Placental and Foetal Metabolism of Acetaldehyde in Rat II. Studies on Metabolism of Acetaldehyde in the Isolated Placenta and Foetus

Abstract: The aldehyde-oxidizing capacity of placenta and foetal liver from the rat was studied using acetaldehyde as substrate. In the placenta the activity was approximately 8 % and in foetal liver 49 % of that found in the liver of adult animal. The placenta seems to prevent most of the acetaldehyde found in maternal blood during ethanol oxidation from entering the foetal circulation.     

Inhalation pharmacokinetics based on gas uptake studies

On the basis of previous determinations of pharmacokinetic parameters for inhaled vinyl chloride in men, rhesus monkeys, and rats, and on improved pharmacokinetic models a pharmacokinetic treatment of the problem of peak concentrations of vinyl chloride, as occuring in industrial practice, became possible. For the calculations, metabolic elimination kinetics of vinyl chloride was assumed to be first order as experiments in different species including rhesus monkeys showed linear pharmacokinetics up to atmospheric exposures of 200–300 ppm. The distribution of vinyl chloride between atmosphere and organism under different conditions was evaluated using steady-state-kinetics. After treating the processes of influx, efflux, and metabolism, the numerical values for the parameters derived from a human kinetic experiment were used to theoretically calculate the time courses of concentration of vinyl chloride in the organism and of the cumulative amount of vinyl chloride metabolized, under the conditions of (a) a 2 h constant exposure to 5 ppm vinyl chloride and (b) two subsequent peaks of 50 ppm with a duration of 5 min each. This model calculation suggested that, regardless of the exposure profile, the amount of (reactive) metabolites formed from vinyl chloride would soleley be a function of the mean atmospheric vinyl chloride concentration over time. The general validity of this suggested rule could subsequently be demonstrated. As the concentration of the reactive metabolite of vinyl chloride responsible for the carcinogenic effect at the target site must be a resultant of both formation and inactivation, an evaluation of the differential risk of different exposure profiles can reasonably be based on biochemical examinations of the detoxifying pathways. This points out the relevance of studies of the patterns of different metabolites of vinyl chloride in man under varying exposure profiles.     

醋酸泼尼松和泼尼松在Beagle犬体内的生物利用度比较

本文通过Beagle犬双周期随机交叉灌胃给予醋酸泼尼松(2.0 mg·kg^-1)和泼尼松(1.8 mg·kg^-1),建立液相色谱-串联质谱(LC-MS/MS)法同时测定Beagle犬血浆中的醋酸泼尼松、泼尼松及活性代谢物泼尼松龙的浓度,比较醋酸泼尼松和泼尼松的生物利用度及药代动力学。本实验方案经中国科学院上海药物研究所实验动物伦理委员会批准。采用地塞米松作为内标,血浆样品以乙腈沉淀蛋白后,经HSS T₃(50 mm×2.1 mm,1.8μm)色谱柱分离,以甲醇-0.1%甲酸的5 mmol·L^-1醋酸铵水溶液作为流动相进行梯度洗脱。采用电喷雾离子源,以多反应监测正离子模式检测。用于定量分析的醋酸泼尼松、泼尼松及泼尼松龙的离子对分别为m/z 401.2→295.2、m/z 359.2→313.2和m/z 361.2→325.1,内标的离子对为m/z 393.2→373.0。结果表明,醋酸泼尼松在血浆中的含量低于分析方法的定量下限1.0 ng·mL^-1,说明醋酸泼尼松在体内吸收过程中...     

Oral 4-week and 13-week toxicity studies of polyvinyl acetate vinyl laurate copolymer in rats

Polyvinyl acetate vinyl laurate copolymer (PVAcVL) is a useful component of gum base for chewing gum production. The safety of PVAcVL was examined in a 4-week and a 13-week oral toxicity study in rats. Finely powdered PVAcVL was administered with the diet at levels of 1.25%, 2.0% and 5% in the 4-week study and 1.25%, 2.5% and 5% in the 13-week study. There were no treatment related effects on mortality, bodyweight gains feed efficiency, ophthalmoscopic findings, hematological and clinical chemical parameters, neurobehavioral observations as well as gross and histopathological changes of standard organs and tissues. The highest dose tested in the 13-week study (3783 and 4396 mg/kg bw/d for males and females, respectively) proved to be a NOAEL.     

醋酸地塞米松聚乙二醇化纳米粒的制备及兔体内药动学研究

目的：制备醋酸地塞米松聚乙二醇（PEG）化纳米粒,并测定其在兔体内的药动学参数。方法：以高压均质法制备醋酸地塞米松PEG化纳米粒,用扫描电镜观察纳米颗粒的形态,用激光粒度分析仪测定粒径。建立检测血浆中醋酸地塞米松浓度的HPLC法,以醋酸地塞米松溶液和普通纳米粒作为对照,测定醋酸地塞米松PEG化纳米粒在兔体内的药动学参数。结果：PEG化纳米粒平均粒径为（180±7）nm。体内半衰期为4.79h,AUC0～12为11.81mg.min.L-1,平均滞留时间为3.15h,重要药动学参数比普通纳米粒及溶液剂增加近1倍。结论：醋酸地塞米松PEG化纳米粒可以延长醋酸地塞米松在兔体内的半衰期,达到体内长循环的目的;其表观特征与普通载药纳米粒无明显差异。     

Investigation into the age-dependence of the pharmacokinetics of cyproterone acetate in healthy male volunteers

Objective: To investigate a possible age-dependence of the pharmacokinetics of cyproterone acetate following single oral administration. Methods: Twenty eight healthy men between 22 and 74 years of age received a single oral dose of 100 mg cyproterone acetate. The pharmacokinetic parameters, area under the serum concentration-time curve, apparent volume of distribution, apparent clearance, terminal half-life and the concentration ratio of 15β-hydroxy-cyproterone acetate/cyproterone acetate were examined for possible age-dependence using regression analysis. Results: The values of area under the serum level-time curve showed high interindividual variability and were not related to age. With regard to apparent clearance and volume of distribution, decreasing and increasing values, respectively, were observed with increasing age. There was also a clear dependence of the terminal half-life on age. Elderly men had values about two times higher (95 h) than men belonging to the younger age groups (45 h). The mean concentration ratio of 15β-hydroxy-cyproterone acetate/cyproterone acetate was 0.8 (0.3) and showed no age-dependent change. Conclusions: Apparent clearance and apparent volume of distribution of cyproterone acetate showed age-dependent changes. Combined, the two effects cause a clear age-dependence of the terminal half-life of cyproterone acetate. An age-related reduction in liver volume is thought to be mainly responsible for the decrease in hepatic clearance with age. Chronic daily administration of the drug to elderly men may therefore lead to somewhat higher steady-state concentrations in the serum than in young men receiving the same dose. Received: 9 December 1996 / Accepted in revised form: 10 April 1997     

Histochemical localisation of carboxylesterase activity in rat and mouse oral cavity mucosa

Vinyl acetate (VA) is widely used within the chemical industry, in the manufacture of polyvinyl alcohol, and as polyvinyl acetate emulsions in latex paints, adhesives, paper and paper board coatings. Chronic oral exposure of rodents to high concentrations of VA induces tumours within the oral cavity. Carboxylesterase-dependent hydrolysis of VA is thought to be critical in the development of nasal tumours following inhalation exposure of animals to VA. Therefore, carboxylesterase activity was determined histochemically in the oral cavities of male F344 rats and BDF mice in order to explore the potential role of carboxylesterase-dependent hydrolysis of VA in the development of oral tumours. Following fixation in 10% neutral buffered formalin heads were decalcified in neutral saturated EDTA, embedded in resin, sectioned at six levels (three each for the upper and lower jaws), and carboxylesterase activity revealed in the tissue using -naphthyl butyrate as substrate. The localisation of carboxylesterase activity in freshly dissected rat oral tissue was compared to that of the resin sections and found to be identical, thus validating the decalcification process. A similar pattern of carboxylesterase activity was observed for the two species. Staining was low in areas surrounding the teeth, and medium/high in the buccal mucosa, the central/posterior upper palate and those regions of the lower jaw not proximal to the teeth. In general the intensity of staining was greater in sections from the rat compared to those from the mouse. By comparison, carboxylesterase activity was considerably higher in mouse nasal olfactory epithelium than in any of the oral tissues. Thus the mucosa of the oral cavity has the potential to hydrolyse VA to its metabolites, acetic acid and acetaldehyde, and the presence of carboxylesterases at this site is consistent with, and may be an important determining factor in, the development of oral cavity tumours following exposure to VA.     

Metabolism of megestrol acetate in vitro and the role of oxidative metabolites

1. There is limited knowledge regarding the metabolism of megestrol acetate (MA), as it was approved by FDA in 1971, prior to the availability of modern tools for identifying specific drug-metabolizing enzymes. We determined the cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) that metabolize MA, identified oxidative metabolites and determined pharmacologic activity at the progesterone, androgen and glucocorticoid receptors (PR, AR and GR, respectively).

2. Oxidative metabolites were produced using human liver microsomes (HLMs), and isolated for mass spectral (MS) and nuclear magnetic resonance (NMR) analyses. We screened recombinant P450s using MA at 62?μM (HLM K_m for metabolite 1; M1) and 28?μM (HLM K_m for metabolite 2; M2). UGT isoforms were simultaneously incubated with UDPGA, nicotinamide adenine dinucleotide phosphate (NADPH), CYP3A4 and MA. Metabolites were evaluated for pharmacologic activity on the PR, AR and GR. CYP3A4 and CYP3A5 are responsible for oxidative metabolism of 62?μM MA.

3. At 28?μM substrate concentration, CYP3A4 was the only contributing enzyme. Mass spectral and NMR data suggest metabolism of MA to two alcohols. After oxidation, MA is converted into two secondary glucuronides by UGT2B17 among other UGTs. MA, M1 and M2 had significant pharmacologic activity on the PR while only MA showed activity on the AR and GR.     

高效液相色谱法测定氯替含漱液中替硝唑和醋酸氯己定含量

目的建立氯替含漱液中替硝唑和醋酸氯已定含量测定方法。方法高效液相色谱法同时测定替硝唑和醋酸氯己定,采用C18（250 mm×4.6 mm,5μm）色谱柱,以0.1 mol L-1磷酸二氢钠-乙腈（72：28,用磷酸调节pH为3.0）为流动相;检测波长：284 nm;流速：1.0 mL min-1;进样量：10μL。结果替硝唑和醋酸氯已定分别在196.6～786.4μg mL-1和97.4～786.4μg mL-1内与峰面积呈良好的线性关系,r均为0.999 8;平均回收率分别为100.4%、100.6%。结论本方法简便可行,结果准确可靠,适用于氯替含漱液的质量控制。     

Validation of human physiologically based pharmacokinetic model for vinyl acetate against human nasal dosimetry data.

Vinyl acetate has been shown to induce nasal lesions in rodents in inhalation bioassays. A physiologically based pharmacokinetic (PBPK) model for vinyl acetate has been used in human risk assessment, but previous in vivo validation was conducted only in rats. Controlled human exposures to vinyl acetate were conducted to provide validation data for the application of the model in humans. Five volunteers were exposed to 1, 5, and 10 ppm 13C1,13C2 vinyl acetate via inhalation. A probe inserted into the nasopharyngeal region sampled both 13C1,13C2 vinyl acetate and the major metabolite 13C1,13C2 acetaldehyde during rest and light exercise. Nasopharyngeal air concentrations were analyzed in real time by ion trap mass spectrometry (MS/MS). Experimental concentrations of both vinyl acetate and acetaldehyde were then compared to predicted concentrations calculated from the previously published human model. Model predictions of vinyl acetate nasal extraction compared favorably with measured values of vinyl acetate, as did predictions of nasopharyngeal acetaldehyde when compared to measured acetaldehyde. The results showed that the current PBPK model structure and parameterization are appropriate for vinyl acetate. These analyses were conducted from 1 to 10 ppm vinyl acetate, a range relevant to workplace exposure standards but which would not be expected to saturate vinyl acetate metabolism. Risk assessment based on this model further concluded that 24 h per day exposures up to 1 ppm do not present concern regarding cancer or non-cancer toxicity. Validation of the vinyl acetate human PBPK model provides support for these conclusions.     

HPLC法测定复方醋酸地塞米松搽剂中醋酸地塞米松和樟脑的含量

目的采用HPLC法测定复方醋酸地塞米松搽剂中醋酸地塞米松和樟脑的含量。方法色谱柱为C18,流动相为甲醇-水（60：40,V／V）,检测波长醋酸地塞米松为240nm和樟脑为290am,流速1mL·min^-1,柱温为室温。结果醋酸地塞米松和樟脑分别在5．05～80．8mg·L^-1（r=0．9999）和0．1～5．0g·L^-1（r=0．9999）浓度内线性关系良好,平均回收率分别为100．6％（RSD=0．49％）和100．7％（RSD=0．61％）。结论本方法简便,准确性、重现性好,适用于复方醋酸地塞米松搽剂中醋酸地塞米松和樟脑的含量测定。     

Evaluation of powder mixtures and hydrophilic gastroretentive drug delivery systems containing zinc acetate and sodium bicarbonate

The aim of this study was to develop and study floating controlled drug delivery systems consisting of a model drug (zinc acetate dihydrate), different forms of a matrix-forming polymer (Metolose 90 SH) and sodium bicarbonate as an effervescent component. The proportions of Metolose and bicarbonate were varied, and the effects of the different ratios on the properties of the resulting powders and tablets were determined. The water uptakes of different powder mixtures were initially evaluated. These tests indicated the interaction of the active and effervescent agent, this phenomenon leading to an unpredicted increase in the amount of liquid taken up. This interaction was evaluated as concerns the degradation of the hydrophilic matrix system. The disintegration of tablets with different compositions revealed that this interaction increases the time required for the disintegration of these systems. The study demonstrated that the interaction of the components induced significant changes in the parameters of this new sensitive delivery system. In the last steps, the buoyancy and dissolution properties of tablets that appeared appropriate for the formulation of a controlled drug delivery system were investigated.     

醋酸汞和醋酸铅对大鼠间质细胞功能的影响

研究结果发现，醋酸汞Ｈｇ２＋（１０－８－１０－５ｍｏｌ／Ｌ）和醋酸铅Ｐｂ２＋（１０－７－１０－４ｍｏｌ／Ｌ）分别使得经ｈＣＧ（１００ｍＩＵ）刺激处理２４小时的Ｌｅｙｄｉｇ细胞内ｃＡＭＰ含量显著下降；同时Ｈｇ２＋（１０－７－１０－５ｍｏｌ／Ｌ）和Ｐｂ２＋（１０－６－１０－４ｍｏｌ／Ｌ）也使得Ｌｅｙｄｉｇ细胞Ｔ含量明显降低并且具有明显的剂量－反应关系。醋酸锌（Ｚｎ２＋）对原代培养的Ｌｅｙｄｉｇ细胞的上述观察指标均无影响，表明用这些指标的变化可以评价Ｈｇ２＋和Ｐｂ２＋对大鼠睾丸Ｌｅｙｄｉｇ的某些毒性。     

梯度洗脱高效液相色谱法测定宁肤露中3 组分的含量

目的 :建立梯度洗脱反相高效液相色谱法测定宁肤露中水杨酸、醋酸氯己定、醋酸地塞米松含量的方法。方法 :ODS2色谱柱 ;流动相 :乙腈 0 .0 1mol·L-1 磷酸氢二钠溶液 (用磷酸调 pH3.6 )梯度洗脱 ,检测波长 2 4 0nm。结果 :水杨酸、醋酸氯己定、醋酸地塞米松的平均回收率分别为 99.4 5 %,RSD为 1 .1 %(n =9) ;99.33%,RSD为 1 .4 %(n =9) ;1 0 0 .1 %,RSD为1 .1 %(n =9)。结论 :用HPLC同时测定宁肤露中水杨酸、醋酸氯己定、醋酸地塞米松含量 ,操作简便 ,结果准确。     

Metabolism and pharmacokinetics of cinobufagin

1. The metabolic fate of cinobufagin, a major component of the cardiotonic Senso, has been studied after i.v. administration to rats. Two metabolites were detected in rat serum and shown by n.m.r. and mass spectroscopy to be desacetylcinobufagin (I) and 3-epidesacetylcinobufagin (II).

2. Inhibitory activities of I and II on guinea-pig heart Na+/K+ -ATPase were less than that of cinobufagin.

3. Serum or plasma levels of cinobufagin, I and II in rats, cats and dogs were determined by h.p.l.c. after i.v. and/or oral administration of cinobufagin. After i.v. administration, cinobufagin, I and II appeared in rat serum, but in dog and cat plasma only unchanged cinobufagin was present. After oral administration, only II was detected in rat serum, but neither cinobufagin nor either of its metabolities (I and II) were found in cat and dog serum.     

Metabolism and pharmacokinetics of cinobufagin

1. The metabolic fate of cinobufagin, a major component of the cardiotonic Senso, has been studied after i.v. administration to rats. Two metabolites were detected in rat serum and shown by n.m.r. and mass spectroscopy to be desacetylcinobufagin (I) and 3-epidesacetylcinobufagin (II). 2. Inhibitory activities of I and II on guinea-pig heart Na+/K+-ATPase were less than that of cinobufagin. 3. Serum or plasma levels of cinobufagin, I and II in rats, cats and dogs were determined by h.p.l.c. after i.v. and/or oral administration of cinobufagin. After i.v. administration, cinobufagin, I and II appeared in rat serum, but in dog and cat plasma only unchanged cinobufagin was present. After oral administration, only II was detected in rat serum, but neither cinobufagin nor either of its metabolites (I and II) were found in cat and dog serum.     

HPLC法同时测定曲氯乳膏中醋酸曲安奈德和氯霉素的含量

目的:建立高效液相色谱法同时测定曲氯乳膏中氯霉素和醋酸曲安奈德的含量。方法:用 Hypersil C_(18)(250mm×4.6mm,5 μm)色谱柱;以甲醇-水-正己烷(65:35:2)为流动相;流速为1.0 mL·min~(-1);柱温为20℃;检测波长为240 nm。结果:氯霉素和醋酸曲安奈德的保留时间分别为4.54 min 和16.17 min,理论塔板数分别为2650和6500;HPLC 法测定的线性范围分别为51.32～975.08μg·mL~(-1)(r=0.9999,n=5)和3.116～46.74μg·mL~(-1)(r=0.9999,n=5);回收率分别为100.5%～102.3%(RSD<1.1%)和98.8%～101.7%(RSD<1.5%)。结论:本法用于曲氯乳膏中氯霉素和醋酸曲安奈德的含量测定,简便、快速、准确、可靠。     

Effect of gender on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093), a new voltage-gated sodium channel blocker

PURPOSE: To determine the effect of gender on the pharmacokinetics of eslicarbazepine acetate, a novel voltage-gated sodium channel blocker in the development for the treatment of epilepsy and bipolar disorder. METHODS: Single-centre, open-label, parallel-group study in 12 female and 12 male healthy subjects. The study consisted of a single-dose (600 mg) period and a multiple-dose (600 mg, once-daily, for 8 days) period, separated by 4 days. RESULTS: Eslicarbazepine acetate was rapidly and extensively metabolized to eslicarbazepine (S-licarbazepine), the main active metabolite. Following a single-dose, arithmetic mean eslicarbazepine maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve over 24 h (AUC(0-24)) and from 0 to infinity (AUC(0-infinity)) were, respectively, 9.3 microg/ml, 128.5 microg h/ml and 171.9 microg h/ml in male subjects and 10.1 microg/ml, 150.1 microg h/ml and 205.0 microg h/ml in female subjects. At steady-state, C(max), AUC(0-24) and AUC(0-infinity) were 15.5 microg/ml, 207.8 microg h/ml and 295.8 microg h/ml in male subjects, and 16.8 microg/ml, 214.5 microg h/ml and 295.2 microg h/ml in female subjects. Steady-state plasma concentrations were attained at 4 to 5 days of administration in both groups.Eslicarbazepine C(max), AUC(0-24) and AUC(0-infinity) female:male geometric mean ratios (90%CI) were, respectively, 1.09 (0.94; 1.24), 1.16 (1.00; 1.33) and 1.17 (0.99; 1.38) following single-dose, and 1.10 (0.97; 1.25), 1.04 (0.92; 1.17) and 1.01 (0.88; 1.16) at steady-state. CONCLUSION: At steady-state, the pharmacokinetic profile of eslicarbazepine acetate was not affected by gender.