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61.
Janis J. Mackichan Dennis R. Pyszczynski William J. Jusko 《Biopharmaceutics & drug disposition》1980,1(4):159-166
The pharmacokinetics and relative systemic availability or oral propranolol were studied in three healthy volunteers following administration of 10, 40, and 80 mg of propranolol hydrochloride. Plasma concentrations of propranolol were determined using a sensitive and specific fluorometric high pressure liquid chromatographic technique. In the dosage range studied, the amount of propranolol reaching the systemic circulation increased with dose, while half-lives remained unchanged. The apparent ‘threshold dose’ for propranolol was much smaller than previously reported, and its contribution to the observed dose-dependent availability is doubtful. Apparent intrinsic clearance values were shown to decrease with increase in dose, with a true maximal intrinsic clearance of 5·4 1kg?1 h?1. These data suggest the saturation of a low capacity enzyme system in the liver and are consistent with theoretical characteristics of a drug that is extensively metabolized during its first pass through the liver. 相似文献
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Equations for the steady-state volumes of distribution (V
ss) and the mean residence times in the body (MRT) are derived for a drug and its metabolite subject to reversible metabolism and separately infused intravenously at a constant rate to steady state of both compounds. The V
ss and MRT parameters are functions of the integrals of plasma concentrations, plasma concentrations at steady state, and times to reach steady state of both drug and metabolite. In addition, the MRT values are functions of the infusion rates. These equations were validated by computer simulations and comparison with IV bolus dose parameters. These relationships extend the ability to assess the pharmacokinetics of linear reversible metabolic systems. 相似文献
66.
The binding of oxazepam and its glucuronide conjugates to human serum albumin (HSA), as well as the binding interactions of the drug and its metabolites, were examined by equilibrium dialysis and kinetic probe studies. Oxazepam and its S(+) glucuronide are bound to the HSA molecule with affinity constants of 3.5 X 10(5) M-1 and 5.5 X 10(4) M-1, respectively, which were independent of protein concentration over a range of 0.1 to 5.0 g/dl. The R(-) glucuronide bound weakly to albumin, with the binding parameter, N X K, increasing at lower albumin concentrations. Pre-acetylation of fatty acid free-HSA resulted in decreased binding of all three compounds, probably by altering the conformation of the binding sites. Kinetic probe studies with p-nitrophenyl acetate indicate that oxazepam and its S(+) glucuronide shared a common binding site on HSA, but that the R(-) glucuronide bound at another site. Oxazepam binding was unaffected by the presence of its glucuronide conjugates but was inhibited by fatty acids. The percentage of oxazepam bound to plasma proteins in patients with renal impairment (94%) was lower than in normal volunteers (97%). This lower binding can neither be attributed to lower albumin concentrations because of the large binding capacity of the protein and linearity of N X K nor to displacement by elevated concentrations of glucuronide conjugates, but it may be ascribed partly to increased plasma fatty acids. 相似文献
67.
Samtani MN Pyszczynski NA Dubois DC Almon RR Jusko WJ 《The Journal of pharmacology and experimental therapeutics》2006,317(1):127-138
Our previous report described the temporal steroid patterns during pharmacokinetic (PK) studies with dexamethasone (DEX) where doses of six 1 micromol/kg injections were given during gestational ages 18 to 20 days in rats. DEX PK was used in conjunction with the endogenous corticosterone profile to understand the regulation of fetal lung pharmacodynamics (PD). Expression of the glucocorticoid receptor (GR) and surfactant proteins A and B mRNA were chosen as lung maturational markers. GR seemed to be insensitive to the circulating glucocorticoids, indicating that unlike the adult situation, GR was not under negative feedback control of its ligand. Surfactant protein B exhibited approximately 400-fold induction in control fetal lung during the last days of gestation, and the inductive effect was even greater in the treatment group. Surfactant protein A displayed approximately 100-fold induction in control fetal lung during late gestation. However, the treatment group exhibited biphasic stimulatory and inhibitory effects for surfactant protein A. The inhibitory effect indicated that the chosen dosing scheme for DEX was not an optimal regimen. These data were used to determine by simulation the DEX regimen that would reproduce the temporal pattern of lung maturation observed in control animals. PK/PD modeling indicated that maintaining steroid exposure at approximately twice the equilibrium dissociation constant for the steroid/receptor interaction should produce optimal stimulation of both surfactant proteins. The simulations illustrate that administering smaller quantities of steroids over extended periods that produce sustained steroid exposure might be the optimal approach for designing dose-sparing antenatal corticosteroid therapy. 相似文献
68.
Hoi‐Kei Lon Yan‐Lin Wang Debra C. DuBois Richard R. Almon William J. Jusko 《Biopharmaceutics & drug disposition》2013,34(4):203-214
Methotrexate (MTX) is an anchor drug used to treat rheumatoid arthritis (RA), but responsiveness is variable in effectiveness and toxicity. Methotrexate and its polyglutamate conjugates (MTXPGn) in red blood cells (RBC) have been associated with patient response. In the current study, 13 collagen‐induced arthritic (CIA) rats and 12 healthy rats were given subcutaneous doses of either saline or 0.3 or 1.5 mg/kg per 2 days of MTX from day 21 to 43 post‐induction. Blood samples were obtained at various times to measure MTX in plasma, and MTX and MTXPGn in RBC. Effects on disease progression were indicated by body weight and paw size. After multiple‐doses, RBC MTX reached steady‐state (82.4 nm ) within 4 days. The MTXPG2 and MTXPG3 in RBC kept increasing until the end of the study, attaining 12.5 and 17.7 nm . Significant weight loss was observed after dosing with 1.5 mg/kg/2 days, whereas moderate effectiveness was observed after dosing with 0.3 mg/kg/2 days. A pharmacokinetic/pharmacodynamic/disease (PK/PD/DIS) model with indirect mechanisms and transduction components incorporating plasma MTX, RBC MTX and RBC MTXPGn concentrations, and paw size was developed using naïve data pooling and ADAPT 5. The PK/PD in CIA rats dosed at 0.3 mg/kg/2 days were captured well by our proposed model. Methotrexate showed modest (Imaxd = 0.16) but sensitive (IC50d = 0.712 nm ) effectiveness on paw edema. The higher dose produced toxicity. The proposed model offers improved understanding of the effects of methotrexate on rheumatoid arthritis. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
69.
Molly K. McCann Todd A. Jusko Courtney M. C. Jones Christopher L. Seplaki Jeremy T. Cushman 《Prehospital emergency care》2021,25(1):82-90
Abstract
Background
Across the spectrum of patient care for opioid overdose, an important, yet frequently overlooked feature is the bystander, or witness to the overdose event. For other acute medical events such as cardiac arrest and stroke, research supports that the presence of a bystander is associated with better outcomes. Despite the similarities, however, this well-established conceptual framework has yet to be applied in the context of overdose patient outcomes. The objective of this study was to assess the association between the nature of the bystander-patient relationship and prehospital care measures in patients being treated for opioid overdose. 相似文献70.
Dandan Luo Carolyn L. Westhoff Alison B. Edelman Melissa Natavio Frank Z. Stanczyk William J. Jusko 《Contraception》2019,99(4):256-263