestine at 24hr. It was concluded that the transfer of carvedilol into fetus was low.