Excretion kinetics

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. 

Sato A, Nakajima T. 1978. Differences following skin or inhalation exposure in the absorption and excretion kinetics of trichloroethylene and toluene. Br J Ind Med 35 43-49. 

Excretion kinetics of chlordane are complex, and different isomers exit through different pathways (USEPA 1980, 1988). In rats, chlordane elimination was almost complete 7 days after receiving single oral doses up to 1 mg/kg body weight (BW) 24 hours after treatment, 70% of the r/. v-chlordane and 60% of the trans-chlordane had been excreted (WHO 1984). In rodents, chlordane and its metabolites were usually excreted in feces, regardless of the administration route the cis-isomer was excreted slightly faster than the trans-isomer, although identical metabolites seemed to be formed (Menzie 1969, 1980 USEPA 1980 WHO 1984 Nomeir and Hajjar 1987). In rabbits, however, up to 47% of the administered dose was voided in the urine, and cis- and /ran.v-chlordanc were excreted at the same rate (Nomeir and Hajjar 1987). 

Atrophy of the thymus is a consistent finding in mammals poisoned by 2,3,7,8-TCDD, and suppression of thymus-dependent cellular immunity, particularly in young animals, may contribute to their death. Although the mechanisms of 2,3,7,8-TCDD toxicity are unclear, research areas include the role of thyroid hormones (Rozman et al. 1984) interference with plasma membrane functions (Matsumura 1983) alterations in ligand receptors (Vickers et al. 1985) the causes of hypophagia (reduced desire for food) and subsequent attempts to alter or reverse the pattern of weight loss (Courtney et al. 1978 Seefeld et al. 1984 Seefeld and Peterson 1984) and excretion kinetics of biotransformed metabolites (Koshakji et al. 1984). 

The Perbellini model for -hexane (Perbellini et al. 1986, 1990a) is an 8-compartment model which simulates the absorption, distribution, biotransformation, and excretion of -hexane during inhalation exposure. The excretion kinetics of the neurotoxic metabolite of -hexane, 2,5-hexanedione, are also simulated. 

Fedtke N, Bolt HM. 1987. The relevance of 4,5-dihydroxy-2-hexanone in the excretion kinetics of -hexane metabolites in rat and man. Arch Toxicol 61 131-137. 

Excretion Kinetics of Urinary Metabolites in a Patient Addicted to Trichloroethylene," Brit. J. Indust. Med. 28, 203-06 (1971). As cited in ref 61. 

The urinary excretion kinetics of chromium have also been examined in eight adults that were administered chromium(III) at 400 pg/day as chromium(III) picolinate for 3 consecutive days (Gargas et al. 1994). The mean time to peak urinary concentration was 7.18 2.11 hours (range 2.9-13.0 hours), the mean peak concentration being 7.92 4.24 pg chromium/g creatinine (range 3.58-19.13 pg/g creatinine). Excretion diminished rapidly after the peak but did not appear to return to background in most of the volunteers before the next daily dose. 

Pena-Egido MJ, Marino-Hernandez EL, Santos-Buelga C, et al. 1988. Urinary excretion kinetics of p-nitrophenol following oral administration of parathion in the rabbit. Arch Toxicol 62 351-354. 

The term scintigraphy, or scanning, describes the production of a planar, two-dimensional image showing the distribution of radioactivity in an organ in which a radioactive substance has been stored. Depending on the radionuclide used, information regarding the hepatic area is obtained on 1.) functional capacity of the RES, (2.) hepatocellular function, (J.) biliary excretion kinetics, and 4.) hepatic blood flow. (4,8, ll, 12,19,21,27,36,37)... 

Comparative (animal, human) ADMEK (absorption, distribution, metabolism, excretion, kinetics) (single-dose human study)... 

Beckett, A. H., Rowland, M. Urinary excretion kinetics of amphetamine in man. 

Beckett AH, Rowland M. Urinary excretion kinetics of methylamphetamine in man. J Pharm Pharmacol 1965 17(suppl) i095-145. 

K Selden, MD Klein, TW Smith. Plasma concentration and urinary excretion kinetics of acetyl strophanthidin. Circulation 47 744, 1973. 

In one case, a worker accidentally inspired an unknown quantity of 90SrCl2 (physical form unknown) and over the subsequent 800 days, 90Sr was excreted in the urine with half-times of 3.3 (52%), 17 (7%), and 347 days (18%) (Petkau and Pleskach 1972). The urinary fecal excretion ratio was 3 1. In a second case, a worker was exposed to 90SrCO3 (physical form unknown) with deposition within the nasal tract as well as the hands, face, and hair. The actual inhaled dose could not be determined however, based on the excretion kinetics of 90Sr over the subsequent 300 days, the reconstructed internal dose was estimated to have been approximately 300-400 nCi (11.1-14.8 kBq) (Rundo and Williams 1961). Excretion in urine occurred with half-times of 2.2 (>90%), 15, and 175 days and the urinary fecal excretion ratio over the first 24 days was 0.71. In a third case, two workers accidentally inhaled 90SrTiO3 (physical form unknown), and 90Sr was detected in urine over a period of 225 days (Navarro and Lopez 1998). 

Linear (or first-order) kinetics refers to the situation where the rate of some process is proportional to the amount or concentration of drug raised to the power of one (the first power, hence the name first-order kinetics). This is equivalent to stating that the rate is equal to the amount or concentration of drug multiplied by a constant (a linear function, hence linear kinetics). All the PK models described in this chapter have assumed linear elimination (metabolism and excretion) kinetics. All distribution processes have been taken to follow linear kinetics or to be instantaneous (completed quickly). Absorption processes have been taken to be instantaneous (completed quickly), follow linear first-order kinetics, or follow zero-order kinetics. Thus out of these processes, only zero-order absorption represents a nonlinear process that is not completed in too short of a time period to matter. This lone example of nonlinear kinetics in the standard PK models represents a special case since nonlinear absorption is relatively easy to handle mathematically. Inclusion of any other type of nonlinear kinetic process in a PK model makes it impossible to write the... 

Piotrowski, J.K., Trojanowskaja, B. and Mogilnicka, E.M. (1975). Excretion kinetics and variability of urinary mercury in workers exposed to mercury vapour. Int. Arch Occup. Environ. Health, 35. 245. 

Data on excretion kinetics of mirex are incomplete. Prairie voles fed mirex for 90 days contained detectable whole body levels four months after being placed on a mirex-free diet. Levels of mirex in voles after four months on uncontaminated feed were still far above levels in their mirex diets. Humans living in areas where mirex has been used for ant control... 

Phase II is done to observe the depletion kinetics for tissue and excreta. Three male rats per sacrifice point, dosed in the same manner as Phase I are used. All other parameters of Phase I are duplicated. A minimus of two additional points are added when tissue and excretion kinetics are desired. However, the maximum study length is 7 days. 

Vfhile the data generated by this proposed strategy can be reduced in a variety of ways, absorption and excretion kinetics are often useful. The skin absorption rate can be expressed as dose/area exposed/interval by the following calculation. 

The experimental design for respiratory exposure necessarily depends on several assumptions and disparate pieces of available data. The excretion kinetics of the pesticide employed must be known. If the total dose is excreted by small animals in 24-48 hr., the same may also be true of humans, and a simple experimental design may suffice. If the dose Is excreted over a period of a week, a simple design correlating dose with the Immediate effect on urine will not correctly assess respiratory exposure. The difficulty with longer sampling periods, occasioned by longer excretion kinetics, derives from the variation normally observed in the urinary exposure estimation for field experiments. It Is not... 

The prior knowledge of the excretion kinetics Is a key piece of data. Unfortunately, many pesticides In common use are not excreted In urine In proportion to dose. This behavior Is common for organochlorlnes. An example of current Interest Is dlcofol. With multiple doses this organochlorlne rapidly reaches a plateau In urine, while excretion levels steadily Increase In the feces O). However, the excretion kinetics available for most compounds have resulted from studies using only one or a very few oral doses. Dlcofol Is an exception. 

We return, consequently, to the problem of the excretion kinetics of pesticides, the complexity of which may render useless any search for a simple linear correlation between dose and urinary metabolites. Some experimenters have attempted to Investigate this area. Drevenkar et al. (20) studied the excretion of phosalone metabolites In one volunteer. Excretion reached a peak In 4-5 hr., but was not complete In 24 hr. Funckes et al. (42) exposed the hand and forearm of human volunteers to 2% parathlon dust. During exposure, the volunteers breathed pure air and placed their forearm and hand Into a plastic bag which contained the parathlon. This exposure lasted 2 hr. and was conducted at various temperatures. There was an Increased excretion of paranltrophenol with Increasing exposure temperature. More importantly, paranltrophenol could still be detected In the urine 40 hr. post exposure. In another human experiment, Kolmodln-Hedman et al. (43) applied methychlorophenoxy acetic acid (MCPA) to the thigh. Plasma MCPA reached a maximum in 12 hr. and MCPA appeared In the urine for 5 days with a maximum after about 48 hr. Given orally, urinary MCPA peaked in 1 hr. with about 40% of the dose excreted In 24 hr. In a rat experiment, seven different organophosphates at two different doses were fed to two rats per compound (21). The rats were removed from exposure after the third day and blood and urine collected for the next 10 days. 

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