The Pharmacokinetics of Recombinant Human Relaxin in Nonpregnant Women After Intravenous,Intravaginal, and Intracervical Administration

The pharmacokinetics of recombinant human relaxin (rhRlx) after intravenous (iv) bolus administration and the absorption of rhRlx after intracervical or intravaginal administration were determined in nonpregnant women. The study was conducted in two parts. In part I, 25 women received 0.01 mg/kg rhRlx iv. After a minimum 7-day washout period, these women were dosed intracervically (n = 10) or intravaginally (n = 15) with 0.75 or 1.5 mg rhRlx, respectively, in 3% methylcellulose gel. Part II was a double-blind, randomized, three-way crossover study in 26 women. At 1-month intervals, each woman received one of three intravaginal treatments consisting of 0 (placebo), 1, or 6 mg rhRlx in 3% methylcellulose gel. The serum concentrations of relaxin following iv administration were described as the sum of three exponentials. The mean (±SD) initial, intermediate, and terminal half-lives were 0.09 ± 0.04, 0.72 ± 0.11, and 4.6 ± 1.2 hr, respectively. Most of the area under the curve was associated with the intermediate half-life. The weight-normalized clearance was 170 ± 50 mL/hr/kg. The observed peak concentration was 98 ± 29 ng/mL, and the weight-normalized initial volume of distribution was 78 ± 40 mL/kg, which is approximately equivalent to the serum volume. If central compartment elimination was assumed, the volume of distribution at steady state (V _ss/W) was 280 ± 100 mL/kg, which is approximately equivalent to extracellular fluid volume. V _ss/W could be as large as 1300 ± 400 mL/kg without this assumption. After intravaginal administration of the placebo gel, endogenous relaxin concentrations were evident (i.e., 20 pg/mL) in 9 of the 26 women (maximum concentrations, 23–234 pg/mL). A similar proportion of women (approximately 35–40%) exhibited measurable serum concentrations of relaxin following intravaginal rhRlx treatment; this proportion increased to 90% following intracervical rhRlx treatment. For both routes of administration, the maximum serum concentrations of relaxin were usually within the range of values observed for endogenous relaxin, suggesting that the absorption of rhRlx was minimal.     

Evidence for an Interaction Between the β-Blocker Pafenolol and Bile Salts in the Intestinal Lumen of the Rat Leading to Dose-Dependent Oral Absorption and Double Peaks in the Plasma Concentration–Time Profile

Pafenolol is a -blocker with unusual oral absorption properties. The blood concentration–time profile exhibits two peaks, and the bioavailability is low and dose dependent because of incomplete and nonlinear intestinal uptake. We addressed the question whether the intestinal absorption of pafenolol was affected by bile depletion in the gut lumen of rats. Further, the hypothesis that variable gastric emptying accounts for double peaks in blood was tested by duodenal administration of pafenolol. Following intraduodenal administration to rats with intact bile secretion, double peaks were observed in the blood concentration–time curve. The bioavailability was 6.8 ± 0.7% for the low dose (1 µmol/kg) and increased significantly to 28 ± 10% following the high duodenal dose (25 µmol/kg). These blood concentration–time profiles exclude interrupted gastric emptying as cause of the twin peaks. In bile duct-cannulated rats the intestinal absorption of the low dose (1 µmol/kg) was still poor (F = 10.7 ± 5.5%) and the blood concentration–time profile contained two peaks. Following administration of a high duodenal dose (25 µmol/kg) to rats with an almost bile-free small intestine, the absorption rate increased and the double-peak phenomenon disappeared in five of seven rats, while the bioavailability increased significantly, to 62 ± 27%. These results suggest that the low bioavailability of pafenolol is due to a complexation between bile and pafenolol in the gut lumen, preventing intestinal uptake in the major part of the small intestine. Further, such complex formation in the intestinal lumen may be the underlying mechanism of the double peaks observed in the blood concentration–time profile.     

Mechanism of Intestinal Absorption of Ranitidine and Ondansetron: Transport Across Caco-2 Cell Monolayers

We have investigated the transport of ranitidine and ondansetron across the Caco-2 cell monolayers. The apparent permeability coefficients (P _app) were unchanged throughout the concentration range studied, indicating a passive diffusion pathway across intestinal mucosa. No metabolism was observed for ranitidine and ondansetron during the incubation with Caco-2 cell monolayers. P _app values for ranitidine and ondansetron (bioavailability of 50 and 100% in humans, respectively) were 1.03 ± 0.17 × 10^–7 and 1.83 ± 0.055 × 10^–5 cm/sec, respectively. The P _app value for ranitidine was increased by 15- to 20-fold in a calcium-free medium or in the transport medium containing EDTA, whereas no significant change occurred with ondansetron, indicating that paracellular passive diffusion is not rate determining for ondansetron. Uptake of ondansetron by Caco-2 cell monolayers was 20- and 5-fold higher than that of ranitidine when the uptake study was carried out under sink conditions and at steady state. These results suggest that ranitidine and ondansetron are transported across Caco-2 cell monolayers predominantly via paracellular and transcellular pathways, respectively.     

丝光沸石催化剂上正己烷异构化反应机理

以轻质烷烃异构化中试放大用的丝光沸石催化剂为研究对象,运用“原位”红外反应技术和催化剂活性评价手段,并结合反应动力学参数计算,探讨了正已烷异构化反应机理。结果表明,可用五配位反应中间物种机理解释正碳离子的生成。用双分子六元环反应中间物机理能较好地解释正已烷在氢型丝光沸石(HM)上的异构化过程。对正已烷在Pd/HM上的反应过程也可用正碳离子机理结合双分子六元环中间物机理解释。     

Comparison of the diuretic effect and absorption of a single dose of furosemide and free and the fixed combinations of furosemide and triamterene in healthy male adults

Summary The absorption and diuretic effect of furosemide 40 mg alone (F), and of the free (F+T) and the fixed (FT) combinations of furosemide 40 mg and triamterene 50 mg have been compared in 12 healthy young men.A slight reduction in the area under the concentration-time curve (AUC) of plasma furosemide was found for the fixed combination (AUC₄₈₀) F 2.58 g · h · ml^–1; F+T 2.46 g · h · ml^–1; FT 1.97 g · h · ml^–1. There was a significant reduction in the AUC₄₈₀ of plasma triameterene (F+T 204.9 g · h · l^–1; FT 130.2 g · h · l^–1). Sodium excretion after F+T and FT was more pronounced than after F (F+T 302 mmol; FT 311 mmol; F 259 mmol). When compared to F alone, there was a reduction in the 24-hour potassium excretion after F+T as well as after FT (F 121 mmol; F+T 104 mmol; FT 107 mmol).It is concluded that the absorption of triamterene was significantly reduced after ingestion of the fixed combination tablet. However, in healthy male adults this had no influence on its natriuretic and potassium-sparing effect as compared to the free combination.     

Mechanism of Ethanol-Enhanced Estradiol Permeation Across Human Skin in Vivo

The influence of ethanol on the permeation of 17-estradiol (estradiol) across viable human skin in vivo was investigated with the human skin sandwich flap model. Maintaining continuous delivery of a constant concentration of the solute in phosphate-buffered saline, pH 7.4 (PBS), or mixtures of ethanol in PBS to the skin surface revealed that steady-state flux of estradiol was achieved within 30–60 min and maintained throughout 4 hr. The 10-fold decrease in in vivo flux and permeability coefficient (K _p) of tracer estradiol solutions in ethanol or ethanol solutions compared with PBS vehicle reflected the 10-fold difference in the apparent partition coefficients (K _m) of estradiol from the respective vehicles into isolated human stratum corneum. Neither the stratum corneum thickness nor the diffusion coefficient of estradiol was significantly different among the vehicles tested. In vivo flux of estradiol in ethanol or ethanol solutions across viable human skin was increased with saturated solutions of estradiol. Further, in vivo flux of estradiol from vehicles such as PBS, ethanol, and ethanol mixtures, which minimally alter the rate-limiting barrier, can be successfully predicted with knowledge of only two physicochemical parameters, the estradiol concentration in the vehicle and the K _m of estradiol from the vehicle into isolated human stratum corneum.     

Bile Salt–Fatty Acid Mixed Micelles as Nasal Absorption Promoters of Peptides. I. Effects of Ionic Strength,Adjuvant Composition,and Lipid Structure on the Nasal Absorption of [D-Arg2]Kyotorphin

Bile salts and synthetic surfactants have been used to promote nasal absorption of peptide drugs. Although a marked increase in nasal absorption has been achieved, this may not be adequate and the possibility of adjuvant-induced membrane toxicity exists. The present study employs a rat in situ nasal perfusion technique and mixed micelles between sodium glycocholate (NaGC) and various lipids as potential nasal absorption enhancers of a stable model dipeptide, [D-Arg²]kyotorphin. NaGC alone enhanced the nasal absorption of the dipeptide in a concentration-dependent manner. When linoleic acid was added to form mixed micelles with NaGC, the absorption was further enhanced (P < 0.01). The effect of mixed micelles was synergistic and much greater than with single adjuvants. Increasing ionic strength was found to increase the adjuvant activity of both NaGC and NaGC–lipid mixed micelles. Structure of the lipid component of the mixed micelles also affected the adjuvant potency. Oleic acid, a cis-unsaturated fatty acid, was more effective than elaidic acid, the trans-isomer, whereas cis-linoleic acid and trans-linolelaidic acid were equally effective ( = 0.05). Mixed micelles of mono-glycerides such as monoolein and monolinolein were also more effective than NaGC alone ( = 0.05). Micellar solubilization of these polar lipids by NaGC appears to be important for nasal absorption enhancement to occur. Reversal of the membrane permeability was also observed within approximately 20–40 min after removal of the adjuvants from the rat nasal cavity. These observations are similar to the effects of mixed micelles on the rectal mucosa and may involve the same mechanism.     

Solute Absorption from the Airways of the Isolated Rat Lung. II. Effect of Surfactants on Absorption of Fluorescein

To determine the effects on the pulmonary barrier of several surface active agents, a series of metered dose inhalers (MDIs) was prepared and used to dose aerosolized surfactant to the airways of isolated perfused rat lungs. The MDIs contained a range of concentrations, from 0.1 to 5.0% (w/w), of either oleic acid, oleyl alcohol, or Span 85, which released 45 µg (0.1%, w/w) to 1660 µg (5.0%, w/w) of surfactant per actuation. The permeability of the pulmonary barrier was assessed by the rate of transfer of disodium fluorescein dosed as 100 µl of aqueous solution (1 mg/ml) after administering the surfactants. Some 12.1 ± 4.7% of the recovered surfactant, per dose, was assessed to reach the pulmonary regions of the lung. All surfactants tested caused an increase in fluorescein transfer rates. A single actuation from the MDI containing 5% (w/w) oleic acid produced gross edema in all lungs tested within 40 min and the first-order half-lives of absorption were reduced almost threefold, from 12.9 ± 2.5 min for controls to 4.5 ± 0.8 min. Differences in absorption were noted between the acid and the alcohol, which is consistent with the hypothesis that both the hydrocarbon chain and the polar head group have roles in the altered permeability to fluorescein. The absorption of fluorescein when dosed from the MDI containing 5% (w/w) Span 85 was increased but all surfactants dosed from the lowest concentration MDI of 0.1% (w/w) did not alter absorption rates of the dye relative to those of controls. Results are discussed in light of current interest in absorption enhancement and the presence of surfactants in currently marketed MDIs.     

高温煤气中HC1气体与脱氯剂的反应动力学

在固定床反应器中研究了自制的脱氯剂与高温煤气中ＨＣ１气体的反应动力学,得出在５５０℃时反应受通过产物层的扩散和化学反应反控制,两埂的阻力之比为０．１３８。同时研究了温度和进口ＨＣ１气体浓度对该反应影响,得出反应对于气相ＨＣ１为一级反应。     

集总动力学模型研究的普遍方法与原则探讨

在积累了大量实践经验的基础上,结合石油加工过程中集总动力学模型的研究,对集总研究的普遍方法与原则进行了讨论与阐述,提出了几点自己的观点及应该注意的事项。