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Equations for the mean number of cycles through the peripheral system (R) and the mean transit time through the central compartment (MTTc) are derived for intravenous drugs with linear distribution and linear or nonlinear central elimination. This R is a function of distribution clearance (CLD), dose, and area under the plasma concentration-time curve (AUC). The MTTc is a function of the central volume of distribution, CLD, dose, and AUC. The application of the proposed calculations of R and MTTc was illustrated by computer simulations. 相似文献
44.
Characteristics of indirect pharmacodynamic models and applications to clinical drug responses 总被引:2,自引:0,他引:2
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This review describes four basic physiologic indirect pharmacodynamic response (IDR) models which have been proposed to characterize the pharmacodynamics of drugs that act by indirect mechanisms such as inhibition or stimulation of the production or dissipation of factors controlling the measured effect. The principles underlying IDR models and their response patterns are described. The applicability of these basic IDR models to characterize pharmacodynamic responses of diverse drugs such as inhibition of gastric acid secretion by nizatidine and stimulation of MX protein synthesis by interferon α-2a is demonstrated. A list of other uses of these models is provided. These models can be readily extended to accommodate additional complexities such as nonstationary or circadian baselines, equilibration delay, depletion or accumulation of a precursor pool, sigmoidicity, or other mechanisms. Indirect response models which have a logical mechanistic basis account for time-delays in many responses and are widely applicable in clinical pharmacology. 相似文献
45.
Wojciech Krzyzanski William J. Jusko 《Journal of pharmacokinetics and pharmacodynamics》1998,26(4):385-408
Indirect response models require differential equations to describe the nonlinear inhibition or stimulation of the production or loss (kout
) of the response variable. Partially integrated solutions for these models developed previously for iv bolus or biphasic pharmacokinetics were extended to consider drug infusions for limited or extended durations. Qualitative examination was made of the role of infusion rate and duration, type and rate of drug disposition, Imax
or Smax
capacity factors, IC50
or SC50
sensitivity factors, and kout
values. Properties of the response curves characterized include curve shapes, maximum or minimum response, onset rate, steady-state, and return to baseline. Some comparisons were made with behavior of iv bolus doses. These relationships provide both a formal and practical basis for better understanding of the time-course of basic indirect response models. 相似文献
46.
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
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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
50.
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