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Biomedical subjects

G Hochhaus

Publications and source records attributed to G Hochhaus.

At least 37 records · Page 2Linked to original sources
PubMed2001

Pharmacokinetics and rectal bioavailability of hydrocortisone acetate after single and multiple administration in healthy subjects and patients.

The pharmacokinetics and bioavailability of hydrocortisone after rectal administration of a hydrocortisone acetate foam were determined after single and multiple dosing in healthy subjects as well as in patients with inflammatory bowel disease. Endogenous hydrocortisone was suppressed by dexamethasone administration. Plasma levels were compared with those observed after intravenous administration of hydrocortisone. Only a very small part of the rectal dose (100 mg) was absorbed; the mean absolute bioavailability was 3.1% in healthy volunteers and 4.5% in patients. There was substantial intersubject variability. Although maximum hydrocortisone levels after single or multiple doses were significantly higher (about 70%) in the patient group, the systemic bioavailability is very low so that the risk of systemic side effects after rectal administration of hydrocortisone acetate foam has to be considered very low.

Administration, Rectal↗
PubMed2001

Single-dose and steady-state pharmacokinetic and pharmacodynamic evaluation of therapeutically clinically equivalent doses of inhaled fluticasone propionate and budesonide, given as Diskus or Turbohaler dry-powder inhalers to healthy subjects.

Direct comparisons of the pharmacokinetic (PK) and systemic pharmacodynamic (PD) properties of inhaled corticosteroids after single and multiple dosing in the same subjects are scarce. The objective of this study was to compare thePK/PDproperties of clinically equivalent, single, and multiple doses of dry-powder formulations of inhaled fluticasone propionate (FP 200 and 500 microg via Diskus) and budesonide (BUD, 400 and 1,000 microg via Turbohaler). Fourteen healthy subjects completed a double-blind, double-dummy, randomized, placebo-controlled, five-way crossover study consisting of a single dose administered at 8 a.m. on day 1 followed by 4 days of twice-daily dosing at 8 a.m. and 8 p.m. on days 2 to 5. Serum concentrations of FP and BUD were measured using validated liquid chromatography/ mass spectrometry assays. The 24-hour cumulative cortisol suppression (CCS) in serum was monitored as the pharmacodynamic surrogate marker. Peak serum concentrations following single and multiple dosing were observed 10 to 30 minutes after inhalation for BUD and 30 to 90 minutes afterinhalation of FP with no influence of dose ordosingregimen. After a single dose of 1000 microg BUD and 500 microg FP the median estimates of terminal half-life and mean residence time were 3.5 and 3.9 hours for BUD and 10.1 and 12.0 hours for FP, respectively. Using previously reported intravenous data, the mean absorption times (MAT) were calculated to be around 2 hours and 7 hours for BUD and FP respectively. On average, the area under the curve (A UC) at steady state (day 5) was up to 30% higher for BUD compared to that over a 12-hour period following the first dose on day 1, whereas A UC estimates were 50% to 80% higherforFP at steady state, indicating accumulation. However, the steady-state Cmax values were seven to eight times and AUC values three to four times higher for BUD than for FP. Comparison of active treatment data with placebo showed that CCS after a single dose was not pronounced for any of the doses/drugs studied. On day 5, both doses of BUD caused statistically significant suppression (CCS of 19% for the 400 microg dose and 36% for the 1,000 microg dose). For FP only the high dose had a statistically significant effect on serum cortisol (CCS of 14% for the 200 microg dose and 27% for the 500 microg dose). Compared to BUD, FP has slower pulmonary absorption and slower elimination kinetics. However, following inhalation of therapeutically equipotent, multiple twice-daily doses in healthy subjects, the systemic effects of FP delivered via Diskus on AUC24 serum cortisol were relatively low and similar to those of BUD delivered via Turbohaler.

Administration, Inhalation↗
PubMed2001

Receptor binding studies of soft anticholinergic agents.

Receptor binding studies were performed on 24 soft anticholinergic agents and 5 conventional anticholinergic agents using 4 cloned human muscarinic receptor subtypes. The measured pK(i) values of the soft anticholinergic agents ranged from 6.5 to 9.5, with the majority being in the range of 7.5 to 8.5. Strong correlation was observed between the pK(i) s determined here and the pA 2 values measured earlier in guinea pig ileum contraction assays. The corresponding correlation coefficients (r2) were 0.80, 0.73, 0.81, and 0.78 for pK(i) (m1), pK(i) (m2), pK(i) (m3), and pK(i) (m4), respectively. Quantitative structure-activity relationship (QSAR) studies were also performed, and good characterization could be obtained for the soft anticholinergics containing at least 1 tropine moiety in their structure. For these compounds, the potency as measured by the pK i values was found to be related to geometric, electronic, and lipophilicity descriptors. A linear regression equation using ovality (O(e)), dipole moment (D), and a calculated log octanol-water partition coefficient (QLogP) gave reasonably good descriptions (r = 0.88) for the pK(i) (m3) values.

Animals↗
PubMed2000

A sensitive LC-MS/MS method for the quantification of fluticasone propionate in human plasma.

A sensitive and selective LC-(APCI) MS/MS method capable of quantifying fluticasone propionate (FP) at levels down to 10 pg ml(-1) in human plasma is reported. The method was validated over a linear range from 10 to 1000 pg ml(-1) using a previously published solid-phase extraction procedure with a 13C3-labeled internal standard. The inter and intra batch precision (coefficient of variation) and accuracy (% bias) of the quality controls samples (20, 25, 50, 100, 200, 500 and 1000 pg ml(-1)) were less than 15 and 11%, respectively. The method is robust, rapid (analysis time of 2 min), selective and hence is ideally suited for pharmacokinetic investigations involving inhalation of therapeutic doses of FP.

Administration, Inhalation↗
PubMed2000

An interactive algorithm for the assessment of cumulative cortisol suppression during inhaled corticosteroid therapy.

The objective of the study was to develop an algorithm based on a pharmacokinetic-pharmacodynamic (PK/PD) modeling approach to quantify and predict cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. Two Excel spreadsheets, one for single dose and another for steady-state multiple doses of inhaled steroids, were developed for predicting CCS. Four of the commonly used inhaled steroids were chosen for the purposes of simulation: fluticasone propionate (FP), budesonide (BUD), flunisolide (FLU), and triamcinolone acetonide (TAA). Drug-specific PK and PD parameters were obtained from previous single- and multiple-dose studies. In cases in which multiple-dose data were not available, the single-dose data were extrapolated. The algorithm was designed to calculate CCS based on 5 input parameters: name of drug, dose, dosing interval, time(s) of dosing, and type of inhaler device. In addition, a generalized algorithm was set up to calculate CCS based on clearance, volume of distribution, absorption rate, protein binding, pulmonary deposition, oral bioavailability, and unbound EC50 of the corticosteroid of interest. The spreadsheet allowed predictions of CCS for single doses as well as steady-state conditions. A simple method has been developed that facilitates comparisons between various drugs and dosing regimens and has the potential to significantly reduce the number of comparative clinical trials to be performed for evaluating the short-term systemic activity of inhaled corticosteroids.

Administration, Inhalation↗
PubMed2000

Loteprednol etabonate: a soft steroid for the treatment of allergic diseases of the airways.

There are several approaches for developing new antiallergic/antiasthmatic agents. One of them is the improvement of an existing class of effective drug classes. Due to some undesired effects of intranasal or inhaled corticosteroids, there is a need for better tolerated corticosteroids. Loteprednol etabonate belongs to the so-called class of soft steroids because it is metabolized by a one-step reaction (hydrolysis) without using the cytochrome P450 monooxygenase system. In in vitro investigations using human cells, loteprednol inhibited the release of proinflammatory cytokines (e.g., TNF-alpha, GM-CSF, IL-4, IL-5) according to its relative binding potency to the glucocorticoid receptor. In in vivo animal studies, loteprednol effectively inhibited allergically induced vascular leakage in the nasal cavity of actively sensitized Brown Norway rats and rhinorrhea in actively sensitized domestic pigs following nasal challenge. In several models of allergic asthma, it was clearly demonstrated that loteprednol was able to suppress the allergically induced late phase eosinophilia in mice, rats and guinea pigs. After intrapulmonary administration of loteprednol, only a slight, statistically nonsignificant reduction in thymus weight was observed in a dose range far less than the therapeutically relevant doses. Its therapeutic ratio is clearly superior to those of beclomethasone and budesonide. Loteprednol is a safe steroid with an extremely wide range between therapeutic and side effect inducing doses. Its elimination profile, its pronounced binding to plasma protein and erythrocytes and the low oral bioavailability makes this drug highly suitable for nasal or pulmonary use.

Journal Article↗
PubMed2000

Optimized therapeutic ratio of inhaled corticosteroids using retrometabolism.

During recent years, the treatment of pulmonary diseases could be significantly improved due to the introduction of modern retrometabolism-based corticosteroids with improved therapeutic ratio. It is the goal of all inhaled corticosteroids to produce long lasting therapeutic effects at the pulmonary target site and to minimize systemic side effects by rapid clearance of the absorbed drug and low oral bioavailability. The development of PK/PD models allows predictions of drug effects based on the administered dose. For example, the cumulative suppression of endogenous cortisol release (CCS) as one of the major systemic side effects of inhaled corticosteroid therapy can be described with an integrated Emax based PK/PD model. In order to assess the predictive power of this model, a study was conducted to compare the PK/PD-based predictions with CCS data obtained from actual clinical trials for flunisolide, fluticasone propionate, budesonide and triamcinolone acetonide. CCS was predicted for different single doses from different inhaler devices for each drug and a good correlation was observed. Thus, the presented PK/PD model proved to be a valid tool for predicting CCS of inhaled corticosteroids. By fully understanding the underlying mechanisms it will be possible to further improve their therapeutic index.

Administration, Inhalation↗
PubMed1999

Analysis of leucine enkephalin by high-performance liquid chromatography using enzymatic derivatization by tyrosinase and electrochemical or fluorescence detection.

Two tyrosine specific, HPLC methods with either electrochemical (HPLC-ED) or fluorescence (HPLC-FL) detection are described for leucine-enkephalin (LE) in cerebrospinal fluid (CSF). Both approaches involve the hydroxylation of the Tyr1-moiety of LE by mushroom tyrosinase. Production of a catechol permitted the selective clean-up of the analyte using boronate gels and produced species which were more readily oxidizable than the LE. The controlled oxidation of the catechol to corresponding chinones enabled the reaction with 1,2-diamino-1,2-diphenylethane (DPE) and subsequent quantification by HPLC-FL. The HPLC-ED and HPLC-FL yielded limits of detection for LE in CSF of 360 and 500 fmol per injection, respectively. Inter-day variability of calibration curve samples was lower than 20% for the HPLC-ED with slightly higher variability for the HPLC-FL assay.

Agaricales↗
PubMed1999

Assessment of complex peptide degradation pathways via structured multicompartmental modeling approaches: the metabolism of dynorphin A1-13 and related fragments in human plasma.

Peptide metabolic pathways in blood or other tissues are often complex because multiple enzyme systems are involved in the degradation of parent drug and its metabolites. Michaelis-Menten-type studies with isolated enzymes have been frequently employed for evaluating the metabolism of peptides. Alternatively, studies with selective enzyme inhibitors or the evaluation of the area under the drug- or metabolite-time profiles have been employed. We tested in this study the usefulness of a multicompartmental pharmacokinetic approach for the assessment of the apparent first-order metabolism of dynorphin A1-13 up to the fourth metabolite generation in human plasma. This multicompartmental kinetic analysis proved instrumental in clarifying ambiguous degradation pathways not easily detectable by the other methods of assessment (enzyme inhibition studies and noncompartmental analysis) because of the lack of specific enzyme inhibitors or specificity problems of the analytical technique employed. The proposed multicompartmental fitting approach was also highly suitable to verify the overall metabolic pathways suggested by the other methods up to the fourth metabolite by testing whether the rate constants obtained by these methods are suitable to describe the overall degradation profile after Dyn A1-13 degradation. Local sensitivity analysis for the degradation of DYNA 1-13 revealed that the model was, however, not able to adequately identify on its own all of the parameters involved in the degradation of dynorphin A1-13. Thus, the method proved beneficial in evaluating and testing the correctness of the overall degradation pathways suggested by other methods.

Algorithms↗
PubMed1999

A pharmacokinetic/pharmacodynamic approach to predict the cumulative cortisol suppression of inhaled corticosteroids.

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16-21% was predicted for FP 250 micrograms, FLU 500 micrograms, and TCA 1000 micrograms. For multiple dosing, a respective CCS of 28-33% was calculated for FLU 500 micrograms bid, FP 250 micrograms, bid, and TCA 1000 micrograms bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.

Administration, Inhalation↗
PubMed1999

Kinetic modeling of plasmid DNA degradation in rat plasma.

A major obstacle in gene delivery is the transport of intact plasmid DNA (pDNA) to target sites. We sought to investigate the kinetic processes underlying the degradation of pDNA in a rat plasma model, as this is one of the main components responsible for the clearance of pDNA after intravenous administration. We further sought to construct a complete kinetic model to describe the degradation of all three topoforms (supercoiled, open circular, and linear) of pDNA in a rat plasma model. Supercoiled pDNA was incubated in isolated rat plasma at 37 degrees C in vitro. At various time points, the plasma was assayed by electrophoresis for the amounts of supercoiled, open circular, and full-length linear pDNA remaining. The calculated amounts remaining were fit to linear differential equations describing this process. In this model, pDNA degradation is considered to be a unidirectional process, with supercoiled degrading to open circular and then to the linear topoform. The calculated kinetic parameters suggested that supercoiled pDNA degrades in rat plasma with a half-life of 1.2 minutes, open circular pDNA degrades with a half-life of 21 minutes, and linear pDNA degrades with a half-life of 11 minutes. Complexation of pDNA with liposomes resulted in a portion of the supercoiled plasmid remaining detectable through 5.5 hours.

Algorithms↗
PubMed1999

Mechanism-based PK/PD model for the lymphocytopenia induced by endogenous and exogenous corticosteroids.

OBJECTIVE: Lymphocytopenia is a sensitive surrogate marker for the immunological effects of corticosteroids. This pharmacokinetic/pharmacodynamic (PK/PD) study investigated whether the circadian variation of blood lymphocytes observed after placebo is secondary to the circadian rhythm of endogenous cortisol, and developed based on this relationship an improved PK/PD model for a more sensitive description of the effect of low-dose corticosteroid therapy on blood lymphocytes considering the net activity of the exogenous corticosteroid budesonide and endogenous cortisol. METHODS: In an open, parallel study design, 3 mg oral budesonide or placebo were given at 8.00 a.m., 4.00 p.m. and midnight to two groups of 12 volunteers. Lymphocyte counts and serum concentrations of budesonide and cortisol were monitored for 24 hours. A mechanism-based PK/PD model which considered the non-linear protein binding of cortisol and the budesonide-induced cortisol suppression was employed to relate changes in blood lymphocytes to free cortisol levels after placebo and to the net activity of free budesonide and free endogenous cortisol after active treatment. RESULTS: The circadian rhythm of blood lymphocytes observed after placebo could inversely be related to the circadian rhythm of serum cortisol. After budesonide administration, lymphocyte counts could accurately be linked to the net activity of budesonide and endogenous cortisol. The resulting EC50 values for the effect of budesonide on cortisol, budesonide on lymphocytes and cortisol on lymphocytes were 0.063 +/- 0.034, 0.22 +/- 0.13 and 26.3 +/- 15.0 ng/ml (placebo group 15.4 +/- 3.4 ng/ml), respectively. CONCLUSIONS: The presented mechanism-based PK/PD model suggests that blood lymphocytes are under physiological control of cortisol. It further indicates that endogenous and exogenous corticosteroids and their pharmacological interaction need to be considered for modeling the effects of low doses of exogenous corticosteroids on the immune system.

Anti-Inflammatory Agents↗
PubMed1998

Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration.

OBJECTIVE: To evaluate the pharmacokinetic and systemic pharmacodynamic properties of inhaled fluticasone propionate (FP). METHODS: Single doses of 0.25, 0.5, 1.0 and 3.0 mg FP were administered to groups of six healthy subjects. Serum concentration profiles of FP were monitored over 24 h by means of high-performance liquid chromatography/mass spectrometry (HPLC/MS-MS). Systemic pharmacodynamic effects were evaluated by measuring endogenous serum cortisol and circulating white blood cells, and analyzed with previously developed integrated pharmacokinetic/pharmacodynamic (PK/PD) models. RESULTS: FP showed a dose-independent terminal half-life with a mean (SD) of 6.0 (0.7) h. Maximum serum concentrations occurred 1.0 (0.5) h after administration, ranging from 90 pg.ml(-1) for the 0.25 mg dose to 400 pg.ml(-1) for the 3.0 mg dose. This, together with an estimated mean absorption time of nearly 5 h and a known oral bioavailability of less than 1%, indicates prolonged residence at and slow absorption from the lungs. In the investigated dose range, the cumulative systemic effect was dose-dependent for both markers of pharmacodynamic activity. For doses of 0.25, 0.50, 1.0 and 3.0 mg FP, the PK/PD-based cumulative systemic-effect parameters were 159, 186, 257 and 372% .h for lymphocyte suppression, 107, 186, 202 and 348% .h for granulocyte induction and 23.6%, 33.8%, 51.0% and 73.6% for cortisol reduction, respectively. The time courses of lymphocytes, granulocytes and endogenous cortisol could be sufficiently characterized with the applied PK/PD models. The measured in vivo EC50 values, 30 pg.ml(-1) and 7.3 pg.ml(-1) for white blood cells and cortisol, respectively, were in good agreement with predictions based on the in vitro relative receptor affinity of FP. CONCLUSION: After inhalation, FP follows linear pharmacokinetics and exhibits dose-dependent systemic pharmacodynamic effects that can be described by PK/PD modeling.

Administration, Inhalation↗
PubMed1998

Pharmacokinetics of intravenous dynorphin A(1-13) in opioid-naive and opioid-treated human volunteers.

BACKGROUND: Dynorphin A(1-13) is a fragment of the endogenous opioid neuropeptide dynorphin A. Previous research suggested that intravenously administered dynorphin A(1-13) has the ability to modulate morphine-induced analgesia. We designed this study to characterize the disposition of intravenous dynorphin immunoreactivity in humans and to determine whether concomitant long-term opioid therapy influenced the pharmacokinetics or side-effects profile of dynorphin A(1-13). METHODS: The study subjects comprised 20 volunteers divided into two groups of 10 each, stratified by dose (low dose, 250 micrograms/kg; high dose, 1000 micrograms/kg). There were four volunteers receiving long-term opioid therapy and six opioid-naive volunteers (nonopioid group) within each dosing group. Dynorphin A(1-13) was infused over 10 minutes, and arterial blood samples were drawn and assayed for dynorphin immunoreactivity. A population modeling approach was used to characterize the pharmacokinetics. Dynorphin effects on heart rate and arterial blood pressure were also studied. RESULTS: The pharmacokinetics of dynorphin immunoreactivity were linear over the dose range studied and were best described by a three-compartment mammillary model whose parameters were volume 1, 5.0 L; volume 2, 0.80 L; volume 3, 12 L; clearance 1, 6.0 L/min; clearance 2, 0.054 L/min; and clearance 3, 0.044 L/min. Concomitant opioid medication did not affect the disposition of dynorphin immunoreactivity. Tachycardia and flushing were commonly observed side effects. The incidence of side effects was dose dependent and was not influenced by long-term opioid use. CONCLUSIONS: Intravenously administered dynorphin A(1-13) is very rapidly metabolized, on the basis of the time course of immunoreactivity in the blood. Long-term opioid therapy did not influence either the pharmacokinetics or incidence of side effects.

Adult↗
PubMed1998

Pharmacokinetics and pharmacodynamics of inhaled corticosteroids.

There are significant differences in the pharmacokinetic properties of inhaled corticosteroids currently used in medical practice. All are rapidly cleared from the body but they show varying levels of oral bioavailability and more importantly variation in the rate of absorption after inhalation. Oral bioavailability is lowest for fluticasone propionate, indicating a low potential for unwanted systemic corticosteroid effects. Mathematical modeling has shown pulmonary residence times to be longest for fluticasone propionate and triamcinolone acetonide but shortest for budesonide and flunisolide. These properties appear to relate to pulmonary solubility, which appears to be the rate-limiting step in the absorption process.

Administration, Inhalation↗
PubMed1998

A selective HPLC/RIA for the determination of budesonide.

A combined HPLC/RIA procedure is described for the selective determination of budesonide (BUD) in plasma. The assay involves the extraction of plasma or serum samples with ethylacetate, consequent HPLC separation of intact budesonide from cross-reacting metabolites on a C8 reversed phase column, collection of the budesonide containing fraction and determination of budesonide immunoreactivity with the budesonide antiserum. The method was accurate, sensitive (IC50 value of 0.9 ng ml-1) and reproducible (intra- and inter-day less than 15%) with a limit of quantification of 0.133 ng ml-1 (RSD < 25%). The evaluation of a limited number of clinical samples after oral administration of budesonide by both the HPLC/RIA procedure and a direct RIA using the same antiserum differed in average by a factor of 2, with the ratio of HPLC/RIA-RIA results declining as a function of time. Thus, this ratio might be a suitable indicator for probing for the ratio of budesonide and overall metabolites on a semi-quantitative level.

Administration, Oral↗
PubMed1998

Effect of dose and release rate on pulmonary targeting of liposomal triamcinolone acetonide phosphate.

PURPOSE: To demonstrate the importance of dose and drug release rate for pulmonary targeting of inhaled glucocorticoids using an animal model of intrapulmonary drug deposition. METHODS: Liposomes composed of 1,2-distearoyl phosphatidylcholine (DSPC), 1,2-distearoyl phosphatidylglycerol (DSPG) and triamcinolone acetonide phosphate (TAP) or liposomes containing triamcinolone acetonide (TA) were prepared by a mechanical dispersion method followed by extrusion through polycarbonate membranes. Encapsulation efficiency was assessed after size exclusion gel chromatography by reverse phase HPLC. The effect of liposome size (200 nm and 800 nm) on the release kinetics of water-soluble encapsulated material was determined in vitro at 37 degrees C using 6-carboxyfluorescein as a marker and Triton X-100 (0.03%) as a leakage inducer. To investigate the relationship between drug release and pulmonary targeting, 100 micrograms/kg of TAP in 800 nm liposomes was delivered to male rats by intratracheal instillation (IT) and the results compared to data for 100 micrograms/kg TA liposomes (recently shown to exhibit a rapid drug release under sink conditions) and to previous studies reported for an equal dose of TAP in solution and TAP in 200 nm (1). Pulmonary targeting was assessed by simultaneously monitoring glucocorticoid receptor occupancy over time in lung and liver using an ex vivo receptor binding assay as a pharmacodynamic measure of glucocorticoid action. To assess the effect of dose on pulmonary targeting experiments were performed using 2.5, 7.5, 25, 100, and 450 micrograms/kg of TAP in 800 nm liposomes. RESULTS: The in vitro efflux of 6-carboxyfluorescein from (DSPC:DSPG) liposomes after exposure to Triton-X was biexponential. The terminal half-lives of 3.7 h and 9.0 h for the 200 nm and 800 nm liposomes, respectively, demonstrated that larger liposomes promote slower release of encapsulated water-soluble solute while previous results already indicated that encapsulation of lipophilic TA does not result in sustained release. Pulmonary targeting, defined as the difference between cumulative lin and liver receptor occupancies was most pronounced for the 800 nm liposomes (370%xh), followed by the 200 nm preparation (150%xh). No targeting was observed for TAP in solution (30%xh) or the rapid releasing TA liposome preparation. Correspondingly, the mean pulmonary effect time (MET) increased from 2.4-3.0 hr for TA liposomes or TAO in solution to 5.7 h and > 6.2 h for TAP in 200 nm and in 800 nm liposomes, respectively. Escalating doses of TAP encapsulated in 800 nm liposomes revealed a distinct bell shaped relationship between the TAP dose and pulmonary targeting with a maximum occurring at 100 micrograms/kg (370%xh). CONCLUSIONS: The in vivo data presented here confirm that pulmonary residence time and dose affect the extent of lung targeting of glucocorticoids delivered via the lung.

Animals↗