The pharmacokinetics of propofol in laboratory animals

1. The pharmacokinetics of propofol in an emulsion formulation (‘Diprivan’) have been studied after single bolus doses to rats, dogs, rabbits and pigs, and after single and multiple infusions to dogs. Venous blood propofol concentrations were determined by h.p.l.c. with u.v. or fluorescence detection. Curve fitting was performed using ELSFIT.

2. The distribution of propofol in blood and its plasma protein binding have been studied in rat, dog, rabbit and man. Protein binding was high (96-98%), and in most species propofol showed appreciable association with the formed elements of blood.

3. Where an adequate sampling period was employed the pharmacokinetics of propofol were best described by a three-compartment open ‘mammillary’ model. Propofol was distributed into a large initial volume (1-21/kg) and extensively redistributed (V_ss=2-10 x body weight) in all species. Clearance of propofol by all species was rapid, ranging from about 30-80ml/kg per min in rats, dogs and pigs to about 340ml/kg per min in rabbits.     

The pharmacokinetics of Casodex in laboratory animals.

1. The pharmacokinetics of Casodex, a novel, non-steroidal antiandrogen, have been investigated following single oral and i.v. doses and during daily oral dosing to male and female rats and male dogs. 2. The binding of 14C-Casodex to rat, dog and human plasma proteins, determined by equilibrium dialysis, was high with values greater than 95%; in dog there was evidence for decreased binding at concentrations greater than 12 micrograms/ml. 3. Casodex was slowly absorbed over prolonged periods and its bioavailability decreased with increase in dose from 72% and 88% in male and female rats respectively at 1 mg/kg to 10% and 12% at 250 mg/kg; in dog bioavailability decreased from 100% at 0.1 mg/kg to 31% at 100 mg/kg. 4. Elimination of Casodex from plasma was slow with terminal elimination half-lives of about 1 day in rat and about 6 days in dog. On daily administration to rats Casodex accumulates slightly in plasma at 10 mg/kg but not at 250 mg/kg; in dog appreciable accumulation (9-12-fold), calculated from the ratio of trough plasma concentrations at steady state to those after a single dose, was observed at 2.5 and 10 mg/kg, but at 100 mg/kg the accumulation ratio was much lower (4-fold).     

The pharmacokinetics of Casodex in laboratory animals

1. The pharmacokinetics of Casodex, a novel, non-steroidal antiandrogen, have been investigated following single oral and i.v. doses and during daily oral dosing to male and female rats and male dogs.

2. The binding of ¹⁴C-Casodex to rat, dog and human plasma proteins, determined by equilibrium dialysis, was high with values >95%; in dog there was evidence for decreased binding at concentrations >12 μg/ml.

3. Casodex was slowly absorbed over prolonged periods and its bioavailability decreased with increase in dose from 72% and 88% in male and female rats respectively at 1?mg/kg to 10% and 12% at 250?mg/kg; in dog bioavailability decreased from 100% at 0.1?mg/kg to 31% at 100?mg/kg.

4. Elimination of Casodex from plasma was slow with terminal elimination half-lives of about 1 day in rat and about 6 days in dog. On daily administration to rats Casodex accumulates slightly in plasma at 10?mg/kg but not at 250?mg/kg; in dog appreciable accumulation (9–12-fold), calculated from the ratio of trough plasma concentrations at steady state to those after a single dose, was observed at 2.5 and 10?mg/kg, but at 100?mg/kg the accumulation ratio was much lower (4-fold).     

L-658,310, a new injectable cephalosporin. III. Experimental chemotherapeutics and pharmacokinetics in laboratory animals

The therapeutic activity of L-658,310 was demonstrated in experimental bacteremias in normal, diabetic and neutropenic mice. Especially potent activity was shown against the usually difficult to control pathogens, Enterobacter cloacae and Pseudomonas aeruginosa, that were resistant to ceftazidime and/or gentamicin. Pharmacokinetic studies in mice showed a linear dose response in serum after the 20 and 50 mg/kg subcutaneous dose and urinary recoveries of administered dose of about 60% in 6 hours. Excretion was mainly by glomerular filtration. In a crossover design in rhesus monkeys, the pharmacokinetics of L-658,310 were similar to those of ceftazidime and suggest a moderately long half-life in serum of humans.     

Pikamilon pharmacokinetics in animals

Pycamilon was shown to be rapidly absorbed in the blood (tmax = 0.23 h), to penetrate well through the blood-brain barrier and to be intensively uptaken by the animal organs and tissues and to be eliminated mainly in the urine (t1/2 = 0.51 h). The drug bioavailability at oral administration to mice is 21.9%, and to rats from 53 to 78.9% (according to the urinary excretion data).     

Comparative pharmacokinetics of propofol in Chinese adults and children.

The pharmacokinetics of propofol were studied in 14 healthy young male Chinese adults, aged 18-38 years, undergoing minor orthopedic surgery. All patients who received a single bolus dose of propofol 2.5 mg/kg were paralyzed with atracurium and mechanically ventilated. Anesthesia was maintained with 67% nitrous oxide plus 1-2% isoflurane in oxygen with alfentanil 5 micrograms/kg intravenously as a bolus injection. Blood concentrations of propofol over the subsequent 24 hours were measured using high pressure liquid chromatography with fluorimetric detection. Data were consistently described by a three compartment model but analysis revealed two significantly different blood propofol concentration-time profiles (p less than 0.05). Five patients, designated "fast" metabolizers, demonstrated a mean elimination half-life which was shorter than that described in Chinese children, while their total body clearance was similar. Nine other patients, designated "slow" metabolizers, had a longer mean elimination half-life and slower total body clearance than those in elderly Caucasian patients. This may be suggestive of propofol metabolism at some extra-hepatic site in some patients, while other patients demonstrate marked lipophilicitic constraint of the drug by the deep compartment.     

中国患者异丙酚群体药代动力学(英文)

目的:用NONMEN程序分析中国患者群体药代动力学,并定量研究性别、年龄和体重对异丙酚药代参数的影响。方法:研究了76例择期手术的患者(男37例、女39例、年 龄19-77岁、体重39-86kg),共收集1459个血液标本。用NONMEN方法分析清除率和分布容积的个体间变异以及年龄、体重和性别的影响。结果:可用三室模型模拟异丙酚的药代动力学参数。体重可影响异丙酚的中央室、浅外周室和深外周室的清除率以及中央室的分布容积,而浅外周室和深外周室的分布容积保持不变。体重60kg的成人的上述药代参数的估计值分别为:1.56L/min、0.737L/min、0.360L/min、12.1L、43L、213L。老人随年龄的增大而清除率和中央室的分布容积减少。结论:中国人的异丙酚的药代动力学可用标准三室模型描述,年龄和体重可影响模型参数。因此根据患者的个体药代参数可改善靶控输注的精密度。     

Disposition of bepridil in laboratory animals and man.

1. The disposition and pharmacokinetics of bepridil (Bp) were studied in mouse, rat, rabbit, rhesus monkey, and man. Bp was essentially completely absorbed by all species. 2. Maximum plasma Bp concentrations were achieved within 2 h of drug administration. Linear but non-proportional, dose-related increases in the area under the curve (AUC) for plasma Bp vs. time were noted after increasing oral doses of Bp.HCl to rats (30-300 mg/kg) and monkeys (25-200 mg/kg). 3. Daily administration of Bp.HCl to rats (100 mg/kg per day for 15 days) and monkeys (200 mg/kg per day for 13 days) produced no statistically significant changes in Bp pharmacokinetic parameters. 4. Oral plasma clearance (CLp) of Bp was very low in man (ca. 0.93 l/h per kg) compared to experimental animals (14.8-63.8 l/h per kg). Terminal elimination half-lives were 1.5-2.0 h for mouse and rat, ca. 4.4 h for monkey and ca. 48 h for man. 5. Bp and a total of 12 metabolites were identified and quantified. Metabolite formation in the five species was adequately described by four interrelated pathways, namely, aromatic hydroxylation, followed by N-dealkylation, N-debenzylation, and N-acetylation. Metabolites produced by this pathway included 4-hydroxy-Bp, N-benzyl-4-aminophenol, 4-aminophenol, and N-acetyl-4-aminophenol. Comparison of the proposed pathways revealed qualitative similarity among species.     

Biotransformation of mianserin in laboratory animals and man.

1. The biotransformation and excretion of the antidepressant mianserin were studied after oral administration of the labelled drug to rats, mice, rabbits, guinea pigs and humans. Mianserin was well absorbed and almost completely metabolized in all five species. 2. Major metabolic pathways of mianserin were p-oxidation of the N-substituted aromatic ring followed by conjugation, and oxidation and demethylation of the N-methyl moiety, followed by conjugation. Direct conjugation of the N-methyl moiety was observed as a metabolic pathway specific for man. 3. Conjugated metabolites were isolated by h.p.l.c. and identified by 1H-n.m.r. and FAB spectrometry. Novel metabolites such as an N-O-glucuronide in the guinea pig and an N-sulphonate in rat and guinea pig, were identified using these techniques. A quaternary N-glucuronide was found only in man.     

Metabolic disposition and pharmacokinetics of pelrinone, a new cardiotonic drug, in laboratory animals and man

The metabolic disposition of pelrinone, a cardiotonic drug, was studied in mouse, rat, rabbit, dog, monkey and man. Pelrinone was rapidly and extensively absorbed in rodents, dogs, monkeys and man. Except in rabbits, the major portion of the serum radioactivity was due to parent drug. Pelrinone was moderately bound to human serum proteins and weakly bound to serum proteins from animals. Radioactive compounds were rapidly eliminated from rat tissues with the highest concentrations found in organs associated with absorption and elimination. After a 1.0 mg/kg i.v. dose, the rapid elimination of pelrinone from mouse, rat and dog serum precluded estimation of an elimination half life (t1/2). However, after higher oral or i.v. doses, a more prolonged elimination phase was apparent and the t1/2 of pelrinone ranged from 8-10 h in rodents and dogs. In human subjects given escalating oral or i.v. doses of pelrinone, the elimination t1/2 was independent of dose and averaged 1-2 h. The serum AUC of pelrinone was linearly dose-related following oral doses up to 20 mg/kg in dogs and 100 mg in man. In mice, a greater proportional increase in AUC occurred between oral doses of 2-100 mg/kg while in rats, the serum AUC increased in less than proportional manner from 10-200 mg/kg p.o. In all species, radioactive compounds were excreted mainly in the urine. No metabolites were detected in dog and human urine while small amounts of unconjugated metabolites were excreted in mouse and rat urine.     

Disposition of flavodilol in laboratory animals

The disposition of flavodilol, a novel antihypertensive agent, was investigated in rats, rabbits, and dogs following iv or oral administration of 14C-flavodilol or unlabeled drug. Peak, plasma levels occurred within 6 hours of an oral dose in all three species. Following an iv dose, plasma elimination half-lives of flavodilol in rats, rabbits, and dogs were 3.0, 3.0, and 4.0 hr, respectively. Total body clearances were 0.71 liter/hr/kg for the rat, 1.89 liters/hr/kg for the rabbit, and 3.07 liters/hr/kg for the dog. Renal clearances were a small fraction of total clearance at 0.042, and 0.114 liter/hr/kg for the rat and dog, respectively, suggesting extensive nonrenal clearance. The volumes of distribution of 3.04 for the rat, 8.10 for rabbit, and 18.13 liters/kg for dog are large, suggesting significant extravascular distribution of flavodilol. Following 10 and 50 mg/kg po doses of 14C-flavodilol in rats, recovery of total radioactivity after 79 hr was 100.7% and 88.4% of the dose, respectively, most of which was recovered in the feces (77.5% and 66.6%, respectively). Tissue distribution studies of 14C in rats at 1.5, 5, 24, and 48 hr after a single po dose of 10 mg/kg 14C-flavodilol showed that the majority of the radioactivity was in the gastrointestinal tract and organs of elimination at all time points. Less than 1% of the dose remained in the body at 48 hr. 14C-Flavodilol was administered to rats iv at 1 mg/kg and orally at 10 mg/kg to assess comparative (label vs. nonlabel) absorption and distribution characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunogenicity of biopharmaceuticals in laboratory animals

The potential immunogenicity of new protein therapeutics raises concerns about the possibility of inducing untoward immune reactions in humans. It is generally assumed that all animals will make antibody to human proteins and therefore, there is sentiment among some scientists that this makes the issue of immunogenicity as a safety concern irrelevant. However, recent clinical trials with some proteins have detected the presence of autoantibodies that have resulted in clinical sequelae. These reactions were also observed in preclinical animal studies. In fact, non-human primate and transgenic mouse models can be useful for predicting the relative immunogenicity of human proteins. In addition, the characterization of the immunogenicity of biotechnology molecules provides a practical basis for determining the significance of antibody formation in preclinical safety studies.     

Disposition and pharmacology of propofol glucuronide administered intravenously to animals.

1. Propofol glucuronide (PG) is the major human metabolite of the i.v. anaesthetic propofol, 2,6-diisopropylphenol. 2. Bolus i.v. doses of 14C-PG (1 mg/kg) to rat and dog were eliminated in urine (40 and 66% respectively) and faeces (48 and 19%); 25 and 48% of the dose were excreted unchanged in urine. 3. In dog, PG was distributed from plasma (t 1/2 4 min) into a volume equivalent to extracellular water and eliminated with t 1/2 80 min. Total body clearance was 1.8 ml/min per kg, and renal clearance about 20% GFR. In rat, plasma 14C concentrations were about one-tenth those in dog, thus PG levels were not quantified. 4. Propofol was not detected in the plasma showing that PG is hydrolytically stable. Enterohepatic circulation of PG occurred in rat and to a lesser extent in dog. Metabolites, mainly side-chain hydroxylation products, were evident in both species from 4 h after dosing. 5. Bolus i.v. doses of PG (200 mg/kg) showed no hypnotic activity in mice.     

The parenteral toxicity of clindamycin 2-phosphate in laboratory animals

The ip and iv LD50 values of 1145 and 855 mg/kg of clindamycin 2-phosphate in the Swiss white mouse were approximately 3 times higher than those of clindamycin hydrochloride. The lesion produced by single injection of 50 or 100 mg/ml of clindamycin 2-phosphate in the loin muscles of the New Zealand White rabbit was graded as slight. The 24-hr serum creatine phosphokinase value was 1500 IU/liter which was less than one-half that of the parent antibiotic.Body weight gains and food conversion ratios in groups of 10 Sprague-Dawley rats injected sc with 120 mg/kg for 6 days were comparable to those of the control group; 90 mg/kg was tolerated in these terms nearly as well for 30 days as no treatment or doses of 30 and 60 mg/kg. From 22 to 33 injections (each equivalent to 30, 60 or 90 mg/kg) were made bilaterally in the posterior thigh muscles of groups of 3 beagle dogs. The terminal elevations of serum glutamic-oxaloacetic transaminase varied from 54 to 400 Reitman-Frankel units. The characteristic pathologic change resulting from the superimposed injections was dose-related progressive scarring of the muscle bundles.Intravenous administration of 60 and 120 mg/kg daily in divided doses in 2 groups of 4 dogs each for 30 days produced no detectable irritation in the peripheral veins or drug-related hemolysis. Tests for drug-induced hemolysis and changes in erythrocyte fragility by in vitro methods were negative. In dogs treated iv with 120 mg/kg for 1 week, as light increase in neutral lipid droplets was present in hepatocytes from 3 hr to 3 days when examined by electron microscopy. This transient change was not observed in dogs injected im with 90 mg/kg for the same period.     

The pharmacokinetics of propofol in ICU patients undergoing long‐term sedation

The aim of this study was to characterize the pharmacokinetics (PK) of propofol in ICU patients undergoing long‐term sedation and to assess the influence of routinely collected covariates on the PK parameters. Propofol concentration–time profiles were collected from 29 patients. Non‐linear mixed‐effects modelling in NONMEM 7.2 was used to analyse the observed data. The propofol pharmacokinetics was best described with a three‐compartment disposition model. Non‐parametric bootstrap and a visual predictive check were used to evaluate the adequacy of the developed model to describe the observations. The typical value of the propofol clearance (1.46 l/min) approximated the hepatic blood flow. The volume of distribution at steady state was high and was equal to 955.1 l, which is consistent with other studies involving propofol in ICU patients. There was no statistically significant covariate relationship between PK parameters and opioid type, SOFA score on the day of admission, APACHE II, predicted death rate, reason for ICU admission (sepsis, trauma or surgery), gender, body weight, age, infusion duration and C‐reactive protein concentration. The population PK model was developed successfully to describe the time‐course of propofol concentration in ICU patients undergoing prolonged sedation. Despite a very heterogeneous group of patients, consistent PK profiles were observed. Copyright © 2016 John Wiley & Sons, Ltd.     

Acute toxicity of 2-butyne-1,4-diol in laboratory animals.

Acute toxicity of 2-butyne-1,4-diol (BYD) was evaluated in laboratory animals. The evaluation involved acute oral and dermal toxicity in rats, dermal and ocular irritation in rabbits and skin sensitization in guinea pigs. The oral LD50 values for BYD were 132 mg kg-1 in male rats and 176 mg kg-1 in female rats. Post-mortem histology showed severe damage in lungs, liver and kidneys. In surviving rats, moderate to severe degenerative changes were observed in the liver but only mild lesions in the kidneys. In acute dermal toxicity studies the test chemical was applied either as a solid substance or as 40% aqueous solution at a dose of 5 g kg-1 for 24 h. Within 48 h of application of the diluted test material, half of the rats died. Liver and kidneys were the primary targets and different stages of degeneration, including necrosis, were observed. No deaths occurred after application of the solid substance. In rabbits, BYD was slightly irritant to skin and eyes. No allergic contact dermatitis was observed in guinea pigs.