HI-6 pharmacokinetics in rabbits after intravenous and intramuscular administration.

The pharmacokinetics of HI-6 ((4-carboxamidopyridinium (1) methyl)-(2'-hydroxyiminomethyl-pyridinium (1') methyl) ether dichloride) have been studied in rabbits receiving an intramuscular (50 micrograms kg-1) or intravenous (12.5 micrograms kg-1) dose. The plasma concentration-time profile for the intramuscular dose (n = 8) fits a one-compartment open model with first-order absorption and elimination. The absorption half-life was 2 min and maximum concentration (51 micrograms mL-1) was reached in 9 min. The pharmacokinetics for the intravenous dose (n = 8) was described by a two-compartment open model with first-order distribution and elimination. The apparent volume of distribution was 0.1 L kg-1. Half-lives of distribution and elimination were 5 and 38 min, respectively. The results indicate HI-6 is rapidly absorbed, distributed and eliminated in rabbits receiving an intramuscular dose.     

Pharmacokinetics of methylprednisolone after intravenous and intramuscular administration in rats

Methylprednisolone (MPL) pharmacokinetics was examined in adrenalectomized (ADX) and normal rats to assess the feasibility of intramuscular (i.m.) dosing for use in pharmacodynamic studies. Several study phases were pursued. Parallel group studies were performed in normal and ADX rats given 50 mg/kg MPL (i.v. or i.m.) and blood samples were collected up to 6 h. Data from studies where normal rats were dosed with 50 mg/kg MPL i.m. and killed over either 6 or 96 h were combined to determine muscle site and plasma MPL concentrations. Lastly, ADX rats were dosed with 50 mg/kg MPL i.m. and killed over 18 h to assess hepatic tyrosine aminotransferase (TAT) dynamics. MPL exhibited bi-exponential kinetics after i.v. dosing with a terminal slope of 2.1 h(-1). The i.m. drug was absorbed slowly with two first-order absorption rate constants, 1.26 and 0.219 h(-1) indicating flip-flop kinetics with overall 50% bioavailability. The kinetics of MPL at the injection site exhibited slow, dual absorption rates. Although i.m. MPL showed lower bioavailability compared with other corticosteroids in rats, TAT dynamics revealed similar i.m. and i.v. response profiles. The more convenient intramuscular dosing can replace the i.v. route without causing marked differences in pharmacodynamics.     

Comparison of dexamethasone pharmacokinetics in female rats after intravenous and intramuscular administration

This study seeks a route of drug administration that would produce a pharmacokinetic profile for dexamethasone not significantly different from the intravenous route in female rats and would offer reproducible drug input with minimal stress to the animals. The intramuscular (i.m.) route of drug administration vs intravenous (i.v.) injection were compared in three female Wistar rats administered 1 mg/kg dexamethasone phosphate. Dexamethasone plasma concentrations were measured by a normal phase HPLC assay for 12 h after drug administration. Dexamethasone exhibited monoexponential behavior after intravenous dosing and was absorbed rapidly after intramuscular dosing (absorption half-life of 14 min) with 86% bioavailability. Dexamethasone had a terminal half-life of 2.3 h after drug administration by either route. The volume of distribution of 0.78 l/kg and the clearance of 0.23 l/h/kg are in good agreement with reported pharmacokinetic parameters in male rats. Intravenous dosing can be replaced by intramuscular dosing without causing any marked difference in dexamethasone pharmacokinetics.     

Disposition of butanal oxime in rat following oral,intravenous and dermal administration

1. The disposition of [1-¹⁴C]butanal oxime (BOX) was determined in the rat after oral, i.v. and dermal administration. 2. Oral doses of [¹⁴C]BOX (2 and 20?mg/kg) were predominantly excreted in the urine (> 42%) and converted to ¹⁴CO₂ (> 30%) and about 10% of the dose remained in the tissues 72 h post-dosing. 3. Eight and 16% of a 2 and 20?mg/kg dermal dose of BOX, respectively, were absorbed, due in part to rapid volatilization from the surface of the skin. 4. Oral doses of BOX were transformed into several polar and/or anionic metabolites that include sulphate conjugates and a significant amount of thiocyanate. 5. The effect of inhibitors on the metabolism of BOX was investigated using 1- aminobenzotriazole (ABT; an inhibitor of diverse cytochrome P450s) and trans-1,2- dichloroethylene (DCE; an inhibitor of CYP2E1). No thiocyanate anion was detected in the urine of rat treated with DCE or ABT. ABT markedly increased the production of ¹⁴CO₂ and excretion as volatile metabolites. DCE had no effect on ¹⁴CO₂ excretion, but increased exhalation of radiolabel. ABT also effectively blocked the expression of toxic effects attributable to cyanide in rat given near-lethal doses of BOX. 6. The data are consistent with two distinct pathways of metabolism for BOX, (1) reduction to an imine, hydrolysis and subsequent conversion of butyraldehyde to ¹⁴CO₂ and (2) CYP3A-catalysed dehydration of BOX to butyronitrile followed by CYP2E1- catalysed release of cyanide.     

Pharmacokinetics of chlorazepate after intravenous and intramuscular administration

Dichlorazepate (DPC) was given to eight healthy volunteers aged 22-38 years (five males and three females). The dose was 20 mg (48.9 mumol) given either as an IV or an IM injection. The interval between the injections was at least 1 week. Plasma samples were analysed for desmethyldiazepam (DMD) by HPLC before and after acid hydrolysis. The kinetics after both IV and IM administration could be explained by a one or two compartment open model. By comparing values before and after hydrolysis an estimate of di- and/or monopotassiumchlorazepate (MPC) could be made. The bioavailability was almost 100% after IM administration. The plasma half lives of DPC and DMD were independent of the form of administration (2.42 and 46.0 h respectively after IV and 2.29 and 45.1 h respectively after IM injection).     

Ukrain: acute toxicity after intravenous, intramuscular and oral administration in rats

The acute toxicity of Ukrain (1 g/30 ml) was determined after a single intravenous, intramuscular or oral administration in rats, performed in accordance with Good Laboratory Practice and the relevant European Community directive. Groups of five (male and/or female) Him:OFA rats were treated once with the following doses: intravenous route: 1.0 ml/kg (males and females), 1.7 ml/kg (males and females) and 3.0 ml/kg (females); intramuscular route: 5.0 ml/kg (males and females); oral route: 15.0 ml/kg (females), 27.0 ml/kg (males and females) and 50 ml/kg (females). The animals were kept for up to 14 days afterwards while clinical observations and body weight determinations were made and were then necropsied. An intravenous injection of Ukrain (1 g/30 ml) induced immediate effects (short-term unconsciousness, followed by cardiovascular signs and, later, signs of general malaise), which if not lethal, disappeared in a short time. It was found that the intravenous LD50 was greater than 43 mg active ingredient/kg body weight in the males and 76 mg active ingredient/kg body weight in the females. An intramuscular injection of Ukrain (1 g/30 ml) in the maximum technically feasible dose induced some transient signs of minor clinical importance which did not become life threatening. In both sexes the intramuscular LD50 was greater than 165 mg active ingredient/kg body weight.     

Disposition of betamethasone in parturient women after intramuscular administration.

When betamethasone phosphate equivalent to 8 mg betamethasone was administered intramuscularly in solution (Celestone Injection) to pregnant women, a large proportion of this ester was absorbed unchanged. Bioavailability of betamethasone from the phosphate ester was as high as after intravenous injection. When pregnant patients received the equivalent of either 6 or 12 mg betamethasone in a formulation containing 3.1 mg/ml betamethasone acetate suspended in a solution of 4 mg/ml betamethasone phosphate (Celestone Chronodose), much of the phosphate ester was absorbed intact but betamethasone acetate was not detected in plasma. Availability of betamethasone from Celestone Chronodose was much lower than from Celestone Injection. After administration of either formulation, maternal plasma cortisol concentrations fell towards a basal level but were rising again within 2 to 3 days of the last dose. We conclude that Celestone Chronodose does not provide prolonged release of betamethasone and offers no advantage over Celestone Injection.     

Oral forms of the oxime HI-6: a study of pharmacokinetics and tolerance after administration to healthy volunteers

New pharmaceutical formulations of the oxime HI-6 as sustained-release and conventional tablets were studied in healthy volunteers. Twenty-six subjects, divided into 3 groups, received 3784 mg or 7568 mg doses of HI-6 conventional tablets or 4027 mg of the oxime in the form of sustained-release tablets. Peak plasma concentrations of HI-6 were reached within 0.6 h (10.2 mumol/l) and 1.6 h (21.4 mumol/l) following the ingestion of conventional tablets. Elimination half-lives were similar (1.7 h and 1.3 h) and the respective urinary recoveries amounted to 3.2% and 2.9%. After the administration of sustained-release tablets of HI-6, maximal concentration (8.8 mumol/l) was attained in 2.2 h, elimination half-life was 1.9 h and 4.2% of the dose was excreted unchanged in urine. Undesirable side effects were not reported by the subjects or revealed by clinical or laboratory tests. The results indicate low bioavailability of the oral formulations of HI-6 in man.     

Absorption, distribution, and excretion of arbekacin after intravenous and intramuscular administration in rats

Absorption, distribution, and excretion of arbekacin (HBK) were studied in rats after intravenous or intramuscular administration of HBK at a dose of 10 mg/kg or 20 mg/kg. Elimination half-lives of HBK were 0.69 hour for bolus intravenous administration, 0.55 hour for constant rate intravenous infusion, and 0.57 hour for intramuscular administration. Cumulative urinary excretions within 24 hours after administration were 74.7% of the dose for bolus intravenous administration, and 79.1% of the dose for intramuscular administration. No significant difference was observed in the cumulative urinary excretions between the 2 administration routes. Cumulative biliary excretions within 24 hours after administration were around 0.1% of doses regardless administration routes, bolus intravenous or intramuscular administration. The tissue or organ distribution of HBK after bolus intravenous administration was similar to that after intramuscular administration. The drug was distributed most abundantly into the kidney followed by plasma and the lung. The distribution of the drug into the liver was the least among the 6 tissues or organs examined in this study. The protein binding of HBK was studied by an equilibrium dialysis method at three different concentrations of HBK, 5, 10, and 20 micrograms/ml. Binding ratios of HBK to human serum, human serum albumin, and rat serum were less than 15%.     

重组人干扰素α2a在小鼠和大鼠体内i.v.和i.m.的药动学研究

目的：研究rj-干扰素α2a（rh—IFNα2a）在小鼠和大鼠体内i．v．和i．m．的血药浓度-时间曲线、药动学参数和分布、排泄特点。方法：用双抗体夹心ELISA法测rh—IFNα2a在小鼠和大鼠体内i．v．和i．m．后血清、胆汁、尿液及组织中的药物浓度，用DAS药动学统计软件进行血药浓度-时间曲线拟合及药动学参数计算，并结合免疫组织化学技术研究rh—IFNα2a的组织分布特点。结果：Rh—IFNα2ai．v．和i．m的药动学行为分别符合二室和一室开放模型，呈一级动力学消除；rh．IFNα2a主要分布在肾、肺组织中；rh-IFNα2a36h尿累计排泄量为0．121％，胆汁累计排泄量为0．247％。结论：I．v．、i．m．rh—IFNα2a的药动学行为分别符合二室一级消除、一室一级消除。     

Disposition of SK&F L-190144 in rats and monkeys after oral,intravenous or ocular administration

The objective of the study was to investigate the systemic disposition of ¹⁴C-SK&F L-190144 after single intravenous (10mg kg^?1) and oral (200 mg kg^?1) doses to rats and after single intravenous and ocular doses (0.33 mg kg^?1) to monkeys. After the intravenous dose, the blood concentration-time profile of ¹⁴C-SK&F L-190144 followed a rapid triexponential decline with half-lives of 2.5, 15, and 246 min in rats and 3, 19, and 2520 min in monkeys. The ¹⁴C-label in blood was mainly the parent compound. The terminal elimination half-life detected in rats using the urinary excretion rate-time data was 700 min. The total body clearance values were 17.6 ± 2.1 (mean ± SD, n = 6) and 1.11 ± 0.41 (n=4) mlmin^?1 kg^?1 for rats and monkeys, respectively. Both species had similar values of volume of distribution at the terminal phase, 4 to 6 l kg^?1, and similar excretion patterns, approximately 60 per cent and 30 per cent of the dose were excreted in the urine and feces, respectively. ¹⁴C-SK&F L-190144 was not absorbed orally in rats with the majority of the dose recovered in the feces. Following ocular administration to monkeys, the plasma drug concentrations peaked at 8 h post-dosing but did not reach a biexponential elimination phase until 18 h post-dosing, suggesting slow systemic absorption of drug from the ocular site. The monkeys excreted 42 per cent of the dose in urine and 50 per cent in feces after ocular administration. This increase in fecal excretion compared to the intravenous route of administration may have been due to the slow absorption by the ocular and nasal tissues altering the relative proportions of drug elimination via the renal and hepatic routes, or to a proportion of the dose passing into the gastrointestinal tract and exiting unabsorbed. Study results demonstrate similar excretion patterns and volume of distribution after intravenous administration in both species. The slow terminal elimination phase in monkeys was attributed to the low body clearance. The low oral bioavailability was possibly due to the poor partitioning behavior of the drug (logarithm of partition coefficient - 2.6). A significant fraction of the dose was absorbed in the body via the ocular route.     

Distribution of the bispyridinium oxime [14C] HI-6 in male and female rats

Female rats poisoned with multiple LD₅₀s of soman or tabun have been shown previously to respond to the protective effects of HI-6 more positively than male rats. This present study was designed first to determine the distribution pattern and concentration of [¹⁴C] HI-6 in rats, and secondly, to determine the possibility that HI-6 might be located in high concentrations in critical tissues in the female as opposed to the male. To these ends, [¹⁴C] HI-6 was administered to groups of male and female rats and its radiolabelled distribution determined by whole body autoradiography and/or by measurement of its actual concentration, by scintillation spectrometry. The experiments were repeated in the presence of 2 × LD₅₀ soman and supporting therapy with atropine. In both sexes, HI-6 levels were highest in the kidney, followed in order by cartilage >plasma >liver >heart >lung > diaphragm >brain and spinal cord. The relative distribution in the two sexes was confirmed by both methods and was not significantly altered in the presence of soman and atropine. The lack of a measurable difference in tissue distribution of [¹⁴C] HI-6 derived radioactivity between males and females suggested that the hormone-dependent difference in the protective effects previously observed was not due to selective accumulation of [¹⁴C] HI-6 in organs believed to be important in its therapeutic activity, such as brain or diaphragm.     

A comparison of the neuroprotective efficacy of individual oxime (HI-6) and combinations of oximes (HI-6+trimedoxime, HI-6+K203) in soman-poisoned rats

The ability of two combinations of oximes (HI-6+trimedoxime, HI-6+K203) to reduce soman-induced acute neurotoxic signs and symptoms was compared with the neuroprotective efficacy of the oxime HI-6 alone, using a functional observational battery. Soman-induced neurotoxicity and the neuroprotective effects of HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with soman at a sublethal dose (90 μg/kg intramuscularly, i.m.; 80% of LD?? value) were monitored by the functional observational battery at 24 hours following soman administration. The results indicate that both tested oxime mixtures combined with atropine were able to allow soman-poisoned rats to survive 24 hours following soman challenge, while 4 nontreated soman-poisoned rats and 1 soman-poisoned rat treated with oxime HI-6 alone combined with atropine died within 24 hours following soman poisoning. While the oxime HI-6 alone combined with atropine treatment was able to eliminate a few soman-induced neurotoxic signs and symptoms, both oxime mixtures showed higher neuroprotective efficacy in soman-poisoned rats. Especially, the combination of HI-6 with trimedoxime was able to eliminate most soman-induced neurotoxic signs and symptoms and markedly reduce acute neurotoxicity of soman in rats. Thus, both tested mixtures of oximes combined with atropine were able to increase the neuroprotective effectiveness of antidotal treatment of acute soman poisonings, compared to the individual oxime.     

Disposition of nitroglycerin in the beagle dog after intravenous and buccal administration

The disposition of nitroglycerin was studied in dogs using a crossover design for I.V. (0.85 mg/kg) and buccal (0.75 mg/kg) administration. The pharmacokinetic parameters after I.V. administration are comparable to those in man. The mean values are: t1/2 = 9.2 min; V beta = 3.8 L/kg, Cltot = 238 ml/kg. Similar values were obtained after buccal administration. The bioavailability buccally is 47%. After 7 days pretreatment with nitroglycerin (0.75 mg/kg twice daily, buccally), the area under the I.V. curve (0.85 mg/kg) decreased by about 23%, indicating possible enzyme induction.     

Comparative pharmacokinetics of cefuroxime lysine after single intravenous,intraperitoneal, and intramuscular administration to rats

Aim:

To compare the pharmacokinetic parameters of cefuroxime lysine, a new second-generation of cephalosporin antibiotics, after intravenous (IV), intraperitoneal (IP), or intramuscular (IM) administration.

Methods:

Twelve male and 12 virgin female Sprague-Dawley rats, weighing from 200 to 250 g, were divided into three groups (n=4 for each gender in each group). The rats were administered a single dose (67.5 mg/kg) of cefuroxime lysine via IV bolus or IP or IM injection. Blood samples were collected and analyzed with a validated UFLC-MS/MS method. The concentration-time data were then calculated by compartmental and non-compartmental pharmacokinetic methods using DAS software.

Results:

After IV, IP or IM administration, the plasma cefuroxime lysine disposition was best described by a tri-compartmental, bi-compartmental or mono-compartmental open model, respectively, with first-order elimination. The plasma concentration profiles were similar through the 3 administration routes. The distribution process was rapid after IV administration [t_1/2(d), 0.10±0.11 h vs 1.36±0.65 and 1.25±1.01 h]. The AUMC_0–∞ is markedly larger, and mean residence time (MRT) is greatly longer after IP administration than that in IV, or IM routes (AUMC_0–∞: 55.33±20.34 vs 16.84±4.85 and 36.17±13.24 mg·h²/L; MRT: 0.93±0.10 h vs 0.37±0.07 h and 0.65±0.05 h). The C_max after IM injection was significantly higher than that in IP injection (73.51±12.46 vs 49.09±7.06 mg/L). The AUC_0–∞ in male rats were significantly higher than that in female rats after IM administration (66.38±16.5 vs 44.23±6.37 mg·h/L). There was no significantly sex-related difference in other pharmacokinetic parameters of cefuroxime lysine between male and female rats.

Conclusion:

Cefuroxime lysine shows quick absorption after IV injection, a long retension after IP injection, and a high C_max after IM injection. After IM administration the AUC_0–∞ in male rats was significantly larger than that in female rats.     

Kinetics of ergotamine after intravenous and intramuscular administration to migraine sufferers

Summary The kinetics of ergotamine has been investigated in migrainous patients using a new, specific, sensitive HPLC assay (detection limit 100 pg/ml plasma). 10 patients were given ergotamine tartrate 0.5 mg i.v. and 5 of them received the same dose i.m. 2–3 weeks later. Blood samples were collected for up to 54 h following administration and the plasma concentration were analysed. After intravenous administration the plasma ergotamine declined rapidly, with an initial distribution half-life of 3 min followed by a mean terminal half-life of 1.86 h (range 90–155 min). The mean total plasma clearance was 11.0 ml kg^–1 min^–1, and the volume of distribution (V_d ) was 1847.6 ml kg^–1. Individual t_1/2 showed a positive linear correlation with the individual V_d . The intramuscular absorption of ergotamine was rapid and maximum plasma levels were usually obtained 10 min following administration. The biological availability was incomplete and variable at 46.6% (range 28.3–60.8%).     

A high-performance liquid chromatographic assay for HI-6 oxime in plasma

A high-performance liquid chromatographic (HPLC) assay was developed to determine HI-6 (1-(2-hydroxyiminomethyl-1-pyridinio-3-(4-carbamoyl-1-py ridiniol-2-oxapropane dichloride)) concentrations in small volumes of plasma. A 100-microL plasma sample added to 900 microL of distilled water was microfiltered. Filtrate (200 microL) was injected onto an HPLC instrument containing a 100-microL sample loop, a C18 column, and an ultraviolet (UV) wavelength detector. Limit of sensitivity for HI-6 was 2.5 micrograms/mL. Extraction of efficiency (n = 12) at 10 and 100 micrograms HI-6/mL plasma was 69.4 +/- 6.6% (SD) and 81.5 +/- 2.0% (SD), respectively. Protein-plasma binding of HI-6 did not occur. HI-6 was stable when frozen at -20 degrees C for up to 10 days (0.025 less than p less than 0.05). Correlation coefficients representing standard curve linearity ranged from 0.9986 to 0.9999 (n = 6). Within-day and between-day coefficients of variation (n = 6) for unknown samples ranged from 4.4 to 8.3% and 5.8 to 17.1%, respectively. Bias of unknown samples ranged from -10.5 to 5.7%. The method's sensitivity, accuracy, and precision indicate that it can be used to accurately measure HI-6 concentrations in 100 microL of plasma.     

Disposition of fullerene C60 in rats following intratracheal or intravenous administration

Fullerene C60 is used in a variety of industrial and consumer capacities. As part of a comprehensive evaluation of the toxicity of fullerene C60 by the National Toxicology Program, the disposition following intratracheal (IT) instillation and intravenous (IV) administration of 1 or 5?mg/kg b.wt. fullerene C60 was investigated in male Fischer 344 rats. Following IT instillation, fullerene C60 was detected in the lung as early as 0.5?h post-exposure with minimal clearance over the 168?h period; the concentration increased ≥20-fold with a 5-fold increase in the dose. Fullerene C60 was not detected in extrapulmonary tissues. Following IV administration, fullerene C60 was rapidly eliminated from the blood and was undetectable after 0.5?h post-administration. The highest tissue concentrations of fullerene C60 occurred in the liver, followed by the spleen, lung and kidney. Fullerene C60 was cleared slowly from the kidney and the lung with estimated half-lives of 24 and 139?h, respectively. The liver concentration of fullerene C60 did not change much with time; over 90% of the fullerene C60 remained there over the study duration up to 168?h. Fullerene C60 was also not detected in urine or feces. These data support the hypothesis that fullerene C60 accumulates in the body and therefore has the potential to induce detrimental health effects following exposure.