Displacement of [3H]-L-glutamate in rat brain membranes by metabolic dynorphin fragments.
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Amino Acid Sequence↗
Biomedical subjects
G Hochhaus
Publications and source records attributed to G Hochhaus.
Pharmacokinetic and pharmacodynamic aspects of salmeterol therapy.
BACKGROUND: Salmeterol xinafoate is a highly selective beta2-adrenoceptor for the maintenance treatment of asthma in adults and children. OBJECTIVE: To review the pharmacokinetics, clinical pharmacology, and therapeutic properties of a recently introduced, long acting antiasthmatic drug. METHODS: Recent English-language publications were selected using Medline as database. RESULTS: Salmeterol's pharmacokinetics, clinical pharmacology, and therapeutic properties are reviewed and aspects related to salmeterol's unusual duration of action, its high potency, beta2-selectivity, possible antiinflammatory actions, its interaction with other drugs, low systemic adverse effects, dosage, and administration are also discussed. CONCLUSION: Salmeterol is a safe long-acting beta2-agonist very useful for maintenance treatment of asthma.
Adrenergic beta-Agonists↗
Pharmacokinetic/pharmacodynamic aspects of aerosol therapy using glucocorticoids as a model.
Glucocorticoids are predominantly prescribed in asthma therapy as aerosols to achieve high pulmonary effects with reduced systemic spill-over and pronounced pulmonary selectivity. A variety of pharmacokinetic parameters are potentially important for determining pulmonary selectivity. The intent of this article, is to provide a practice-relevant theoretical approach to put the importance of these parameters on pulmonary targeting using pharmacokinetic/pharmacodynamic modeling as a tool in perspective. The applied pulmonary pharmacokinetic/pharmacodynamic model revealed that, in addition to recognized parameters such as systemic clearance, oral bioavailability, and efficiency of pulmonary deposition, other factors, such as the pulmonary release (dissolution) rate and dose, are relevant. However, the volume of distribution (for effect parameters not undergoing a diurnal rhythm) and the receptor affinity of a given glucocorticoid are not important for achieving lung targeting.
Aerosols↗
Pharmacokinetic/pharmacodynamic evaluation of systemic effects of flunisolide after inhalation.
The pharmacokinetics and pharmacodynamics of flunisolide were studied in healthy volunteers after inhalation. In the morning on the day the study began, volunteers inhaled 0.5 mg of flunisolide with and without oral administration of charcoal, or 1 mg, 2 mg, and 3 mg of flunisolide with concomitant administration of charcoal. A placebo group was used to assess the endogenous cortisol, granulocyte, and lymphocyte baseline levels. Flunisolide plasma levels were determined by high-performance liquid chromatography using a tandem mass spectrometer as detector (HPLC/MS/MS). Cortisol plasma levels and differential white blood cell counts were obtained over 12 hours. An integrated pharmacokinetic/pharmacodynamic (PK/PD) model was applied to link the flunisolide plasma concentrations with the effects on lymphocytes, granulocytes, and cortisol. Maximum concentration levels of 3 to 9 ng/mL of flunisolide were observed after 0.2 to 0.3 hours for all of the investigated doses. The terminal half-life ranged from 1.3 to 1.7 hours. There was no statistical difference between treatments in the presence or absence of orally administered charcoal. The pharmacokinetic/pharmacodynamic (PK/PD) models satisfactorily described the time-courses of the effects on granulocytes, lymphocytes, and cortisol suppression. The resulting E50-values (concentrations to induce 50% of the maximum effect) concurred with the reported values of in vitro receptor binding affinities. The duration of the systemic effects were short because of the short half-life of the drug. Cumulative cortisol suppression increased with dose administration and ranged from 20% to 36%. The PK/PD simulations resulted in a smaller degree of cortisol suppression for the drug administered at 10 PM. The cumulative change from baseline was slightly smaller for the effects on granulocytes and lymphocytes than those on cortisol. This information promotes the comparison with other inhaled glucocorticoids.
Administration, Inhalation↗
Pharmacokinetics of methylprednisolone and prednisolone after single and multiple oral administration.
The pharmacokinetics of methylprednisolone and prednisolone were evaluated in 24 healthy men after oral administration of single and multiple doses for 3 days. For each drug, 6 different administration regimens with doses ranging from 1 to 80-mg of methylprednisolone and 1.25 to 100-mg of prednisolone, and administration intervals ranging from 3 to 24 hours for both were investigated. Plasma was assayed using a normal phase high-performance liquid chromatography (HPLC) method. Methylprednisolone showed linear pharmacokinetics with no apparent dose or time dependency. Prednisolone showed marked dose dependency with higher clearance and volume of distribution for higher doses. This can be explained by its saturable protein binding of plasma, because unbound clearance and unbound volume of distribution were not dose-dependent. After multiple administration, prednisolone showed significant time-dependent pharmacokinetics with increased unbound clearance and increased unbound volume of distribution. Due to the complicated pharmacokinetic properties of prednisolone, it is extremely difficult to determine the dose needed to obtain a desired target concentration. The pharmacokinetics of methylprednisolone are more predictable because methylprednisolone concentrations are proportional to dose, and no determination of plasma protein binding is needed.
Administration, Oral↗
Dependency of cortisol suppression on the administration time of inhaled corticosteroids.
Endogenous cortisol suppression is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. A previously developed pharmacokinetic/ pharmacodynamic approach was used to evaluate the influence of administration time on the cumulative cortisol suppression (CCS) after single doses of the inhaled corticosteroids flunisolide and fluticasone propionate. Administration time-dependent simulations of CCS were performed with drug-specific pharmacokinetic and pharmacodynamic parameters obtained from previous clinical trials. Both drugs showed similar diurnal variation in CCS, dependent on the administration time, with maximum suppression when administered in the early morning at approximately 3 AM. The optimum administration time for minimized CCS was in the afternoon but was shifted from 3 PM for fluticasone propionate to later time points around 7 PM for flunisolide, probably because of the shorter terminal elimination half-life of flunisolide. Regarding peak to trough fluctuation, however, CCS after fluticasone propionate showed only half the administration time dependency as after flunisolide. Therefore, the ratio between CCS after flunisolide and after fluticasone propionate also followed administration time-dependent variations. This led to the conclusion that administration time has to be considered as a pivotal influential factor in clinical studies comparing CCS among different inhaled corticosteroids.
Administration, Inhalation↗
An HPLC/RIA method for dynorphin A1-13 and its main metabolites in human blood.
A selective HPLC/RIA procedure for the determination of dynorphin A1-13 (Dyn A1-13) and its major metabolites in human blood was developed. In order to block peptidase activity, blood samples were transferred into an aliquot of a blocking solution (5% aqueous ZnSO4 solution-acetonitrile-methanol; 5:3:2, v/v/v). After solid phase extraction, reconstituted aliquots were injected into an isocratic reversed phase HPLC system to separate Dyn A1-13 from its main metabolites (Dyn A2-13, Dyn A1-12 and Dyn A2-12). The isolated and concentrated HPLC-fractions were assayed by RIA using a commercially available antiserum. Intra-day variabilities for quality controls (0.07, 0.25, and 1 ng ml-1) of Dyn A1-13, A2-13, A1-12, A2-12 were between 9 and 41%. Accuracy was between 86 and 132%. Inter-day variability for single quality controls analyzed on five days for Dyn A1-13, A2-13, A1-12, A2-12 was between 4 and 49% for 0.07, 0.25 and 1 ng ml-1 samples, respectively. Accuracy was between 72 and 129%. Five different batches of control blood showed blood levels no different from zero. Considering the complexity of the assay, the method is selective, accurate and reproducible with a limit of detection of 0.07 ng ml-1 for Dyn A1-13, Dyn A2-13, Dyn A1-12 and 0.21 ng ml-1 for Dyn A2-12. The assay was applied to the determination of Dyn A1-13 and its metabolites in blood samples of 2 subjects receiving i.v. infusions of 250 micrograms or 1000 micrograms kg-1 Dyn A1-13 over 10 min.
Acetonitriles↗
Clinical PK/PD modelling as a tool in drug development of corticosteroids.
Corticosteroids are used for the treatment of a variety of different diseases both locally and systemically. Most therapeutic effects result from glucocorticoid receptor-mediated events, and there seems to be no substance-specific difference in the post-receptor reaction cascade. Therefore, the extent and duration of glucocorticoid effects depend only on the availability of the respective steroid at the receptor site and its affinity to the receptor. This makes glucocorticoids an ideal candidate for PK/PD modelling. Availability at the receptor site is governed by pharmacokinetic parameters such as bioavailability, clearance, protein binding, and volume of distribution. The receptor affinity can easily be measured in vitro. A suitable indirect-response PK/PD model is presented that allows description of the receptor-mediated drug effects such as endogenous cortisol suppression as a function of time. Furthermore, this model allows prediction of the systemic activity of newly developed corticosteroids based on their pharmacokinetics and their respective receptor-binding affinity. The model can also be applied in order to study systemic steroid effects after topical administration or to investigate the effect of the time of dosing on cortisol suppression. Comparison of predictions based on this model and results from large clinical studies are in excellent agreement. Corticosteroids may represent an ideal class of drugs for the successful use of PK/PD modelling during drug development allowing to save time and expenses.
Adrenal Cortex Hormones↗
Metabolism of dynorphin A1-13 in human CSF.
In-vitro incubation of human cerebrospinal fluid (CSF) obtained from patients ranging from 22-78 years with 10 microM of dynorphin A1-13 (Dyn A1-13) resulted in several cleavage products. Dyn A1-12 and A2-13 were identified as the major CSF metabolites by matrix-assisted laser desorption mass spectrometry (LD-MS). Further metabolites were Dyn A1-6, A2-12 and A4-12. LD-MS further suggested the formation of Dyn A1-8, A1-7, A1-10, A7-10, A3-12, A7-12, A3-13, A7-13 and A8-13. The metabolic half-life of Dyn A1-13 at 37 degrees C was approximately 2.5 h (range 1.75-8.5 h), compared to less than one minute in plasma. The half-life of Dyn A1-13 decreased markedly with age or age-associated processes (n = 20, r2 = 0.498). Noncompartmental kinetic analysis in the absence or presence of enzyme inhibitors (leucinethiol 10 microM, captopril 100 microM and GEMSA 20 microM) suggested that Dyn A1-13 is mainly metabolized by carboxypeptidase to A1-12 (51%) and by aminopeptidases to A2-13 (35%). The generation of A1-6 (13%) was only detected under enzyme inhibition. The extent of conversion into the main metabolites did not follow an age-associated trend, thus over-all enzyme levels but no specific enzymatic systems are elevated with age.
Adult↗
Pulmonary targeting of liposomal triamcinolone acetonide phosphate.
PURPOSE: To explore the use of triamcinolone acetonide phosphate liposomes as a pulmonary targeted drug delivery system. METHODS: Triamcinolone acetonide phosphate liposomes composed of 1,2-distearoyl phosphatidylcholine and 1,2-distearoyl phosphatidyl glycerol and triamcinolone acetonide 21-phosphate dipotassium salt were prepared by dispersion and extruded through polycarbonate membranes. Encapsulation efficiency and in vitro stability at 37 degrees C were assessed after size exclusion chromatography. TAP liposomes (TAP-lip) or TAP in solution (TAP-sol) were delivered to rats either by intratracheal instillation (IT) or intravenous (IV) administration. Pulmonary targeting was assessed by simultaneous monitoring of glucocorticoid receptor occupancy over time in lung (local organ) and liver (systemic organ) using an ex vivo receptor binding assay as a pharmacodynamic measure of glucocorticoid action. RESULTS: In vitro studies in different fluids over 24 hours, showed that more than 75% of the TAP remained encapsulated in liposomes. Cumulative pulmonary effects after IT administration of TAP-lip were 1.6 times higher than liver receptor occupancy. In contrast, there was no difference in the pulmonary and hepatic receptor occupancy time profiles when TAP was administered intratracheally as a solution. No preferential lung targeting was observed when TAP-lip was administered IV. As indicated by the mean effect times, lung receptor occupancy was sustained only when TAP-lip was administered IT. CONCLUSIONS: Intratracheal administration of TAP-lip provided sustained receptor occupancy, and increased pulmonary targeting which was superior to IT administration of TAP-sol or IV administration of TAP-lip. The use of liposomes may represent a valuable approach to optimize sustained delivery of glucocorticoids to the lungs via topical administration.
Animals↗
Pharmacokinetics and pharmacodynamics of cloprednol.
The pharmacokinetics and pharmacodynamics of cloprednol after oral administration in doses of 2.5 to 15 mg to healthy volunteers were determined. The half-life of cloprednol ranged from 1.8 h to 2.7 h, the oral clearance (CL/F) was determined to be 15-22 l/h. Since cloprednol shows nonlinear plasma protein binding, the plasma concentrations were converted to their free, unbound concentrations for the PK/PD-analysis. Due to this nonlinearity, the half-life of free, unbound cloprednol was shorter than that of the total drug. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK/PD) approach using a modified Emax-model was applied to link unbound corticosteroid concentrations to the effect on lymphocytes and granulocytes. The E50 value for unbound cloprednol ranged from 3.6 to 4.7 ng/ml and 1.2 to 4.6 ng/ml for granulocytes and lymphocytes, respectively. The PK/PD model allowed a good prediction of the observed effects and was consistent with reported values for glucocorticoid receptor binding affinities for cloprednol.
Administration, Oral↗
Interspecies comparison of in vitro plasma degradation of dynorphin A 1-13.
Enzymatic cleavage of peptides might release metabolites with distinct pharmacological profile. Interspecies differences in the metabolism of peptides might represent a potential source of error when animal data are intended to predict the human situation. Therefore, the metabolism of dynorphin (Dyn) A1-13 was investigated in the plasma of various species used in experimental practice (monkey, rabbit, rat, guinea pig) and compared to previously reported human data. The metabolic pathways were evaluated by enzyme inhibition and kinetic analysis, both yielding almost identical results. Rapid metabolism was observed with all dynorphin fragments across all species (half-lives from 0.3 min for Dyn A1-12 in guinea pig plasma to 2.6 min for Dyn A2-12 in monkey plasma). The metabolism of Dyn A1-13 differed mainly with respect to the half-life (from 0.5 min in guinea pig plasma) to 1.1 min in monkey plasma), while the metabolic routes were similar across the species (Dyn A1-12 major metabolite of Dyn A1-13: from 88% in guinea pig plasma to 71% in rabbit plasma). The metabolic fate of Dyn A1-12, the most important metabolite of Dyn A1-13 is much more heterogeneous across the species then the one observed for Dyn A1-13. For a first assessment, the metabolic routes and rates of Dyn A1-13 in plasma of all investigated species, except from guinea pigs, resemble those in human plasma sufficiently.
Animals↗
Pharmacokinetic and pharmacodynamic evaluation of triamcinolone acetonide after intravenous, oral, and inhaled administration.
Triamcinolone acetonide (TCA) is a corticosteroid that is frequently used in the treatment of asthma. After inhalation, TCA can become systemically available when the inhaled formulation is swallowed, causing undesirable systemic effects. A clinical study was conducted to determine the systemic side effects of TCA after intravenous (2 mg as phosphate ester), oral (5 mg), and inhaled (2 mg) administration. Blood samples were collected at appropriate times over 24 hours, and TCA concentrations in plasma were measured by high-performance liquid chromatography and radioimmunoassay. Free drug concentrations were determined by ultrafiltration for correlating pharmacokinetics and pharmacodynamics. The free fraction of TCA (+/- standard deviation) was 29.0 +/- 1.3% and was independent of the investigated concentration range up to 1,000 ng/mL. Pharmacodynamic parameters were determined by monitoring lymphocytes, granulocytes, and cortisol. Pharmacokinetic/pharmacodynamic modeling was performed using a modified Emax model for lymphocytes and granulocytes. A novel linear release rate model was used to characterize the cortisol data. The E50 values determined from all three pharmacodynamic endpoints were not significantly different for the three treatments, indicating that these effects can be explained based on systemic steroid concentrations.
Administration, Inhalation↗
Pharmacokinetics of triamcinolone acetonide after intravenous, oral, and inhaled administration.
The pharmacokinetics of triamcinolone acetonide were studied after intravenous (2 mg), oral (5 mg), and inhaled (2 mg) administration. Triamcinolone acetonide concentrations were measured in plasma by high-performance liquid chromatography/radioimmunoassay. After intravenous administration, triamcinolone acetonide was eliminated with a total body clearance of 37 L/h and a half-life of 2.0 hours. The volume of distribution was 103 L, and oral bioavailability averaged 23%. Absorption was rapid, achieving maximum triamcinolone acetonide levels of 10.5 ng/mL after 1 hour. After inhalation, bioavailability averaged 22% with maximum levels of 2.0 ng/mL observed after 2.1 hours. The resulting systemic levels for all three treatments caused a significant decrease in the number of lymphocytes in blood.
Administration, Inhalation↗
Metabolism of dynorphin A 1-13 in human blood and plasma.
PURPOSE: A detailed investigation of the metabolic routes and rates of Dyn A1-13 in human blood and plasma was performed. METHODS: Human plasma was incubated at 37 degrees C with dynorphin A 1-13 (Dyn A1-13, 15-20 microM). The generated dynorphin fragments were separated by a new ion-pair chromatographic method and identified by matrix assisted laser desorption mass spectroscopy. The kinetic behavior of parent compound and metabolites was evaluated in the absence and presence of enzyme inhibitors. RESULTS: The major plasma metabolites of Dyn A1-13 were Dyn A1-12, A2-12, A4-12 and A4-8. Further metabolites were Dyn A2-13, A3-13, A3-12, A5-12, A6-12, A7-12, A1-10, A2-10, A2-8 and A3-8. At 37 degrees C, Dyn A1-13 had a half-life of less than one minute in plasma and blood. Plasma half-lives of major metabolites ranged between 0.5 and 4 min. Inter- and intra-individual differences in healthy volunteers were 30% (c.v.). Dyn A1-13 is mainly metabolized by carboxypeptidases to Dyn A1-12 (80%) and by aminopeptidases to Dyn A2-13 (15%). Dyn A1-12 and Dyn A2-13 are predominantly converted into Dyn A2-12 (67% of Dyn A1-13). Subsequent metabolic steps yield Dyn A3-12 (16%), Dyn A4-12 (37%) and Dyn A4-8 (33%). Aminopeptidases generate Dyn A2-12, A3-12, A4-12, A5-12. ACE metabolizes Dyn A1-12 (19%), A2-12 (33%), A3-12 (34%) and A4-12 (46%). Bestatin-sensitive endopeptidases (possibly endopeptidase 24.11) metabolize 30% of Dyn A2-12. Dyn A4-8 is formed via Dyn A4-12 (23% of Dyn A4-12) and Dyn A2-10 (37% of Dyn A2-10). CONCLUSIONS: The combination of enzyme inhibition experiments and noncompartmental kinetic analysis proved to be a powerful tool for the detailed evaluation of the metabolic fate of Dyn A1-13 in human blood and plasma.
Adult↗
Assessment of glucocorticoid lung targeting by ex-vivo receptor binding studies in rats.
Triamcinolone acetonide (TA, 22 micrograms) was given to rats by intravenous (i.v.) injection or intratracheal (IT) instillation. Free glucocorticoid receptors were monitored over time in liver and lung using an ex-vivo receptor binding technique. After i.v. administration of a TA solution, the reduction of free receptors over time was very similar in lung and liver (AUCLung = 280 +/- 47% h; AUCLiver = 320 +/- 76% h). Intratracheal instillation of the same solution produced time profiles which mirrored those of i.v. injection (AUCLung = 260 +/- 41% h; AUCLiver = 330 +/- 50% h). The lack of lung targeting was also reflected in the failure to show any significant difference in the pulmonary targeting factor T (AUCLung/AUCLiver) between i.v. (T = 0.84 +/- 0.18) and IT (T = 0.78 +/- 0.03) administration. In contrast, a certain degree of lung specificity was observed after IT instillation of a glucocorticoid suspension (22 micrograms; AUCLung = 160 +/- 135% h; AUCLiver = 65 +/- 91% h, T = 2.3 +/- 0.5) as indicated by significant differences in T between i.v. injection and IT instillation (p = 0.038). The method presented provides a means of simultaneously assessing pulmonary and systemic effects after different forms and routes of administration and might be of value in further studying multiple aspects of inhalation glucocorticoid therapy.
Animals↗
Pharmacokinetic/pharmacodynamic evaluation of deflazacort in comparison to methylprednisolone and prednisolone.
PURPOSE: The pharmacokinetics and pharmacodynamics of deflazacort after oral administration (30 mg) to healthy volunteers were determined and compared with those of 20 mg of methylprednisolone and 25 mg of prednisolone. METHODS: Methylprednisolone, prednisolone and the active metabolite of deflazacort, 21-desacetyldeflazacort, were measured in plasma using HPLC. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was applied to link corticosteroid concentrations to the effect on lymphocytes and granulocytes. RESULTS: Deflazacort is an inactive prodrug which is converted rapidly to the active metabolite 21-desacetyldeflazacort. Maximum concentrations of 21-desacetyldeflazacort averaged 116 ng/ml and were observed after 1.3 h. The average area under the curve was 280 ng/ml.h, and the terminal half-life was 1.3 h. 21-Desacetyldeflazacort was cleared significantly faster than both methylprednisolone and prednisolone. The PK-PD-model was suitable to describe time course and magnitude of the observed effects. The results were consistent with reported values for glucocorticoid receptor binding affinities for the investigated compounds. CONCLUSIONS: Due to the short pharmacokinetic half-life of its active metabolite, pharmacodynamic effects of deflazacort are of shorter duration than those of methylprednisolone and prednisolone. The PK-PD model allows good prediction of pharmacodynamic effects based on pharmacokinetic and receptor binding data.
Absorption↗
Pharmacokinetic interaction between endogenous cortisol and exogenous corticosteroids.
A problem in the evaluation of pharmacokinetic interactions between prednisolone and cortisol is that both steroids bind to cortisol binding globulin (CBG) and albumin. The binding of both steroids to CBG is saturable in the therapeutic concentration range. General drug binding equations were applied to two drugs and two binding sites and two implicit cubic equations were derived. These equations cannot be solved algebraically. However, the free concentration can be calculated using spreadsheet programs on a personal computer. A spreadsheet for these equations was developed using EXCEL 5.0 and its SOLVER option. Free concentrations of prednisolone and cortisol were determined as a function of total concentrations of both ligands. The simulations show that the protein binding of cortisol remains relatively constant in the physiological range but changes when exogenous corticosteroid is present. However, the degree of protein binding of exogenous corticosteroids that bind to CBG depends on the cortisol concentration which competes for binding sites. At the same time, the exogenous corticosteroid suppresses the release of endogenous cortisol. The presented approach is able to take all of these pharmacokinetic and pharmacodynamic interactions into account leading to a more accurate estimation of active free corticosteroid concentrations.
Adult↗