Absorption, tissue distribution, and excretion of zinc acexamate in rats

AIM: The SRK II formula has been widely used for intraocular lens (IOL) power calculations. The predictability of this formula is evaluated in axial myopic patients. METHODS: Planned extracapsular cataract extraction and posterior chamber IOL implantation (PECCE + IOL) were performed on 98 eyes of 98 patients with axial length > 24.5 mm. Cases had no preoperative complications and postoperative visual acuity was at least 0.5 (Snellen). Corneal refractive power and axial length were measured preoperatively and emmetropic IOL power calculations were made using the SRK II formula. Long-term (mean 4.7 months) visual acuities and refractions were noted postoperatively. RESULTS: The absolute refractive error was < 1.00 Diopters (D) in 57 eyes (58.2%) and < 2.00 D in 83 eyes (84.7%). The mean absolute error of the SRK II formula in axial myopia was 1.16 D +/- 0.78 SD. CONCLUSIONS: The SRK II formula is not very accurate in axial myopic patients.     

Metabolism of linoleamides. I. Absorption, excretion and metabolism of N-(alpha-methylbenzyl)linoleamide in rat and man

1. In urine of rats dosed with N-(alpha-methylbenzyl)linoleamide (MBLA), three dicarboxylic acid monoamides, N-(alpha-methylbenzyl)succinic acid monoamide, N-(alpha-methylbenzyl)glutaric acid monoamide and N-(alpha-methylbenzyl)adipic acid monoamide, were identified. Conjugated alpha-methylbenzylamine, hippuric acid and conjugates of the dicarboxylic acid monoamides were also found in the urine. N-(alpha-Methylbenzyl)succinic acid monoamide was the main metabolite in rats. 2. Biliary excretion of radioactivity was studied in rats, cannulated for collection of bile and duodenal infusion, after oral administration of N-(alpha-methylbenzyl)[1-14C]linoleamide. With constant duodenal infusion of bile, about 7% of the dose was excreted in the bile, while excretion of radioactivity was negligible without bile infusion. 3. The g.l.c. analysis of human urine after oral administration of MBLA revealed that two dicarboxylic acid monoamides were present and N-(alpha-methylbenzyl)succinic acid monoamide was the main metabolite. 4. MBLA was excreted unchanged in the faeces of men who received MBLA to the extent of about 53% dose in 3 days. 5. MBLA was not detected (less than 1 mug/ml) in the serum of a volunteer who had been taking an oral daily dose of 1500 mg of MBLA for 3 months.     

Absorption, distribution and excretion of 14C-cefatrizine (14C-S-640 P) in rat (author''s transl)

The reliability and rapidity of methods utilizing radioimmunoassay ( RIA) for detecting chorionic gonadotropin (CG) and estrogens in plasma, competitive protein binding assay for plasma progestins, and the hemagglutination inhibition test for urinary CG in the diagnosis of early pregnancy was evaluated in baboons. The hemagglutination inhibition test for detection of urinary CG did not give satisfactory results as late as Day 25 of pregnancy. Confirmation of pregnancy could not be established on Days 8 and 12 of pregnancy by RIA of estrogens, progestins, or CG. However, detection of plasma CG by RIA was 96.6% successful by Day 16, though the method was time-consuming. However, the determination of plasma estrogens and progestins by RIA was determined more quickly on Day 16, and gave equally successful results as the RIA for CG.     

Absorption, distribution, and excretion of [14C]patulin by rats

Adult rats of both sexes were given a single oral dose of [14C] patulin and were sacrificed at various time intervals from 4 hr to 7 days following administration of the mycotoxin. Two groups of rats were employed; the treated group had been exposed to daily oral doses of unlabeled patulin (dissolved in pH 5.0 citrate buffer) in utero and for 41-66 wk after weaning, while the controls were given the buffer only throughout gestation and for 38-81 wk after weaning. Approximately 49% of the administered 14C radioactivity was recovered from feces and 36% from urine within 7 days after dosing. Most of the excretion of labeled material occurred within the first 24 hr. All of the 14C activity detected in the urine samples was either metabolites and/or conjugates of the original [14C]patulin. About 1-2% of the total radioactivity was recovered as 14CO2 from expired air. Carbon-14 radioactivity in various tissues and organs was determined throughout the 7 day period; the most significant retention site was the red blood cells.     

Metabolism of linoleamides. II. Absorption, distribution, excretion and metabolism of N-[alpha-phenyl-beta-(p-tolyl)ethyl]linoleamide

1. Absorption, distribution, excretion and metabolism of (-)N-[alpha-phenyl-beta-(p-tolyl)ethyl][14C]linoleamide (14C-PTLA) were studied in rats and dogs. Faecal excretion of PTLA was studied in dogs and men by g.l.c. 2. 14C-PTLA (10 mg/kg) given orally to rats resulted in urinary and faecal excretion of radioactivity of 2 and 93%, respectively, by male rats and 8 and 87% by female rats in 48 h. Faecal excretion of PTLA in men was similar to that in rats. 3. Distribution of radioactivity in rats and dogs after oral administration of 14C-PTLA showed that a major part of the dose was not absorbed. 4. N-[alpha-phenyl-beta-(p-tolyl)ethyl]glutaric acid monoamide were detected in the urine of rats dosed orally with 14C-PTLA.     

Absorption, pharmacokinetics and metabolism of 14C-sumatriptan following intranasal administration to the rat

1. Studies have been carried out to investigate the absorption of sumatriptan after intranasal administration to rats. The pharmacokinetics, metabolism and excretion of 14C-sumatriptan were compared following intranasal and intravenous dosing to male and female albino rats using an aqueous buffered formulation at pH 5.5. 2. Following intravenous administration sumatriptan was eliminated from plasma with a half-life of about 1.1 h. After intranasal administration there was rapid absorption of part of the dose and two peak plasma concentrations were observed, initially at 0.5 and then at 1.5-2 h. The elimination half-life after the second peak was estimated as being about 4 h. 3. Radioactivity was largely excreted in urine (up to 89% of dose in 168 h) after both intravenous and intranasal administration, with a faster rate of excretion after intravenous dosage (73% males, 64% females within 6 h) than after intranasal dosage (37% males, 40% females within 6 h). 4. 14C-sumatriptan was the major component in urine and in extracts of faeces after both intravenous and intranasal administration. The major metabolite excreted in urine and faeces was GR49336, the indole acetic acid analogue. 5. The results of this in vivo rat study suggest that absorption of the dose via the nasal mucosa is incomplete after intranasal administration and that there is a secondary absorption phase probably reflecting oral absorption of part of the dose. The bioavailability is estimated as about 30%, for the period 0-6 h.     

Absorption, excretion, and tissue deposition of titanium in sheep

Titanium metabolism was measured in three 18 kg lambs each fed 450 g chopped hay daily. Two of the lambs were dosed orally and one intravenously with 3 muCi titanium-44 each. Clearance of the intravenous dose was extremely slow; after oral administration, however, no titanium-44 was detected in blood plasma for 48 h. Over 96% of the oral dose was recovered in feces and digestive tract contents. Titanium-44 absorption, estimated from total carcass recovery and by comparison of concentrations in internal organs of orally and intravenously dosed lambs, was less than .5%. Fecal titanium could be a satisfactory index of soil ingestion by grazing ruminants.     

Assimilation, excretion and distribution of cobalt-60 in the rat after daily ingestion of contaminated marine food products

An unusual electrocardiogram (ECG) is presented which demonstrates two mechanisms of communication between the atria and the ventricles. The first appears to reflect ordinary atrio-ventricular impulse propagation. The second appears likely to represent stimulation of the ventricles by mechanical atrial systole.     

Kinetics of absorption, equilibration (or distribution), and excretion of orally and intraperitoneally administered cholesterol in the rat

Forty patients with abdominal injury and massive hemoperitoneum had left thoracotomy and thoracic aortic occlusion. All 40 patients had tense abdominal distention and 37 patients were hypotensive at the time of skin incision despite aggressive resuscitation with blood and crystalloid solution. Laparotomy was performed initially in 11 patients; seven patients had sudden cardiovascular collapse as the abdominal wall tamponade was released and four patients remained hypotensive. With thoracotomy and thoracic aortic occlusion six of the 11 patients were resuscitated and had their injuries repaired. Thoracotomy and thoracic aortic occlusion were performed before laparotomy in 29 patients: seven patients remained hypotensive and expired; blood pressure was promptly restored in 22 patients and 11 of them survived the operative procedure. Left thoracotomy and thoracic aortic occlusion, before laparotomy, is offered as an alternative approach in patients with refractory hypotension and tense, abdominal distention. This technique aids in rapid restoration of vital signs, insures continued perfusion of the brain and myocardium, provides proximal arterial control, and prevents sudden cardiac arrest as the abdominal wall tamponade is released.     

Absorption and metabolism of nivalenol in pigs

Effects of chronic concentrations of linuron (0, 0.5, 5, 15, 50, and 150 micrograms/L) were studied in indoor, macrophyte dominated, freshwater microcosms. The concentrations were kept at a constant level for 4 weeks. This paper is the first in a series of two and summarizes the course of the linuron concentrations in time and its effects on macrophytes, periphyton, and phytoplankton. These endpoints were studied from 3 weeks before the start of the treatment until 11 weeks after the start. The degradation of linuron in the water was lower at higher treatment levels, probably due to a decrease in pH. Linuron treatment resulted in a decrease in biomass of the macrophyte Elodea nuttallii and a clear decrease in abundance of the algae Cocconeis, Chroomonas, and Phormidium foveolarum. It was found that Cocconeis first decreased in biovolume and after 2 weeks also in abundance. The alga Chlamydomonas increased in abundance at the two highest doses, resulting in higher chlorophyll-a levels. The NOECs of 0.5 micrograms/L for the inhibition of the growth and photosynthesis of Elodea nuttallii, the abundance of Cocconeis and Chroomonas, and the oxygen and pH levels were the lowest recorded in the microcosms. The safety factors adopted by the EU in the Uniform Principles appeared to ensure adequate protection for the ecosystem in the case of chronic exposure to linuron.     

Estrogen metabolism and excretion in Oriental and Caucasian women

BACKGROUND: Caucasian and Oriental women have different incidence rates of breast cancer. Among the underlying risk factors for the development of breast cancer in the women of these two groups may be their different diets and patterns of estrogen metabolism and excretion. The absolute levels and relative ratios of 16 alpha-hydroxylated estrogens and 2-hydroxylated estrogens (catechol estrogens) in the body may have a role in the etiology of breast cancer, but studies so far have provided only conflicting results. PURPOSE: Our goal was to study estrogen metabolism, in particular, the extent of 2-hydroxylation and 16 alpha-hydroxylation of estrogens in two groups of women, one Caucasian and one Oriental, with inherently different breast cancer risks. METHODS: Dietary records were analyzed over 3-day periods in the mid-follicular phase, twice, at 6-month intervals for 13 premenopausal Oriental women, recent immigrant arrivals in Hawaii with presumed low risk of breast cancer, and for 12 premenopausal Finnish women with presumed higher risk. The urinary estrogen profile was measured by gas chromatography-mass spectrometry and plasma and fecal estrogens were assayed by chromatographic radioimmunoassays. RESULTS: Mean fat intake per 1000 kcal was 73% higher (P < .001) in the Finnish women, but the mean fiber intake and fecal weights were similar to those of the Oriental women. Compared with Oriental women, Finnish women had 46% higher plasma estradiol (P < .01) and 124% higher plasma estrone sulfate (P < .01); however, after adjustment for differences in age and body mass index, only the difference in estrone sulfate remained statistically significant (P < .05). Mean plasma levels of estrone and estradiol correlated with height after adjustment for body mass index (P < .05). Mean plasma levels of estrone and sex hormone-binding globulin were similar. The Finns had higher mean urinary estrone (193%), estradiol (166%), various catechol estrogens (130%-439%), and total estrogen excretion (123%) (all P < .001), but similar 16 alpha-hydroxylated estrogen excretion. As calculated, 16 alpha-hydroxylation of estrone was significantly increased (P < .01) in the Oriental women, but 2-hydroxylation, 4-hydroxylation, and 16 beta-hydroxylation of estrone were similar in both groups. The ratio of catechol estrogen to 16 alpha-hydroxylated estrogen was four to five times higher (P < .001) in the Finnish women. The Oriental women had two to three times higher fecal excretion of estrogens than the Finnish women (P < .01). CONCLUSIONS: Our results indicate that high catechol estrogen formation may be a greater risk factor for breast cancer than high 16 alpha-hydroxylation of estrogens. However, the main risk factor for the Finnish women, as opposed to the Oriental women, may be their higher estrogen levels that result from a higher fat diet, higher estrogen production related to their greater height, and lower fecal estrogen excretion.     

Uptake, distribution and metabolism of isoprenaline in the dog saphenous vein

Morphine withdrawal was precipitated by injection of various morphine antagonists into restricted parts of the ventricular system or by microinjection of levallorphan into specific brain areas of rats made dependent on morphine by repeated pellet implantation. When the antagonists could spread only within the lateral ventricles and the 3rd ventricle, a weak withdrawal syndrome was induced; by antagonist administration into the restricted 4th ventricle, however, strong withdrawal signs like jumping were elicited even at small dosages. In microinjection experiments, structures in the midbrain and the lower brain stem proved to be the most sensitive to antagonist action. Although microinjections into thalamic nuclei also had some effect, it could not be excluded that the effects were due to uncontrolled spreading of the drug. This became especially clear from experiments with tritium-labeled levallorphan. It is concluded that brain structures located in the anterior parts of the floor of the 4th ventricle and/or caudal parts of the periaqueductal gray matter are important sites of action for the development of physical dependence on morphine.     

Role of metabolism in the biliary excretion of methadone metabolites

1. The effects of six local anaesthetics have been studied on the activities of soluble phospholipases A2 (EC 3.1.1.4) and lysophospholipase (EC 3.1.1.5). 2. Phospholipase A2 activity in human seminal plasma towards sonicated radioactively-labelled phosphatidylethanolamine was slightly stimulated a low and inhibited at high concentrations of all anaesthetic compounds employed. The order of decreasing potency was chlorpromazine, dibucaine, tetracaine, lidocaine, cocaine and procaine. In line with previous findings, the mode of inhibition was seen to be competitive with respect to Ca2+. 3. Phospholipase A2 activity in crude venom of Crotalus adamanteus was not affected or slightly stimulated by local anaesthetics up to 10(-2) M concentrations, when egg yolk was used as substrate. However, with sonicated radioactively-labelled phosphatidylcholine or phosphatidylethanolamine as substrate, stimulation of phospholipase activity was seen with all local anaesthetics up to 10(-2) M, the order of decreasing potency again being chlorpromazine, dibucaine, tetracaine, lidocaine, cocaine and procaine. The mode of stimulation was seen to be un-competitive with respect to substrate and probably independent of any involvement of Ca2+. 4. As in seminal plasma phospholipase A2, the activity in crude Naja naja venom towards sonicated radioactively labelled phosphatidylcholine was stimulated at low and inhibited at high concentrations of dibucaine and chloropromazine, for example. The mode of inhibition was seen to be competitive with respect to Ca2+, whereas stimulation by the anaesthetic drugs was independent of Ca2+. Binding between drug and enzyme was demonstrated by equilibration filtration of purified phospholipase A2 of Naja naja venom through a Sephadex G 25-fine column, previously equilibrated with 0.5 mM radioactively labelled chlorpromazine. 5. Lysophospholipase activity in rat liver cytosol towards radioactively labelled lysophosphatidylcholine was inhibited by all local anaesthetics used; the order of decreasing potency was chlorpromazine, dibucaine, tetracaine, cocaine, lidocaine and procaine. The inhibition was un-competitive with respect to substrate. 6. The inhibitory and stimulatory potencies of the local anaesthetics employed closely parallel their lipid solubilities and anaesthetic potencies.     

Tissue distribution, metabolism, and clearance of the convulsant trimethylolpropane phosphate in rats

The distribution, metabolism, and clearance of trimethylolpropane phosphate (TMPP), a potent, bicyclophosphate, gamma-aminobutyric acid-ergic convulsant, were studied in male Fischer-344 rats. Intraperitoneal administration of TMPP was compared with oral gavage with respect to rates of absorption, distribution, and clearance. Distribution of TMPP to major body tissues was evaluated for the first 24 hr after administration or, in the case of regional brain distribution, immediately after the first TMPP-induced clinical seizure. Samples purified from the urine, feces, and bile of rats exposed to TMPP, as well as from rat liver microsomes incubated with TMPP in vitro, were analyzed for possible phase I and phase II metabolism, using HPLC. The disposition and clearance of TMPP in the blood and major body tissues were measured. TMPP was found to be well distributed to highly vascularized tissue compartments, with little retention >24 hr after administration. TMPP was eliminated through the urine and feces as the parent compound, with no evidence of phase I or phase II metabolism. TMPP was rapidly cleared from the blood during the first 30 min after exposure, with slower clearance of >87% of the drug during the following 8-hr period and >99.5% clearance by 100 hr after injection. Repeated daily exposure to TMPP for up to 5 successive days resulted in no measurable accumulation in the brain or other major tissue compartments. Possible mechanisms for TMPP-induced, short- and long-term, neurobehavioral modulation are discussed.     

Absorption and intestinal metabolism of purine dideoxynucleosides and an adenosine deaminase-activated prodrug of 2',3'-dideoxyinosine in the mesenteric vein cannulated rat ileum

This study investigates the mechanisms of absorption and the role of intestinally localized purine salvage pathway enzymes on the ileal availabilities of 2',3'-dideoxyinosine (ddI), a substrate for purine nucleoside phosphorylase (PNP); 2'-fluoro-2',3'-dideoxyinosine (F-ddI), a non-PNP substrate; and 6-chloro-2',3'-dideoxypurine (6-Cl-ddP), an adenosine deaminase (ADA) activated prodrug of ddI. The potential for increasing the intestinal availability of 6-Cl-ddP through the use of ADA inhibitors, namely, 2'-deoxycoformycin (DCF) and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), is also explored. Drug permeability coefficients across the intestinal epithelium were determined in in situ perfusions in the mesenteric vein cannulated rat ileum based on both drug appearance in blood (Pblood) and disappearance from the lumen (Plumen) and their paracellular and transcellular components were estimated by comparison to the permeabilities of two paracellular markers, mannitol and urea. Values of Pblood for ddI were determined to be (1.1 +/- 0.3) x 10(-6) cm/s, in close agreement with the value of (1.0 +/- 0.3) x 10(-6) cm/s obtained for F-ddI, a PNP resistant analogue of ddI having virtually the same molecular size and lipophilicity as ddI. This indicates that PNP may not play an important role in the low intestinal absorption of ddI. The Pblood for 6-Cl-ddP, (19 +/- 2) x 10(-6) cm/s, was 4.5-fold lower than Plumen, (84 +/- 12) x 10(-6) cm/s, which means that 77 +/- 6% of 6-Cl-ddP was metabolized during its intestinal transport, thus qualitatively accounting for the low oral bioavailability (7%) of 6-Cl-ddP observed in vivo in rats. Extensive intracellular metabolism of 6-Cl-ddP by ADA was confirmed by the high concentrations of ddI found both in the intestinal lumen and blood during 6-Cl-ddP perfusions and by a rate of ddI appearance in blood which was approximately 10-fold higher than ddI controls. Co-perfusion of the potent, hydrophilic ADA inhibitor DCF (Ki = 0. 001-0.05 nM) with 6-Cl-ddP led to only partial inhibition of intestinal ADA, while complete inhibition was obtained using the less potent but more lipophilic inhibitor EHNA (Ki = 1-20 nM). Hence, EHNA may be used to improve intestinal absorption of 6-Cl-ddP in vivo.