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51.
Guy M. L. Meno-Tetang Yuen Yi Hon William J. Jusko 《Immunopharmacology and immunotoxicology》1996,18(3):443-456
The interaction between dehydroepiandrosterone (DHEA) and prednisolone (PD) in the inhibition of rat lymphocyte proliferation was evaluated. The in vitro proliferative response of splenocytes from male Sprague-Dawley rats stimulated with phytohemagglutinin (PHA) was measured by the incorporation of 3H-thymidine into the DNA. DHEA and PD were added at the initiation of cultures individually and in various molar ratio combinations. The search for synergy additivity or antagonism between the two compounds was performed by using the median-effect method of Chou and Talalay and Drewinko's statistical analysis. Both compounds individually inhibit the proliferation of PHA-stimulated rat lymphocytes. DHEA with an IC50 value of 13.4 pM was a thousand times less potent than PD which had an IC50 value of 5.4 nM. Synergy was observed between DHEA and PD. The intensity of the interaction appeared to be function of the molar ratio of the two drugs. The association of DHEA and PD could produce enhanced steroid effects in anti-inflammatory therapy. 相似文献
52.
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54.
Stanley J. Szefler M.D. James Q. Rose Ph.D. Elliot F. Ellis M.D. Sheldon L. Spector M.D. Andrew W. Green M.D. William J. Jusko Ph.D. 《The Journal of allergy and clinical immunology》1980,66(6):447-451
Troleandomycin (TAO), a macrolide antibiotic, has an apparent “steroid-sparing” effect when used in the treatment of severe steroid-dependent asthma. This study was designed to investigate the effect of TAO on methylprednisolone elimination. Pharmacokinetic studies were performed before and 1 wk after starting TAO in 10 severe steroid-dependent asthmatics. Baseline total body clearance of methylprednisolone was 406 ± 139 (mean ± SD) ml/min/1.73 m2 and decreased significantly (p < 0.001) to 146 ± 57 ml/min/1.73 m2 1 wk after TAO therapy was initiated. Methylprednisolone half-life was 2.46 ± 0.75 hr before TAO and increased significantly (p < 0.001) to 4.63 ± 1.35 hr after 1 wk on TAO therapy. A follow-up evaluation of methylprednisolone pharmacokinetics in three patients after at least 1 mo on TAO therapy demonstrated continuation of the reduced methylprednisolone elimination. TAO inhibition of methylprednisolone clearance may contribute to the beneficial effects observed initially with combined methylprednisolone-troleandomycin therapy in severe steroid-dependent asthma. 相似文献
55.
Single oral and intramuscular (i.m.) doses of imipramine (IMI) were administered to four normal males. Serum and urine concentrations of IMI, desipramine (DMI) and their unconjugated 2-hydroxy metabolites were measured by high-pressure liquid chromatography (HPLC). Urinary conjugated 2-hydroxy metabolites were also measured after enzyme hydrolysis. Computer analysis of serum concentration and urinary excretion rate data allowed confirmation of drug and metabolite kinetics, and calculation of pharmacokinetic parameters. The rapid appearance of the metabolites in serum indicates that sequential firstpass metabolism of IMI involves both hydroxylation and demethylation. However, the dose-normalized areas under the serum concentration-time curves indicate that the fractions of the doses converted to metabolites were similar after both routes of IMI administration. Similar total fractions of the i.m. and oral doses recovered in urine indicate complete absorption of the oral doses. Inclusion of the metabolites increased the apparent availability of active components after oral IMI from 22%–50% to 45%–94%. Both the 2-hydroxy metabolites exhibited formation rate-limited kinetics, whereas DMI kinetics were elimination rate-limited. The t
1/2 of IMI and 2-hydroxyimipramine (2-OH-IMI) was 6–18 h, while that of DMI and 2-hydroxydesipramine (2-OH-DMI) was 12–36 h. The t
1/2 of these compounds was 1.5–2 times longer after the i.m. doses. The metabolite/parent ratios and the disposition of the individual metabolites confirm findings that chronic dosing results in only limited accumulation of hydroxy metabolites. 相似文献
56.
Renal transplant patients commonly receive triple-drug immunosuppression with standardized doses of cyclosporine, azathioprine, and methylprednisolone. Although cyclosporine may decrease the clearance of oral prednisone, data are lacking for methylprednisolone, a glucocorticoid commonly prescribed via a standardized protocol for intravenous therapy and during periods of acute rejection. The disposition of methylprednisolone (doses: 10-60 mg/day) was examined in nine renal transplant patients during the post-transplant period (0.8-14 months). Plasma samples were collected over 24 hr and analyzed for methylprednisolone via HPLC. Pharmacokinetic parameters were determined by noncompartmental analysis. The mean total clearance of methylprednisolone was 379 ml/hr/kg (range 105-672) and the volume of distribution was 1.4 +/- 0.5 L/kg. The mean plasma half-life was 2.7 +/- 1.1 hr. When normalized to a 1 mg dose of methylprednisolone, the mean peak concentration at 1 hr was 10.0 +/- 3.5 ng/ml with an 8 hr concentration ranging from 0.3 to 5.5 ng/ml. An appreciable variability in methylprednisolone metabolism thus exists in renal transplant recipients receiving triple-drug immunosuppression. This may partially explain the variable response to steroid therapy during acute rejection episodes and chronic immunosuppression as well as the unpredictable occurrence of chronic steroid toxicity. 相似文献
57.
Myocardial distribution of digoxin and renal function 总被引:1,自引:0,他引:1
58.
Effects of thyroid dysfunction on prednisolone and prednisone interconversion and disposition in the rat 总被引:4,自引:0,他引:4
The effects of thyroid dysfunction on the reversible metabolism and disposition of prednisolone and prednisone were examined in male Wistar rats. Hyperthyroid rats were produced by daily ip injections of 20 micrograms of I-triiodothyronine/100 g body weight for 6 days. Hypothyroid rats were obtained by providing 0.05% 6-propyl-2-thiouracil in drinking water ad libitum for 21 days. Rats were given 10 mg/kg of prednisolone or prednisone iv, blood samples were collected, and the steroids in plasma were assayed by HPLC. A recently developed pharmacokinetic model encompassing interconversion kinetics was applied. Unexpectedly, the hyperthyroid state increased the AUC (by 163%) of prednisolone (unlike in man) via reduced (66%) prednisolone elimination clearance (CL10), but also caused enhanced (101%) prednisone elimination clearance (CL20). The hypothyroid state increased the AUC (by 117%) of prednisolone via a 56% reduction in CL10 and a reduction in CL20. Prednisone formation of prednisolone (CL21) was about 13-fold greater than the reverse process (CL12), and both interconversion clearances were increased 20-40% by thyroid dysfunction. Experimental thyroid disorders thus alter prednisolone/prednisone pharmacokinetics in rats primarily by selective and sometimes unusual changes in elimination clearance rather than affecting the relative rates of steroid interconversion. Reversible metabolism is much less important in rats compared to man. 相似文献
59.
David B. Haughey William J. Jusko 《Journal of pharmacokinetics and pharmacodynamics》1992,20(4):333-355
Several approaches to receptor down-regulation were examined to extend previous receptor/ genemediated pharmacokinetic/dynamic models of corticosteroids. Down-regulation of the glucocorticoid receptor was considered as an instantaneous event or as a gradual steroid-receptor-mediated process. Concentrations of plasma methylprednisolone, free hepatic cytosolic receptors, and the activity of hepatic tyrosine aminotransferase (TAT) enzyme were measured for 16 hr following administration of 0, 10, and 50 mg/kg methylprednisolone sodium succinate to 93 adrenalectomized rats. Receptor down-regulation was best described by a fractional decrement in the rate of return of free cytosolic glucocorticoid receptor. Predicted values for free receptor, bound receptor, nuclear bound receptor, and transfer compartments were in accord with the expected rank order values based on the high and low steroid doses. Model parameter estimates were independent of dose and described the rapid depletion of free cytosolic receptor, latephase return of cytosolic receptor to a new baseline level that was 20–40% lower than control, and the TAT induction/dissipation pattern following steroid dosing. The microscopic association and dissociation constants describing the steroidreceptor interaction were 0.23 L/nmole per hr (kon and 4.74 hr–1 (koff) for methylprednisolone compared to previously obtained values of 0.20 L/nmole per hr and 15.7 hr–1 for the related steroid prednisolone. The time course of TAT induction was similar to that observed previously for prednisolone. Efficiency of TAT induction was more closely related to steroid receptor occupancy than plasma methylprednisolone concentrations due to receptor saturability and receptor recycling.Supported in part by Grant No. 24211 from the National Institutes of General Medical Sciences, NIH, and by a Fellowship from the American Foundation for Pharmaceutical Education for D.H. 相似文献
60.
J A Wald R M Law E A Ludwig R R Sloan E Middleton W J Jusko 《Journal of pharmacokinetics and biopharmaceutics》1992,20(6):567-589
The pharmacokinetics and pharmacodynamics of prednisolone were evaluated in normal male volunteers. Seven subjects completed 3 phases: 16.4- and 49.2-mg iv prednisolone, and a phase with no drug to assess baseline responses. Plasma concentrations of prednisolone and urine concentrations of prednisolone and 5 metabolites were assayed by HPLC. Protein binding of prednisolone was measured by ultrafiltration. The polyexponential disposition of free and total plasma prednisolone were evaluated and apparent parameters were compared between doses. Suppression of plasma cortisol and alterations in blood basophil and helper-T cell trafficking were used as pharmacodynamic indices. Pharmacodynamic models were used to relate total or free plasma prednisolone concentrations to each of these effects generating response parameters and IC50 (50% inhibitory) concentrations common to both doses. The pharmacokinetics of total drug were comparable to previous findings with CL and Vss increasing with dose. Free prednisolone exhibited slight capacity-limited elimination and distribution as CL and Vss decreased with the larger dose. Pharmacodynamic models jointly fitting all three phases characterized the suppression/trafficking phenomena equally well with use of total or free drug concentrations. In each case the models provided realistic values of parameters relating to steroid sensitivity--in particular IC50--and to the underlying physiology of the affected systems. This study comprehensively elucidates the complexities of prednisolone pharmacokinetics and demonstrates how plasma concentration--time profiles of total or free prednisolone can be utilized for evaluation of prednisolone pharmacodynamics. 相似文献