Cold Flow Evaluation in Transdermal Drug Delivery Systems by Measuring the Width of the Oozed Adhesive.

The objective of this study was to develop a simpler and more practical quantitative evaluation method of cold flow (CF) in transdermal drug delivery systems (TDDSs). CF was forcibly induced by loading a weight on a punched-out sample (bisoprolol and tulobuterol tapes). When the extent of CF was analyzed using the area of oozed adhesive as following a previously reported method, the CF profiles were looked different between the samples 12 mm in diameter subjected to a 0.5-kg weight and samples 24 mm in diameter subjected to a 2.0-kg weight despite an equal load per unit area (4.42 g/mm2). The width of oozed adhesive around the original sample was suggested to be an index that properly describes the relationship between the load per unit area and the extent of CF. Further, it was clarified that the average CF width over the entire circumference of the sample was the same whether the samples were round or square as long as the sample area and load were the same. We also observed a linear relationship between the CF width and the aspect ratio of oval and rectangular samples. These results indicated that the CF properties of typical TDDS products lacking CF-proof processing at the edges could be determined by testing samples cut from the product rather than the whole TDDS patch. The proposed width measuring method was simple and useful for optimizing the composition of the adhesive and for testing the quality of the product.

Bioequivalence assessment of tulobuterol transdermal delivery system in healthy subjects
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OBJECTIVE: The purpose of this study was to evaluate the bioequivalence in the pharmacokinetics of two 2-mg tulobuterol transdermal delivery systems (TDSs) in healthy subjects. MATERIALS AND METHODS: The pharmacokinetic (PK) analysis was performed using data from a randomized, open-label, single-dose, two-way, two-period, crossover study. Eligible subjects received either the Bretol®patch (test drug) or Hokunalin®patch (reference drug) in sequence according to their allocated group. Serial blood samples for PK analyses were collected for up to 48 hours after tulobuterol TDS application. The PK parameters, including the maximum concentration (Cmax) and area under the curve from time zero to the last quantifiable concentration time (AUClast), were estimated by using noncompartmental analysis. The geometric mean ratios (GMRs) of the Cmax and AUClast and their 90% confidence intervals (CIs) were estimated. RESULTS: A total of 27 subjects completed the study as planned. The concentration-time profiles of tulobuterol were similar in both formulations. The GMRs (90% CIs) of Cmax and AUClast were 0.9443 (0.8790 - 1.0144) and 0.9600 (0.8660 - 1.0642), respectively. CONCLUSION: The PK profiles of both tulobuterol TDSs were comparable. In addition, the 90% CIs of the GMR were within the bioequivalence criteria of 0.800 - 1.250. Therefore, the Bretol®patch can be used as an alternative to the Hokunalin®patch for the treatment of patients with asthma and chronic obstructive pulmonary disease.
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The novel combination of theophylline and bambuterol as a potential treatment of hypoxemia in humans.

Hypoxemia can be life-threatening, both acutely and chronically. Because hypoxemia causes vascular dysregulation that further restricts oxygen availability to tissue, it can be pharmacologically addressed. We hypothesized that theophylline can be safely combined with the ß2-adrenergic vasodilator bambuterol to improve oxygen availability in hypoxemic patients. Ergogenicity and hemodynamic effects of bambuterol and theophylline were measured in rats under hypobaric and normobaric hypoxia (12% O2). Feasibility in humans was assessed using randomized, double-blind testing of the influence of combined slow-release theophylline (300 mg) and bambuterol (20 mg) on adverse events (AEs), plasma K+, pulse, blood pressure, and drug interaction. Both drugs and their combination significantly improved hypoxic endurance in rats. In humans, common AEs were low K+ (<3.5 mmol/L; bambuterol: 12, theophylline: 4, combination: 13 episodes) and tremors (10, 0, 14 episodes). No exacerbation or serious AE occurred when drugs were combined. A drop in plasma K+ coincided with peak bambuterol plasma concentrations. Bambuterol increased heart rate by approximately 13 bpm. Drug interaction was present but small. We report promise, feasibility, and relative safety of combined theophylline and bambuterol as a treatment of hypoxemia in humans. Cardiac safety and blood K+ will be important safety endpoints when testing these drugs in hypoxemic subjects.

Enantioselective analysis of bambuterol in human plasma using microwave-assisted chiral derivatization coupled with ultra high performance liquid chromatography and tandem mass spectrometry.

In this study, an enantioselective analytical method based on microwave-assisted chiral derivatization coupled with ultra high performance liquid chromatography and tandem mass spectrometry was developed for the determination of bambuterol enantiomers in human plasma. The chiral derivatization reaction was greatly accelerated by microwave irradiation. Under the optimized conditions, both the derivatization time and separation time on column was only 3 min, and the lower limit of quantification was 2.5 pg/mL. The recoveries were in the range of 90.1-93.0% without significant matrix effect. Compared with the conventional heating chiral derivatization, microwave-assisted chiral derivatization obtained higher chiral derivatization yields with much shorter time due to the effect of microwave irradiation. Furthermore, the racemization during the derivatization reaction was systematically investigated. The results showed the concentration of acetic acid and the reaction time had significant effects on the racemization, which could be well controlled during microwave-assisted chiral derivatization for the short reaction time. Finally, this novel approach was demonstrated by determining bambuterol in human plasma of a clinical pharmacokinetic study in eight healthy volunteers. On the basis of the results, microwave-assisted chiral derivatization coupled with ultra high performance liquid chromatography and tandem mass spectrometry as a simple and effective enantioselective analysis technique for the determination of chiral drugs in complex biological samples showed great promise.

Influence of exercise in normal and hot ambient conditions on the pharmacokinetics of inhaled terbutaline in trained men.

This study investigated the pharmacokinetics of inhaled terbutaline at rest and after exercise in normal and hot ambient conditions with respect to doping analysis. Thirteen trained young men participated in the study. Urine and blood samples were collected after inhalation of 4 mg terbutaline during three trials: exercise in hot ambient conditions (30-35 °C) (EXH), exercise in normal ambient conditions (20-25 °C) (EX), and rest (20-25 °C) (R). Exercise consisted of 130 min at various intensities. Adjustment of urine concentrations of terbutaline to a specific gravity (USG) of 1.02 g/mL was compared with no adjustment. Area under the serum concentration-time curve within the first 6 h was higher for EX (27 ± 3 ng/mL/h) (P ≤ 0.01) and EXH (25 ± 4 ng/mL/h) (P ≤ 0.05) than for R (20 ± 3 ng/mL/h). When unadjusted for USG, urine concentrations of terbutaline after 4 h were different in the order EXH > EX > R (P ≤ 0.01). When unadjusted for USG, urine concentrations of terbutaline were 299 ± 151 ng/mL higher (P ≤ 0.001) after 4 h compared with adjusted concentrations in EXH. Excretion rate of terbutaline was higher (P ≤ 0.001) for EX than for EXH and R within the first 0-1½ h. In conclusion, EXHs results in higher urine concentrations of terbutaline. This should be considered when evaluating doping cases of terbutaline.

Formulation and In Vitro and In Vivo Evaluation of Lipid-Based Terbutaline Sulphate Bi-layer Tablets for Once-Daily Administration.

The objective of this study was to prepare and evaluate terbutaline sulphate (TBS) bi-layer tablets for once-daily administration. The bi-layer tablets consisted of an immediate-release layer and a sustained-release layer containing 5 and 10 mg TBS, respectively. The sustained-release layer was developed by using Compritol®888 ATO, Precirol® ATO 5, stearic acid, and tristearin, separately, as slowly eroding lipid matrices. A full 4 × 2(2) factorial design was employed for optimization of the sustained-release layer and to explore the effect of lipid type (X 1), drug-lipid ratio (X 2), and filler type (X 3) on the percentage drug released at 8, 12, and 24 h (Y 1, Y 2, and Y 3) as dependent variables. Sixteen TBS sustained-release matrices (F1-F16) were prepared by melt solid dispersion method. None of the prepared matrices achieved the targeted release profile. However, F2 that showed a relatively promising drug release was subjected to trial and error optimization for the filler composition to develop two optimized matrices (F17 and F18). F18 which consisted of drug-Compritol®888 ATO at ratio (1:6 w/w) and Avicel PH 101/dibasic calcium phosphate mixture of 2:1 (w/w) was selected as sustained-release layer. TBS bi-layer tablets were evaluated for their physical properties, in vitro drug release, effect of storage on drug content, and in vivo performance in rabbits. The bi-layer tablets showed acceptable physical properties and release characteristics. In vivo absorption in rabbits revealed initial high TBS plasma levels followed by sustained levels over 24 h compared to immediate-release tablets.

A sensitive LC-MS/MS method for simultaneous determination of R-bambuterol and its active metabolite R-terbutaline in human plasma and urine with application to a clinical pharmacokinetic study.

A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of R-bambuterol and its active metabolite R-terbutaline in human plasma and urine was established. The inhibition for the biotransformation of R-bambuterol in plasma was fully investigated. Plasma samples were prepared on ice and neostigmine metilsulfate added as a cholinesterase inhibitor immediately after sample collection. All samples were extracted with ethyl acetate and separated on a C18 column under gradient elution with a mobile phase consisting of methanol and water containing 5 mm ammonium acetate at a flow rate of 0.6 mL/min. The analytes were detected by an API 4000 tandem mass spectrometer with positive electrospray ionization in multiple reaction monitoring mode. The established method was highly sensitive with the lower limit of quantification (LLOQ) of 10.00 pg/mL for each analyte in plasma. In urine samples, the LLOQs were 20.00 and 500.0 pg/mL for R-bambuterol and R-terbutaline, respectively. The intra- and inter-day precisions were <12.7 and <8.6% for plasma and urine, respectively. The analytical runtime within 6.0 min per sample made this method suitable for high-throughput determination. The validated method has been successfully applied to the human pharmacokinetic study of R-bambuterol involving 10 healthy volunteers.

Pharmacokinetics of terbutaline in chronic kidney disease.

PURPOSE: In healthy individuals upwards of 90 % of an injected dose of terbutaline is excreted in the urine. The purpose of this study is to determine the pharmacokinetic properties of terbutaline in patients with severe renal impairment as defined by a glomerular filtration rate (GFR) below 30 mL/min. METHODS: Ten patients were included in the study. GFR was measured with Cr-EDTA clearance. They were given an intravenous injection of 0.500 mg of terbutaline. Blood samples were collected at intervals for 60 h and urine samples were collected for 96 h. The concentration of terbutaline in the blood and in the urine was used to calculate pharmacokinetic parameters. RESULTS: In patients with normal renal function the total clearance of terbutaline is 2.23-3 mL/min/kg. In our population the total clearance of terbutaline was found to be 1.72 (SD: 0.49) mL/min/kg of which approximately 15 % (0.25 mL/min/kg) was renal clearance. We calculated a distribution volume at steady state of 0.74 (SD: 0.22) L/kg with a terminal half-life of 7.93 (SD: 4.06) hours. The mean residence time (MRT) was 8.35 (SD: 4.93) hours. CONCLUSIONS: In healthy individuals the excretion of terbutaline is foremost renal but this study shows that severe renal impairment does not lower the total clearance of terbutaline to a degree that might be expected from the Cr-EDTA clearance. However, more research is needed to determine if dosage adjustment is warranted in patients with CKD.

Clinical pharmacokinetics of terbutaline in humans: a systematic review.

Terbutaline is used for the management of bronchospasm associated with asthma, bronchitis, emphysema, and chronic obstructive pulmonary disease. A systematic review would be beneficial to assess the impact of routes of administration, stereoisomerism, disease states, smoking, age, exercise, and chronobiology on pharmacokinetics (PK) of terbutaline in humans. PubMed and Google Scholar databases were searched to screen all the relevant articles consisting of at least one of the PK parameters after administration of oral, inhaled, and intravenous (IV) terbutaline in humans. Oral studies of terbutaline depicted a linear relationship between plasma concentration (Cp) and the administered dose. The IV studies demonstrated multi-exponential behavior for disposition and renal clearance. Higher systemic availability was observed with inhaled as compared to oral route, and chrono-pharmacokinetic behavior was notable. Time to reach maximum plasma concentration (Tmax) was prolonged, and maximum plasma concentration (Cmax) was lowered after exercise. The primary route of excretion in chronic kidney disease (CKD) patients is reported to be nonrenal. In pregnant women, the Cp of terbutaline is lowered and clearance is increased. The addition of theophylline to terbutaline did not affect the PK of terbutaline; hence, both can be used without dose adjustment. This review summarizes all the available PK parameters of terbutaline, and it may be helpful for researchers in the development and evaluation of PK models as well as in designing optimal dosage regimens in different clinical conditions.

Modified release terbutaline (SKP1052) for hypoglycaemia prevention: a proof-of-concept study in people with type 1 diabetes mellitus.

AIMS: In this randomized, single blind, cross-over study 2.5 mg and 5 mg of the modified-release terbutaline formulation (SKP-1052) were compared with conventional immediate-release terbutaline (IRT, 5 mg) and placebo on overnight blood glucose (BG) and hypoglycaemia in 30 subjects with type 1 diabetes mellitus. METHODS: Subjects received subcutaneous injections of insulin glargine (individualized doses) before dinner. SKP-1052, IRT or placebo was administered around 21:00 hours. BG and terbutaline concentrations were monitored overnight for 10 h post-dosing. Endpoints comprised of the nadir BG (BGn 0-10 h, primary endpoint), mean overnight BG (BGmean), morning BG (BGmorning) and hypoglycaemia rates as well as pharmacokinetic (PK) endpoints. RESULTS: SKP-1052 delayed release of terbutaline by 2 h [PK-tmax (mean ± SD) 5.0 ± 2.1 h (2.5 mg) and 4.7 ± 1.7 h (5 mg) vs. 2.6 ± 1.3 h with IRT, p < 0.01, respectively]. Compared with placebo, no significant differences were observed for BGn 0-10 h across treatments, but both 5 mg formulations showed less hypoglycaemic events [10 (IRT), 16 (SKP-1052) vs. 33], higher BGmean (120, 114 and 95 mg/dl) and BGmorning (126, 126 and 101 mg/dl, all comparisons p < 0.05 vs. placebo). Numerically higher BG-levels between 3 and 8 h post-dosing were observed with 2.5 mg SKP-1052 vs. placebo. CONCLUSIONS: Compared with IRT SKP-1052 delays release of terbutaline. 2.5 mg SKP-1052 led to numerically higher BG 3 to 8 h post-dose without fasting hyperglycaemia while 5 mg SKP-1052 resulted in fasting hyperglycaemia vs. placebo. Future studies will investigate optimized doses of SKP-1052 for nocturnal hypoglycaemia prevention.

Evaluation of the predicted time-concentration profile of serum tulobuterol in human after transdermal application.

We proposed an in vitro/in vivo/in silico method for evaluating the clinical performance of matrix type transdermal therapeutic systems (TTSs). This method is based on the following four approaches: (1) drug release experiment, (2) in vitro penetration experiment using excised hairless mouse skin, (3) clinical pharmacokinetic study, and (4) mathematical model for evaluating the pharmacokinetic profile. The tulobuterol TTS was used as an example of a matrix type TTS in this study. The drug diffusion coefficient in the matrix device was calculated from the result of the release experiment. The drug diffusion coefficient and the partition coefficient in the skin were calculated from the results of in vitro skin penetration experiments where hairless mice and rats were used. Those parameters were used as substitutes of human. Further, these parameters were used for solving the governing partial differential equation on skin penetration. The time profiles of the serum concentration in human after applying the tulobuterol TTS were predicted and compared with the clinical data. The predicted profiles obtained from the data of hairless mice reproduced the influence of drug depletion adequately and well agreed with the clinical data, while those from the data of rats differed clearly in the initial rise. This method is useful for prediction of pharmacokinetic profiles of TTSs.

Relative bioavailability of terbutaline to the lung following inhalation, using urinary excretion.

AIMS: The aim of the study was to determine the relative lung and systemic bioavailability of terbutaline. METHODS: On separate days healthy volunteers received 500 µg terbutaline study doses either inhaled from a metered dose inhaler or swallowed as a solution with and without oral charcoal. Urine samples were provided at timed intervals post dosing. RESULTS: Mean (SD) urinary terbutaline 0.5 h post inhalation, in 12 volunteers, with (IC) and without (I) oral charcoal and oral (O) dosing was 7.4 (2.2), 6.5 (2.1) and 0.2 (0.2) µg. I and IC were similar and both significantly greater than O (P<0.001). Urinary 24 h terbutaline post I was similar to IC + O. The method was linear and reproducible, similar to that of the urinary salbutamol method. CONCLUSIONS: The urinary salbutamol pharmacokinetic method post inhalation applies to terbutaline. Terbutaline study doses can replace routine salbutamol during these studies when patients are studied.

Design and mechanism of on-off pulsed drug release using nonenteric polymeric systems via pH modulation.

The aim was to design a pH-sensitive pulsatile drug delivery system that allows for an on-off pulsed release of a drug using polyacrylic acid (PAA) blended with ethyl cellulose (EC) in different ratios. PAA, a polyelectrolyte polymer, exhibits a highly coiled conformation at low pH but a highly extended structure at high pH. Fumaric acid, which is an internal acidifying agent, was incorporated into the hydroxypropyl methylcellulose-based core tablets to create an acidic microenvironmental pH (pH(M)). The concentration of fumaric acid inside the core tablet and the ratio of PAA/EC in the coating layer were very crucial in modulating drug release behaviors. When the fumaric acid was retained in the core tablet, it gave a more acidic pH(M), so that the PAA was kept in a highly coiled state in the coated film, which hindered drug release ("off" release pattern). Interestingly, the release profiles of the drug and fumaric acid from coated tablets showed the on-off pulsed pattern upon dissolution. Imaging analyses using scanning electron microscopy, near-infrared imaging, confocal laser scanning microscopy, and Fourier transform infrared spectroscopy confirmed this on-off release behavior of the drug and fumaric acid from coated tablets.

The effect of terbutaline on the absorption of pulmonary administered insulin in subjects with asthma.

AIM: To investigate the effect of prior administration of a bronchodilator on the absorption of inhaled insulin in people with asthma treated with inhaled corticosteroids. METHODS: A single-centre, randomized, open-label, two-period cross-over trial was carried out in 41 nondiabetic subjects with asthma treated with inhaled steroids, with reversible bronchoconstriction (Rev+; n= 25) or without reversible bronchoconstriction (Rev-; n= 16). A dose of 0.10 U kg(-1) inhaled human insulin was administered on each dosing day with or without prior administration of the bronchodilator terbutaline (in random order). RESULTS: Prior administration of terbutaline led to a 44% increase in absorption of insulin over 6 h for the Rev+ group compared with no prior administration of bronchodilator [ratio (95% confidence interval) 1.44 (1.13, 1.82), P= 0.004], whereas no effect was seen for the Rev- or the whole group. The maximum insulin concentration (C(max)) increased by 34% for the Rev+ group (P = 0.018) and 17% for the whole group (P= 0.046), whereas no significant effect of prior terbutaline administration was seen for Rev-. The time to C(max) was not significantly different for the Rev+ group, whereas it was approximately 30% longer after bronchodilator administration for the Rev- group (P= 0.044) and the whole group (P= 0.032). CONCLUSIONS: In people with asthma and reversible bronchoconstriction, the administration of a bronchodilator prior to administration of inhaled insulin led to increased absorption of insulin, whereas no effect on insulin absorption in subjects without significant reversibility could be detected.

Comparative study of skin permeation profiles between brand and generic tulobuterol patches.

Tulobuterol patches are long-acting bronchodilators for percutaneous absorption including the ß(2)-adrenoreceptor agonist tulobuterol, as a main ingredient, used for long-term management of pediatric asthma. Since patients who have pediatric asthma often also have atopic dermatitis in which the skin barrier is impaired, we compared the skin penetration profiles of the brand and generic patches using a skin barrier-impaired rat model. Skin penetration was significantly (p<0.001) higher in the generic patches compared with the brand patch, suggesting that it is important to understand the pharmaceutical properties of available products by giving careful consideration not only to the patient's asthma control but also to their skin condition before using tulobuterol patches.

Investigation of distribution and elimination of terbutaline sulfate in the perfused rat liver preparation.

Hepatic distribution and elimination of terbutaline sulfate (TBS) was investigated in the in situ isolated perfused rat liver preparation. Perfusion experiments were conducted using Krebs bicarbonate buffer delivered via the portal vein in a single-pass mode at a total flow rate of 15 mL min(-1). TBS was administered as a bolus (2 mg mL(-1)) in the absence and presence of erythrocytes (50% hematocrit) or albumin (1%). Immediately after a bolus administration, the outflow perfusate was collected and then concentration of TBS was determined by a validated HPLC method. Regardless of the condition, the extraction of TBS (0.35-0.51) across the liver during single pass was intermediate. Although protein binding of TBS was very low (2.5%), it was taken up slowly and continuously by erythrocytes. A blood to plasma concentration ratio of 2.8 obtained at the end of incubation period clearly indicates that TBS has an affinity to erythrocytes. However, under the conditions used in this study, hepatic distribution and elimination of TBS were not influenced by the presence of erythrocytes or albumin.

A novel nanogel loaded with chitosan decorated bilosomes for transdermal delivery of terbutaline sulfate: artificial neural network optimization, in vitro characterization and in vivo evaluation.

The objective of the present work was to formulate, optimize, and evaluate transdermal terbutaline sulfate (TBN)-loaded bilosomes (BLS) in gel, compared to conventional oral TBN solution and transdermal gel loaded with free TBN, aiming at evading the hepatic first-pass metabolism. A face-centered central composite design was adopted to observe the effects of different formulation variables on TBN-BLS, and artificial neural network (ANN) modeling was employed to optimize TBN-BLS. TBN-BLS were prepared by a thin film hydration method integrating soybean phosphatidylcholine and cholesterol as a lipid phase and sodium deoxycholate (SDC) as a surfactant with or without the coating of chitosan (CTS). After being subjected to physicochemical characterization, TBN-BLS were enrolled in a histopathological study and pharmacokinetic investigation in a rat model. The optimized TBN chitosan-coated bilosomes (TBN-CTS-BLS) were spherical vesicles (245.13 ± 10.23 nm) with adequate entrapment efficiency (65.25 ± 5.51%) and good permeation characteristics (340.11 ± 22.34 µg/cm2). The TBN-CTS-BLS gel formulation was well-tolerated with no inflammatory signs manifested upon histopathological evaluation. The pharmacokinetic study revealed that the optimized TBN-CTS-BLS formulation successively enhanced the bioavailability of TBN by about 2.33-fold and increased t1/2 to about 6.21 ± 0.24 h as compared to the oral solution. These findings support the prospect use of BLS as active and safe transdermal carrier for TBN in the treatment of asthma. Graphical Abstract.

Chemical mapping of tulobuterol in transdermal tapes using microscopic laser Raman spectroscopy.

Microscopic Laser Raman Spectroscopy and Mapping (MLRSM) technique was used to investigate the distribution of tulobuterol (TBR) crystals in transdermal tapes. TBR is one of suitable compounds for the transdermal pharmaceuticals because it has high permeability into skin. In case of TBR transdermal tapes, some commercial products also contain TBR crystals in order to control a release rate from a matrix. Therefore, the presence of TBR crystals in the matrix is a critical factor for quality assurance of this type of TDDS tapes. The model tapes prepared here employed two kinds of matrices, i.e., rubber or acrylic, which are generally used for transdermal pharmaceuticals. TBR crystals in the matrix were observed by MLRSM. Accurate observation of the distribution of TBR in the tapes was achieved by creating a Raman chemical map based on detecting unique TBR peak in each pixel. Moreover, differences in the growth of TBR crystals in the two kinds of matrices were detected by microscopic observation. MLRSM also enabled the detection of TBR crystals in commercial products. The present findings suggest that Raman micro-spectroscopic analysis would be very useful for verifying and/or assessing the quality of transdermal pharmaceuticals in development, as well as for manufacturing process control.

Terbutaline lessens protein fluxes across the alveolo-capillary barrier during high-volume ventilation.

OBJECTIVE: To evaluate whether a beta2-adrenergic agonist may reduce acute alveolo-capillary barrier alterations during high-volume ventilation. DESIGN: Experimental study. SETTING: Animal research laboratory. SUBJECTS: A total of 48 male Wistar rats. INTERVENTIONS: A zone of alveolar flooding was produced by liquid instillation in a distal airway. Proteins in the instilled solution were traced with 99mTc-albumin. 111In, which binds to transferrin, was injected into the systemic circulation. Terbutaline was administered in the instilled solution or intra-peritoneally. Conventional ventilation was applied for 30 min followed by different ventilation strategies for 90 min: conventional ventilation, high-volume ventilation with or without 6 cmH2O PEEP. MEASUREMENTS AND MAIN RESULTS: Protein fluxes across the alveolar and microvascular barriers were evaluated by scintigraphy. High-volume ventilation resulted in immediate leakage of 99mTc-albumin from alveolar spaces and increased pulmonary uptake of systemic 111In-transferrin. Terbutaline in the instilled solution and PEEP lessened alveolar 99mTc-albumin leakage and pulmonary 111In-transferrin uptake due to high-volume ventilation, whereas terbutaline given intra-peritoneally only lessened 111In-transferrin uptake. Terbutaline in the instilled solution also lessened the increase in lung wet-to-dry weight ratio due to high-volume ventilation. CONCLUSIONS: Terbutaline reduces protein fluxes across the alveolar epithelial and pulmonary microvascular barriers during high-volume ventilation in vivo. The route of administration may be important.

Pharmacokinetics of intraperitoneally instilled aminophylline, terbutaline and tobramycin in pigs.

INTRODUCTION: Venous catheters are sometimes difficult or even impossible to insert and may also be associated with serious complications. This study was carried out to investigate whether intraperitoneal administration of drugs may be an alternative to the intravenous route in patients with limited vascular access. MATERIALS AND METHODS: Three drugs commonly in use in clinical practise, aminophylline, terbutaline and tobramycin, were administered to pigs intravenously and intraperitoneally in small volumes. Serum concentrations were analysed over a period of 6 h and pharmacokinetic key variables for each drug were calculated. RESULTS: Aminophylline (theophylline), terbutaline and tobramycin were absorbed from the peritoneal space and into systemic circulation. For theophylline, the concentration/time profiles after intraperitoneal and after intravenous administration were almost identical, and the intraperitoneal bioavailability was calculated to 0.94. For terbutaline and tobramycin, the intraperitoneal absorption was delayed without any initial peak. Moreover, the intraperitoneal bioavailability was lower than for theophylline (0.71 and 0.65, respectively). CONCLUSION: The pharmacokinetic properties after intraperitoneal administration differed among the three drugs, but the results are encouraging and provide a basis for further investigation in humans.