Excretion constant

Sources of TPO include kidney and skeletal muscle cells but it is primarily produced by the liver, from where it is excreted constantly into the blood. This regulatory factor supports the proliferation, differentiation and maturation of megakaryocytes and their progenitors and... 

Once the principles of these studies have been grasped, the distribution of a drug can be investigated in more detail. The dose schedules for sulpho-namides in Table 3.6 were obtained as follows. The drug was given orally to healthy human volunteers, and specimens of blood and urine were taken at frequent intervals and analysed. The rate constants for the metabolism of various sulphonamides were obtained also those for their excretion (see Fig. 3.7). Further work enabled the composite excretion constant to be split into two microscopic constants describing respectively the... 

Thiamine requirements vary and, with a lack of significant storage capabiHty, a constant intake is needed or deficiency can occur relatively quickly. Human recommended daily allowances (RDAs) in the United States ate based on calorie intake at the level of 0.50 mg/4184 kj (1000 kcal) for healthy individuals (Table 2). As Httle as 0.15—0.20 mg/4184 kJ will prevent deficiency signs but 0.35—0.40 mg/4184 kJ are requited to maintain near normal urinary excretion levels and associated enzyme activities. Pregnant and lactating women requite higher levels of supplementation. Other countries have set different recommended levels (1,37,38). 

In zero-orrler kinetics, a constant amount of a chemical compound is excreted per unit of rime. In most cases, this phenomenon is caused by the saturation of a rate-limiting enzyme, and the enzyme commonly functions at its maximal rate, i.e., a constant amount of a chemical compound is metabolized per unit time. A good example is ethyl alcohol alcohol dehydrogenase becomes saturated at relatively low concentrations. Because of this saturation, ethyl alcohol is eliminated at a constant rate about 7 g/h. However, rhe reason is not always an enzyme anv... 

In a study of pregnant rats that were exposed to radiolabeled methyl parathion by single dermal application, half-life elimination rate constants for various tissues ranged from 0.04 to 0.07 hour, highest values noted in plasma, kidneys, and fetus. Of the applied radioactivity, 14% was recovered in the urine in the first hour postapplication. By the end of the 96-hour study, 91% of the applied dose had been recovered in the urine. Fecal excretion accounted for only 3% of the administered dose (Abu-Qare et al. 2000). 

Sato et al. (1991) expanded their earlier PBPK model to account for differences in body weight, body fat content, and sex and applied it to predicting the effect of these factors on trichloroethylene metabolism and excretion. Their model consisted of seven compartments (lung, vessel rich tissue, vessel poor tissue, muscle, fat tissue, gastrointestinal system, and hepatic system) and made various assumptions about the metabolic pathways considered. First-order Michaelis-Menten kinetics were assumed for simplicity, and the first metabolic product was assumed to be chloral hydrate, which was then converted to TCA and trichloroethanol. Further assumptions were that metabolism was limited to the hepatic compartment and that tissue and organ volumes were related to body weight. The metabolic parameters, (the scaling constant for the maximum rate of metabolism) and (the Michaelis constant), were those determined for trichloroethylene in a study by Koizumi (1989) and are presented in Table 2-3. 

Figure 39.4a represents schematically the intravenous administration of a dose D into a central compartment from which the amount of drug Xp is eliminated with a transfer constant kp. (The subscript p refers to plasma, which is most often used as the central compartment and which exchanges a substance with all other compartments.) We assume that mixing with blood of the dose D, which is rapidly injected into a vein, is almost instantaneous. By taking blood samples at regular time intervals one can determine the time course of the plasma concentration Cp in the central compartment. This is also illustrated in Fig. 39.4b. The initial concentration Cp(0) at the time of injection can be determined by extrapolation (as will be indicated below). The elimination pool is a hypothetical compartment in which the excreted drug is collected. At any time the amount excreted must be equal to the initial dose D minus the content of the plasma compartment Xp, hence ...

Fig. 39.4. (a) One-compartment open model with single-dose intravenous injection of a dose D. The transfer constant of elimination (excretion and metabolism) is kp - (b) Time course of the plasma concentration Cp and of the contents in the elimination pool Xp. 

Thus, the overall elimination rate constant (ke[) here is the sum of the urinary excretion rate constant (ke) and the metabolism rate constant (km) ... 

This optimization method, which represents the mathematical techniques, is an extension of the classic method and was the first, to our knowledge, to be applied to a pharmaceutical formulation and processing problem. Fonner et al. [15] chose to apply this method to a tablet formulation and to consider two independent variables. The active ingredient, phenylpropanolamine HC1, was kept at a constant level, and the levels of disintegrant (corn starch) and lubricant (stearic acid) were selected as the independent variables, X and Xj. The dependent variables include tablet hardness, friability, volume, in vitro release rate, and urinary excretion rate in human subjects. 

This book is written for the practicing pharmaceutical scientist involved in absorption-distribution-metabolism-excretion (ADME) measurements who needs to communicate with medicinal chemists persuasively, so that newly synthesized molecules will be more drug-like. ADME is all about a day in the life of a drug molecule (absorption, distribution, metabolism, and excretion). Specifically, this book attempts to describe the state of the art in measurement of ionization constants (p Ka), oil-water partition coefficients (log PI log D), solubility, and permeability (artificial phospholipid membrane barriers). Permeability is covered in considerable detail, based on a newly developed methodology known as parallel artificial membrane permeability assay (PAMPA). 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

The rate constants for metabolism and excretion were further combined to a rate constant for the disappearance of the drug, k. Four dosage forms were studied and it was found that was constant for all forms except for a coarse, slowly dissolving powder. 

Portmann and co-workers then studied the kinetic pathways in man for hydroxynalidixic acid, the active primary metabolite.(26) The rate constants for glucuronide formation, oxidation to the dicarboxylic acid and excretion of hydroxynalidixic acid were calculated. Essentially total absorption of hydroxynalidixic acid was found in every case. Good agreement between experimental and theoretical plasma levels, based on the first order rate approximations used for the model, was found. Again, the disappearance rate constant, kdoi was found to be very similar for each subject, although the individual excretion and metabolic rate constants varied widely. The disappearance rate constant, k was defined as the sum of the excretion rate constant, kg j and the metabolic rate constants to the glucuronide and dicarboxylic acid, kM-j and kgj, respectively. 

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