Disposition of orally and intravenously administered methyltetrahydrofuran in rats and mice

The disposition of [14C]methyltetrahydrofuran (14C-MTHF) in rats and mice was determined by following changes in the radioactivity in tissue and excreta with time after dosing. MTHF administered orally (1, 10, or 100 mg/kg) or intravenously (1 mg/kg) to either rats or mice was rapidly metabolized and excreted with <8% (mice) or 8-22% (rats) of the dose remaining in the body after 24 h (1 and 10 mg/kg doses) or 72 h (100 mg/kg dose). Based on recovery of radioactivity in excreta (other than feces) and tissues (other than the gastrointestinal [GI] tract), absorption of orally administered MTHF was essentially complete (93-100%). There were no overt signs of toxicity observed at any dose studied. The major route of excretion in mice was in urine followed by exhaled CO2. In rats the major route of excretion was exhaled CO2 followed by urinary excretion. The excretion of exhaled volatile organic compounds (VOC) was dose-dependent in both species; at lower doses exhaled VOC represented 1-5% of dose, but at the highest dose (100 mg/kg) this proportion rose to 14% (mice) and 27% (rats). Analysis of the VOCs exhaled at the high dose indicated that the increase was due to exhalation of the parent compound, 14C-MTHF. Analysis of urine showed three highly polar peaks in the mouse urine and two polar peaks in the rat urine. Because the 14C label in MTHF was in the methyl group, the polar metabolites were considered likely due to the one-carbon unit getting into the metabolic pool and labeling intermediate dietary metabolites.     

Central inhibition of gastric motility by intravenously administered nicotine in rats

Effects of intravenously (i.v.) administered nicotine on gastric motility were investigated in urethane-anesthetized rats in which an intragastric balloon had been placed. I.v. administered nicotine at 75-300 nmole/kg dose-dependently decreased gastric motility. Decrease in gastric motility induced by nicotine at the dose of 300 nmole/kg was inhibited by intracisternally administered hexamethonium. Gastric motility was also decreased by intracisternally applied nicotine (1-10 nmole). These doses were much smaller than those by the intracerebroventricular route in our previous report. Bilateral vagotomy significantly suppressed basal gastric motility. In bilaterally vagotomized animals, nicotine at 1 mumole/kg but not 300 nmole/kg given i.v. significantly decreased the gastric motility maintained at a normal level by electrical stimulation of the vagus nerve. This nicotine-induced decrease in gastric motility, under conditions of electrical stimulation of the vagus nerve, was inhibited by pretreatment with phentolamine. These results suggest that a smaller dose of nicotine given i.v. activates nicotinic receptors in the brainstem and elicits vagally-mediated inhibition of gastric motility. Activation of peripheral alpha-adrenergic mechanisms together with that of central nicotinic mechanisms may be involved in the decreasing effects of a larger dose of nicotine on gastric motility.     

Tissue distribution and toxicity of intravenously administered titanium dioxide nanoparticles in rats

The tissue distribution and toxicity of intravenously administered nanoparticles of titanium dioxide (TiO₂) (>10 wt.% at <100 nm size) were investigated because of the fundamental importance to obtain information on the kinetics of this widely used nanoparticle in a situation of 100% bioavailability. Male Wistar rats were treated with single intravenous injections of a suspension of TiO₂ in serum (5 mg/kg body weight), and the tissue content of TiO₂ was determined 1, 14, and 28 days later. Biochemical parameters and antigens in serum were also assessed to determine potential pathological changes. The health and behavior of the animals were normal throughout the study. There were no detectable levels of TiO₂ in blood cells, plasma, brain, or lymph nodes. The TiO₂ levels were highest in the liver, followed in decreasing order by the levels in the spleen, lung, and kidney, and highest on day 1 in all organs. TiO₂ levels were retained in the liver for 28 days, there was a slight decrease in TiO₂ levels from day 1 to days 14 and 28 in the spleen, and a return to control levels by day 14 in the lung and kidney. There were no changes in the cytokines and enzymes measured in blood samples, indicating that there was no detectable inflammatory response or organ toxicity. Overall, rats exposed to TiO₂ nanoparticles by a route that allows immediate systemic availability showed expected tissue distribution, no obvious toxic health effects, no immune response, and no change in organ function. Therefore, even with 100% bioavailability of the 5 mg/kg TiO₂ dose afforded by the intravenous route of administration, there were no remarkable toxic effects evident in the experimental animals. These results indicate that TiO₂ nanoparticles could be used safely in low doses.     

Pharmacokinetics of chitobiose and chitotriose administered intravenously or orally to rats

Chitooligosaccharides have attracted much attention as new biomedical materials. The biologic availability of each of these chitooligosaccharides, however, has not yet been studied. In the present study, we found that chitobiose and chitotriose appeared in the blood of rats with maximum plasma concentrations at around 1 h after administration when given orally at a dose of 30 mg/kg. However, chitotetraose and chitopentaose did not appear in the blood when given at a dose of 300 mg/kg. Pharmacokinetic analysis of chitobiose and chitotriose after intravenous administration at 100 mg/kg revealed that both sugars were eliminated from the body following a one-compartment model and that the former relative to the latter was higher for both the total body clearance (224+/-43 vs. 155+/-26 ml/h/kg) and the distribution volume (107+/-15 vs. 65+/-9 ml/kg). The absolute oral bioavailability of chitobiose was higher than that of chitotriose at all doses (30, 100, and 300 mg/kg) examined. The first-order absorption rate constants for chitobiose and chitotriose at all doses were less than 1.0 h(-1) and smaller than the elimination rate constants (2.2+/-0.3, 2.7+/-0.1 h(-1), respectively). The absorption was slow, resulting in flip-flop kinetics. This study indicates that among various chitooligosaccharides, only chitobiose and chitotriose can be appreciably absorbed from the gastrointestinal tract.     

Embryo-fetal development toxicity of honokiol microemulsion intravenously administered to pregnant rats

The aim of this study was to evaluate the embryo-fetal development toxicity of honokiol microemulsion. The drug was intravenously injected to pregnant SD rats at dose levels of 0, 200, 600 and 2000 μg/kg/day from day 6–15 of gestation. All the pregnant animals were observed for body weights and any abnormal changes and subjected to caesarean-section on gestation day (GD) 20; all fetuses obtained from caesarean-section were assessed by external inspection, visceral and skeletal examinations. No treatment-related external alterations as well as visceral and skeletal malformations were observed in honokiol microemulsion groups. There was no significant difference in the body weight gain of the pregnant rats, average number of corpora lutea, and the gravid uterus weight in the honokiol microemulsion groups compared with the vehicle control group. However, at a dose level of 2000 μg/kg/day, there was embryo-fetal developmental toxicity observed, including a decrease in the body length and tail length of fetuses. In conclusion, the no-observed–adverse-effect level (NOAEL) of honokiol microemulsion is 600 μg/kg/day, 75 times above the therapeutic dosage and it has embryo-fetal toxicity at a dose level of 2000 μg/kg/day, which is approximately 250 times above the therapeutic dosage.     

Antibacterial activity of ciprofloxacin administered intravenously in a pharmacodynamic in vitro model.

The antibacterial activity of ciprofloxacin against Gram-positive and Gram-negative bacteria was evaluated in an in vitro model by simulating its pharmacokinetics following a single 100 or 200 mg administration intravenously. The one compartment open model described by Grasso and coworkers was used for these experiments. Ciprofloxacin concentrations in the model were reproduced by calculations based on the concentration-time curve in human volunteers as reported by Wise and others. The maximum reduction of viable cell count for Enterococcus faecalis and Staphylococcus aureus was from two-to three-orders of magnitude; for Pseudomonas aeruginosa and Enterobacter cloacae from four to seven orders. A rapid killing was recorded both for Gram-positive and Gram-negative bacteria, but the initial killing was more prolonged and more pronounced for the higher dosage. The last did not interfere with regrowth that occurred for all strains after eight hours.     

PEGylated cholecystokinin prolongs satiation in rats: dose dependency and receptor involvement

BACKGROUND AND PURPOSE: Acute intraperitoneal (i.p.) administration of cholecystokinin (CCK) is known to induce a significant, but short-lasting, reduction in food intake, followed by recovery within hours. Therefore, we had covalently coupled CCK to a 10 kDa polyethylene glycol and showed that this conjugate, PEG-CCK(9), produced a significantly longer anorectic effect than unmodified CCK(9). The present study assessed the dose-dependency of this response and the effect of two selective CCK(1) receptor antagonists, with different abilities to cross the blood-brain barrier (BBB), on PEG-CCK(9)-induced anorexia. EXPERIMENTAL APPROACH: Food intake was measured, for up to 23 h, after i.p. administration of different doses (2, 4, 8, 16 and 32 microg kg(-1)) of CCK(9) or PEG-CCK(9) in male Wistar rats. Devazepide (100 microg kg(-1)), which penetrates the BBB or 2-NAP (3 mg kg(-1)), which does not cross the BBB, were coadministered i.p. with PEG-CCK(9) (6 microg kg(-1)) and food intake was monitored. KEY RESULTS: In PEG-CCK(9)-treated rats, a clear dose-dependency was seen for both the duration and initial intensity of the anorexia whereas, for CCK(9), only the initial intensity was dose-dependent. Intraperitoneal administration of devazepide or 2-NAP, injected immediately prior to PEG-CCK(9), completely abolished the anorectic effect of PEG-CCK(9). CONCLUSIONS AND IMPLICATIONS: The duration of the anorexia for PEG-CCK(9) was dose-dependent, suggesting that PEGylation of CCK(9) increases its circulation time. Both devazepide and 2-NAP completely abolished the anorectic effect of i.p. PEG-CCK(9) indicating that its anorectic effect was solely due to stimulation of peripheral CCK(1) receptors.     

Pharmacokinetics of intravenously administered stealth liposomal doxorubicin modulated with verapamil in rats.

Treatment of cancer through co-administration of anticancer drugs and multidrug resistance (MDR) modulators as a strategy to overcome drug resistance has been extensively explored. However, success has been limited by pharmacokinetic interactions because of non-specific blockade of P-glycoprotein (P-gp) in normal tissues or inability to reach relevant concentrations clinically. We hypothesized that stealth liposomal co-encapsulation of doxorubicin (DOX) with a P-glycoprotein inhibitor, verapamil (DARSLs), may overcome these limitations. Using intravenous (i.v.) administrations, the effects of verapamil (VER) either free (FV) or liposome co-encapsulated with DOX (DARSLs) on the pharmacokinetics and tissue distribution characteristics of DOX either as free (FD) or liposome-encapsulated (LD) were evaluated in normal rats. FV increased (P<0.05) the plasma AUC of free DOX (FD). Preparations containing LD had significant prolonged systemic exposure and slow tissue distribution of DOX. LDFV (liposomal DOX with free verapamil) and DARSLs shared similar DOX pharmacokinetics but the latter showed slower DOX distribution in most tissues studied and slower (P<0.05) DOX biliary transport. The addition of VER into LD in these two preparations significantly increased the AUC (P<0.01) and reduced the clearance (P<0.01) of DOX when compared to LD. Specifically, DARSLs reduced initial DOX distribution to the heart (P<0.05) corresponding to initial alleviation (P<0.05) of bradycardia when compared to other DOX with VER preparations. In conclusion, liposomal co-encapsulation of DOX with VER has promise of significant therapeutic advantages, and should be explored further in therapeutic studies with animal tumor xenograft models.     

Uptake by hepatocytes and biliary excretion of intravenously administered polystyrene microspheres in rats

The in vivo uptake by hepatocytes and biliary excretion of fluorescein isothiocyanate-labeled polystyrene microsphere with a particle size of 50 nm (MS-50) after intravenous administration was studied in rats. It was confirmed by using confocal laser scanning microscopy that MS-50 was partially phagocytosed by the hepatocytes and that MS-50 taken up by the hepatocytes existed exclusively inside the cells 1 h after intravenous administration. Studies on the mechanism of the uptake of MS-50 by the hepatocytes using the liver perfusion technique revealed that a process mediated by apo-E was involved. After intravenous administration of MS-50, about 4% of dose was excreted into bile in 24 h. Pharmacokinetic evaluation of the excretion rate of MS-50 into bile showed that the process followed first-order kinetics. Qualitative evaluation of the fluorescence detected in the bile after intravenous administration of MS-50 revealed that the particles were certainly excreted into bile in an intact form. From these results, it was suggested that intravenously administered MS-50 would be partially phagocytosed by hepatocytes through a process mediated by apo-E and that MS-50 ingested by hepatocytes would be partially excreted into the bile.     

Hypotensive effects of intravenously administered uridine and cytidine in conscious rats: involvement of adenosine receptors

In the present study, we investigated the cardiovascular effects of intravenously injected uridine or cytidine, and the role of adenosine receptors in mediating these effects, in conscious normotensive rats. Intravenous (i.v.) administration of uridine (124, 250, 500 mg/kg) dose-dependently decreased arterial pressure and heart rate. Cytidine (124, 250, 500 mg/kg; i.v.) produced slight dose-related hypotension without changing heart rate. Plasma uridine and cytidine concentrations increased time- and dose-dependently while plasma adenosine levels did not change after injection of the respective nucleosides. Pretreatment with intravenous caffeine (20 mg/kg), 8-phenyltheophylline (8-PT) (1 mg/kg), nonselective adenosine receptor antagonists, or 8-p-sulfophenyltheophylline (8-SPT) (20 mg/kg), a nonselective adenosine receptor antagonist which does not cross the blood-brain barrier, abolished the cardiovascular effects of uridine (250 mg/kg; i.v.) or cytidine (250 mg/kg; i.v.). Intracerebroventricular (i.c.v.) caffeine (200 microg) or 8-SPT (50 microg) pretreatment did not change the magnitude of the cardiovascular responses induced by nucleosides. Intravenous 8-cyclopenthyl-1,3-dipropylxanthine (DPCPX) (5 mg/kg), a selective adenosine A(1) receptor antagonist, greatly attenuated the cardiovascular responses to uridine and cytidine. Pretreatment with 3,7,-dimethyl-1-propargylxanthine (DMPX) (2 mg/kg), an adenosine A(1)/A(2) receptor antagonist, attenuated hypotension induced by uridine and blocked the arterial pressure decrease in response to cytidine. Uridine-induced bradycardia was blocked by DMPX. 4-(2-[7-amino-2-(2-furyl[1,2,4]-triazolo[2,3-a[1,3,5]triazin-5-yl-aminoethyl)phenol (ZM241385) (1 mg/kg; i.v.), a selective adenosine A(2A) receptor antagonist, pretreatment produced an only very small blockade in the first minute of the hypotensive effects of uridine without affecting the bradycardia. ZM241385 pretreatment completely blocked cytidine's hypotensive effect. In Langendorff-perfused rat heart preparation, uridine (10(-3) M), but not cytidine, decreased the heart rate. Our results show that intravenously injected uridine or cytidine is able to decrease arterial pressure by activating peripheral adenosine receptors. The data also implicates that the mainly adenosine A(1) receptor activation is involved in the uridine-induced cardiovascular effects, while both adenosine A(1) and A(2A) receptor activations mediate the cytidine's effects.     

Pharmacokinetics of intravenously administered bumetanide in man

Disposition of [ ¹⁴C] bumetanide administered intravenously to four healthy volunteers could be described by a triexponential equation. The mean half-lives associated with each exponent were 5.9 min, 46 min, and 3.1 hr, respectively. The largest fraction of dose was eliminated during the second phase; only 17% was eliminated during the last phase. The total plasma clearance averaged 228 ml/min, with renal clearance about one-half of this value. The recovery of unchanged bumetanide in urine over 2 days was 47% of the dose, while the total recovery of radioactivity in urine averaged 82% of dose. In plasma 93% of bumetanide was bound to proteins. Thus bumetanide is rapidly eliminated by both renal and nonrenal mechanisms. The elimination kinetics resembled those described for furosemide.     

Effect of genistein on the pharmacokinetics of paclitaxel administered orally or intravenously in rats

As many anticancer agents paclitaxel is a substrate for ATP-binding cassette (ABC) transporters such as P-glycoprotein-mediated efflux, and its metabolism in humans mainly catalyzed by CYP 3A4 and 2C8. Genistein, an isoflavonoid, is supposed to be an inhibitor of some ABC transporters, and its oxidative metobolism catalyzed by CYP 3A4 and 2C8. The purpose of this study was to investigate the effect of orally administered genistein on the pharmacokinetics of paclitaxel administered through oral and intravenous (i.v.) route in rats. A single dose of paclitaxel administered orally (30 mg/kg) or i.v. (3mg/kg) alone or 30 min after oral administration of genistein (3.3mg/kg or 10mg/kg). The presence of 10mg/kg genistein significantly (p<0.05) increased the area under the plasma concentration-time curve (AUC, 54.7% greater) of orally administered paclitaxel, which was due to the significantly (p<0.05) decreased total plasma clearance (CL/F) of paclitaxel (35.2% lower). Genistein also increased the peak concentration (C(max)) of paclitaxel significantly (p<0.05 by 3.3mg/kg, 66.8% higher; p<0.01 by 10mg/kg, 91.8% higher). Consequently, the absolute bioavailability (F) of paclitaxel in the presence of genistein was 0.020-0.025, which was elevated more than the control group (0.016); and the relative bioavailability (Fr) of orally administered paclitaxel was increased from 1.26- to 1.55-fold. Ten milligrams per kilogram genistein also significantly (p<0.05) increased the AUC (40.5% greater) and reduced the total clearance (CLt, 30% lower) of i.v. administered paclitaxel. The presence of genistein improved the systemic exposure of paclitaxel in this study. The pharmacokinetic interaction between them should be taken into consideration when paclitaxel is used with genistein or the dietary supplements full of genistein.     

Pharmacological suppression of photically evoked after-discharges in rats: Incremental dose,hippocampal EEG and behavioral activity correlates

In subjects lightly restrained (Experiment I) pharmacological arousal via pilocarpine, physostigmine, or amphetamine administration, as compared to saline and methyl atropine treated controls, suppressed photically evoked after-discharge (PhAD) activity in visual cortex, while concomitantly inducing rhythmical slow-wave activity (RSA) in dorsal hippocampus. Incremental doses of amphetamine and pilocarpine correspondingly suppressed PhAD parameters in a dose-response fashion. While physostigmine treatment resulted in significant PhAD suppression, this effect could not be quantified in a dose-response manner. Incrementally increased cholinergic blockade via atropine administration also suppressed PhAD bursting yet simultaneously induced large amplitude irregular slow-wave activity (LIA) in dorsal hippocampus. When tested under identical conditions but in an unrestrained environment (Experiment II) PhADs were similarly suppressed with the concomitant induction of hippocampal patterns as specified in Experiment I; however, general ambulatory activity (grid-crossing) was differentially affected by the drugs. Amphetamine and atropine markedly enhanced while pilocarpine and physostigmine suppressed such activity. In both experiments, previously established PhAD-movement, PhAD-RSA-LIA, and RSA-LIA-movement relationships, occurring as hypothesized in amphetamine, methyl atropine, and saline treated animals, did not remain fully intact during cholinergic alteration.     

Factors influencing the tissue distribution of coenzyme Q10 intravenously administered in an emulsion to rats: emulsifying agents and lipoprotein lipase activity

The tissue distribution of coenzyme Q10 (CoQ10) administered intravenously in an emulsion prepared with egg yolk phosphatidylcholine (PC), egg yolk sphingomyelin (SPM) or a combination of PC and a polyoxyethylene derivative of hydrogenated castor oil (HCO-60) (PC + HCO-60) was investigated. The disappearance from the plasma of CoQ10 administered in three different emulsions of lipid particle size less than 0.5 micron varied with the particular emulsifier. Its disappearance occurred most rapidly from the PC emulsion; with the addition of HCO-60, its disappearance was much slower. In the reticuloendothelial system, the concentration of CoQ10 was higher in the spleen, for both the SPM and PC + HCO-60 emulsions than for the PC emulsion. HCO-60 reduced the CoQ10 distribution in the liver from the PC emulsion. Differences in disappearance rates from the plasma are thus considered to be due to the extent of CoQ10 distribution in the liver. CoQ10 concentration in the heart, a target organ, was greatest with the PC emulsion. Its distribution was related to lipoprotein lipase (LPL) activity in this organ. The effects caused by HCO-60, however, could not be explained by LPL activity alone. CoQ10 distribution in the adrenal gland and kidney can be explained partly by LPL activity but in the presence of HCO-60, the distribution mechanism apparently involves other factors.     

Pharmacological activity of hyperforin acetate in rats

Hyperforin, the main antidepressant component of Hypericum extract, is not stable with regard to heat and light. Therefore, we investigated a newly synthetized derivative, hyperforin acetate. Herein we demonstrate its efficacy in animal models sensitive to antidepressant and anxiolytic drugs. In the forced swimming test, triple administration of hyperforin (5-20 mg/kg) significantly reduced the immobility time of rats, while in the learned helplessness test a daily treatment of 10 mg/kg for seven consecutive days was necessary to elicit an antidepressant effect. In the elevated plus-maze and in the light-dark test, the acute administration of hyperforin acetate (3-5 mg/kg) exerted an anxiolytic activity, which, however, was smaller than that of diazepam. The effect was inhibited by the pretreatment of rats with metergoline, a serotoninergic antagonist, but not with CGS-8216, a benzodiazepine receptor antagonist. Hyperforin acetate (3-10 mg/kg) was also able to reduce locomotion in rats without eliciting myorelaxant activity. As Hypericum extract was claimed to exert a potential influence on the liver drug metabolizing system, we showed that neither acute nor repeated oral doses of hyperforin acetate altered pentobarbital sleeping time in rats. Taken together, the present results show that hyperforin acetate is a pharmacologically active derivative of hyperforin and may be a starting point from which to develop new compounds for therapeutic purposes.     

Inhibition by intravenously administered sodium bicarbonate of neuronal activity in medial vestibular nucleus neurons

The effects of 7% sodium bicarbonate on medial vestibular nucleus (MVN) neurons were examined to elucidate the mechanism underlying its anti-vertigo action, using alpha-chloralose-anesthetized cats. Intravenous injection of the drug at 1, 2 and 4 ml/kg every 10 min dose-dependently inhibited rotation- and glutamate-induced firing of type 1 neurons, although a low dose of the drug enhanced firing in a few neurons. However, microiontophoretic application of bicarbonate ions did not inhibit rotation- or glutamate-induced firing. After injection of the drug, the Po2 level in arterial blood did not differ from previous levels, but the bicarbonate ion levels dose-dependently increased concomitantly with an increase in pH, as compared with previous levels. These results suggest that the intravenous injection of 7% sodium bicarbonate directly inhibits the neuronal activity of the MVN, although the lower dose may enhance neuronal activity by acting on the peripheral vestibule.     

Pharmacokinetics of intravenously administered glutathione in the rat

By means of an open two compartment model with a distribution and elimination phase, the pharmacokinetic properties of intravenously administered GSH (reduced glutathione) have been investigated in the rat. After a bolus injection of four various GSH doses (50 to 300 mumol kg-1), arterial plasma concentrations of GSH, GSSG (= oxidized glutathione), total thiols and soluble thiols minus GSH were elevated and then rapidly decreased nonexponentially. With increasing dose, the rate constant for drug elimination and plasma clearance increased from 0.84 to 2.44 ml min-1 and the half-life of the elimination phase decreased from 52.4 to 11.4 min. Both the apparent volume of distribution and the degree of penetration of GSH into the tissues were diminished with increasing dose (from 3.78 to 1.33 litres kg-1 and from 6.00 to 0.51 as k12/k21, respectively). The data indicate that GSH is rapidly eliminated. This is mainly due to rapid oxidation in plasma rather than by increased tissue extraction or volume distribution. Thus plasma GSH levels appear to be quickly regulated by which the body may maintain concentrations within narrow physiological limits.     

Kinetics of intravenously administered carnitine in haemodialysed children

The pharmacokinetics of low-dose bolus L-carnitine (5 mg kg-1 body wt) in five haemodialysed children were investigated. Kinetic variables were obtained by applying a two-compartment open model. The elimination half-life was very short, 2.43 +/- 0.35 h, despite the reduced plasma clearance of 41.2 +/- 5.7 ml min-1, compared with healthy adults. The apparent volume of distribution, 0.27 +/- 0.07 1 kg-1 body wt, corresponds well to the size of the extracellular space. The kinetic behaviour of intravenously supplied carnitine may assist in future evaluations of the therapeutic application of this drug in uraemic children.