Metabolism, and Excretion

In humans, both the d- and L-forms undergo hydroxylation and A-demethylation to their respective / hy dr ox y me thainphetamine and amphetamine metabolites. Amphetamine is the major active metabolite of methamphetamine. Under normal conditions, up to 43% of a D-methamphet-amine dose is excreted unchanged in the urine in the first 24 h and 4 to 7% will be present as amphetamine. In acidic urine, up to 76% is present as parent drug10 compared with 2% under alkaline conditions. Approximately 15% of the dose was present as /7-hydroxymethamphetamine and the remaining minor metabolites were similar to those found after amphetamine administration. Urine concentrations of methamphetamine are typically 0.5 to 4 mg/L after an oral dose of 10 mg. However, methamphetamine and amphetamine urine concentrations vary widely among abusers. Lebish et al.11 reported urine methamphetamine concentrations of 24 to 333 mg/L and amphetamine concentrations of 1 to 90 mg/L in the urine of methamphetamine abusers. 

L-Methamphetamine is biotransformed in a similar manner to the D-isomer but at a slower rate. Following a 13.7-mg oral dose, the 24-h urine contained an average of 34% of the dose as L-methamphetamine and 1.7% of the dose as L-amphetamine.3 Oyler et al.13 described the appearance of methamphetamine and amphetamine in urine after volunteers (n = 8) ingested 4 X 10-mg doses of methamphetamine hydrochloride daily for 7 days followed by 4 X 20 mg daily several weeks later. Parent and metabolite were generally detected in the first or second void post dose in a concentration range of 82 to 1827 and 12 to 180 ng/ml, respectively. Peak methamphetamine urine concentrations (1871 to 6004 ng/ml) occurred within 1.5 to 60 h after a single dose. 

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Sutures are required to hold tissues together until the tissues can heal adequately to support the tensions exerted on the wound duting normal activity. Sutures can be used ia skin, muscle, fat, organs, and vessels. Nonabsorbable sutures are designed to remain ia the body for the life of the patient, and are iadicated where permanent wound support is required. Absorbable sutures are designed to lose strength gradually over time by chemical reactions such as hydrolysis. These sutures are ultimately converted to soluble components that are then metabolized and excreted ia urine or feces, or as carbon dioxide ia expired air. Absorbable sutures are iadicated only where temporary wound support is needed. 

Physiological effects of air pollution are deperrdent on dosage, the ability of the exposed organism to metabolize and excrete the pollution, and the type of pollutant. Many pollutants affect the futretiotring of the respiratory tract some change the structure and function of molecules others can enter the nucleus and turn getres otr or off atrd some cause chromosomal aberrations or mutations that result in cancer. 

Interactions resulting from a change in the amount of diug reaching the site of action are called pharmacokinetic interactions (Fig. 1). A co-administered diug can affect any of the processes of absorption, distribution, metabolism, and excretion of the original diug, which are determinants of its pharmacokinetic profile [1-3]. 

Pharmacokinetics refers to activities within the body after a dmg is administered. These activities include absoqrtion, distribution, metabolism, and excretion (ADME). Another pharmacokinetic component is the half-life of the drug. Half-life is a measure of the rate at which drains are removed from the body. 

The overall objective of clinical trials is to establish a drug therapy that is safe and effective in humans, to the extent that the risk-benefit relationship is acceptable. The ICH process has developed an internationally accepted definition of a clinical trial as Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy. ... 

Absorption, Distribution, Metabolism, and Excretion. Evidence of absorption comes from the occurrence of toxic effects following exposure to methyl parathion by all three routes (Fazekas 1971 Miyamoto et al. 1963b Nemec et al. 1968 Skiimer and Kilgore 1982b). These data indicate that the compound is absorbed by both humans and animals. No information is available to assess the relative rates and extent of absorption following inhalation and dermal exposure in humans or inhalation in animals. A dermal study in rats indicates that methyl parathion is rapidly absorbed through the skin (Abu-Qare et al. 2000). Additional data further indicate that methyl parathion is absorbed extensively and rapidly in humans and animals via oral and dermal routes of exposure (Braeckman et al. 1983 Flollingworth et al. 1967 Ware et al. 1973). However, additional toxicokinetic studies are needed to elucidate or further examine the efficiency and kinetics of absorption by all three exposure routes. 

Practically all toxicokinetic properties reported are based on the results from acute exposure studies. Generally, no information was available regarding intermediate or chronic exposure to methyl parathion. Because methyl parathion is an enzyme inhibitor, the kinetics of metabolism during chronic exposure could differ from those seen during acute exposure. Similarly, excretion kinetics may differ with time. Thus, additional studies on the distribution, metabolism, and excretion of methyl parathion and its toxic metabolite, methyl paraoxon, during intermediate and chronic exposure are needed to assess the potential for toxicity following longer-duration exposures. 

Pharmacokinetics—The science of quantitatively predicting the fate (disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides the means of studying the absorption, distribution, metabolism and excretion of chemicals by the body. 

Nohle U, Beau JM, Schauer R (1982) Uptake, metabolism and excretion of orally and intravenously administered, double-labeled A-glycoloylneuraminic acid and single-labeled 2-deoxy-2,3-dehydro-A-acetylneuraminic acid in mouse and rat, Eur J Biochem 126 543-548 Oxford J (2005) Oseltamivir in the management of influenza. Expert Opin Pharmacother 6 2493-2500... 

For convenience, the processes identified in Figure 2.1 can be separated into two distinct categories toxicokinetics and toxicodynamics. Toxicokinetics covers uptake, distribution, metabolism, and excretion processes that determine how much of the toxic form of the chemical (parent compound or active metabolite) will reach the site of action. Toxicodynamics is concerned with the interaction with the sites of action, leading to the expression of toxic effects. The interplay of the processes of toxicokinetics and toxicodynamics determines toxicity. The more the toxic form of the chemical that reaches the site of action, and the greater the sensitivity of the site of action to the chemical, the more toxic it will be. In the following text, toxicokinetics and toxicodynamics will be dealt with separately. 

Preexisting disease, such as renal or hepatic disease, can especially influence the metabolism and excretion of certain drugs. In clinical trials, and in electronic longitudinal medical records, it is important to have sufficient variability in disease states and concomitant diseases among subjects in both the... 

Study and control groups. Investigators need to consider whether the adverse events that occur are due to abnormalities in the distribution, metabolism, and excretion of drugs as a result of underlying disease. These analyses could be systematically facilitated by having standardized ways of measuring blood (and in some cases, tissue) levels of drugs and their metabolites. 

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. 

Trichloroethylene is exhaled following inhalation and oral exposures (Dallas et al. 1991 Koizumi et al. 1986 Stewart et al. 1970), whereas metabolites are mainly excreted in the urine (Fernandez et al. 1977 Koizumi et al. 1986 Monster etal. 1979 Sato et al. 1977). Based on the knowledge of trichloroethylene metabolism and excretion, potential methods for reducing the body burden are presented. These methods have not been used in persons or animals exposed to trichloroethylene and should be researched further before being applied. 

Bartonicek V. 1962. Metabolism and excretion of trichloroethylene after inhalation by human subjects. Br J Ind Med 19 134-141. 

SHAPIRO T A, FAHEY J w, WADE K L, STEPHENSON K K and TALALAY p (2001) Chemoprotective glucosinolates and isothiocyanates of broccoli sprouts metabolism and excretion in humans . Cancer Epidemiol Biomarkers Prev, 10 501-8. 

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